Lactam-Containing Compounds and Derivatives thereof as Factor Xa Inhibitors

专利摘要:
The present application relates to lactam-containing compounds of formula (I) and derivatives thereof or pharmaceutically acceptable salt forms thereof. <Formula I> In the above formula, Ring P, if present, is a 5-7 membered carbocycle or heterocycle, Ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the invention are useful as trypsin-like serine proteases, especially inhibitors of factor Xa.
公开号:KR20040041167A
申请号:KR10-2004-7004025
申请日:2002-09-17
公开日:2004-05-14
发明作者:도날드 파인토；미미 쿠안；마이클 오와트；윤-롱 리；웨이 한；제니퍼 퀴아오；패트릭 램；스테파니 쿠치
申请人:브리스톨-마이어스스퀴브컴파니；
IPC主号:

专利说明:

Lactam-Containing Compounds and Derivatives Speech as Factor Xa Inhibitors}
[2] WO0 / 20460 discloses angiotensin II compounds of the formula
[3]
[4] Wherein X may be several substituents and Het may be a nitrogen-containing heterobicycle. However, WO0 / 20460 does not suggest factor Xa inhibition or exemplify analogous compounds of the compounds of the invention.
[5] WO96 / 12720 describes phosphodiesterase type IV and TNF production inhibitors of the formula:
[6]
[7] Wherein X may be oxygen and R ² and R ³ may be several substituents including heterocycle, heterocycloalkyl and phenyl. However, the compounds claimed in the present invention do not correspond to the compounds of WO96 / 12720. In addition, W096 / 12720 does not suggest factor Xa inhibition.
[8] W098 / 52948 details ceramide-mediated signal transduction inhibitors. One type of inhibitor described is of the formula:
[9]
[10] Wherein Y ₁ may be NR ₆ , R ₆ may be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl, and R ₁ may be a substituted aryl group. W098 / 52948 does not mention factor Xa inhibition or refer to analogous compounds of the compounds of the invention.
[11] US Pat. Nos. 3,365,459, 3,340,269 and 3,423,414 show anti-inflammatory inhibitors of the formula
[12]
[13] Wherein A is 2 to 3 carbon atoms, X may be 0, and R ¹ and R ³ may be substituted or unsubstituted aromatic groups. However, none of the above patents illustrate the compounds of the present invention.
[14] In WO99 / 32477, factor Xa inhibitors of the formula are reported.
[15]
[16] Wherein the inhibitor contains at least three aryl or heterocyclic groups (ie C, B and R ³ ) separated by two linking groups (ie E and D). Compounds of this kind are not considered part of the invention.
[17] WO00 / 39131 describes heterobicyclic factor Xa inhibitors which are exemplified by the following formula.
[18]
[19] Wherein Z is C or N, G is a monocyclic or bicyclic group, A is a cyclic moiety, and B is a basic group or a cyclic moiety. In particular, the compounds described in W000 / 39131 are not considered part of the invention.
[20] W098 / 28269, W098 / 28282, W099 / 32454, US 6,020,357 and US 6,271,237 describe Factor Xa inhibitors of the formula
[21]
[22] Wherein ring M is heterocycle, Z is a linker, A is a ring, B is a basic or cyclic group, D is a basic moiety, and E is a ring. In particular, the compounds described in W098 / 28269, W098 / 28282, W099 / 32454, US 6,020,357 and US 6,271,237 are not considered part of the present invention.
[23] W098 / 57951 describes factor Xa inhibitors of the formula:
[24]
[25] In the above formula, Ring M may be a variety of heterocycles, and Ring D-E represents a heterobicyclic group. In particular, the compounds described in W098 / 57951 are not considered part of the present invention.
[26] W098 / 57934 and US Pat. No. 6,060,491 describe factor Xa inhibitors of the formula:
[27]
[28] Wherein ring M is a 6 membered heteroaryl, Z is a linker, A is a ring, B is a basic or cyclic group, D is a basic moiety, and E is a ring. In particular, the compounds described in W098 / 57934 and US Pat. No. 6,060,491 are not contemplated as part of the present invention.
[29] W098 / 57937 and US Pat. No. 5,998,424 describe Factor Xa inhibitors of the formula
[30]
[31] Wherein M is a variety of rings, D is an aromatic ring, and R and E are nonbasic groups. In particular, the compounds described in W098 / 57937 and US Pat. No. 5,998,424 are not contemplated as part of the present invention.
[32] WO99 / 50255 and US Pat. No. 6,191,159 describe pyrazoline and triazolin factor Xa inhibitors of the formula:
[33]
[34] In particular, the compounds described in WO99 / 50255 and US Pat. No. 6,191,159 are not considered part of the invention.
[35] WO00 / 59902 describes factor Xa inhibitors of the formula:
[36]
[37] Wherein ring M can be any of a variety of rings substituted with ZAB, Z is a linker, A is a ring, B is a sulfonyl-containing heterobicycle, and ring DE is a heterobicyclic group or a six-membered ring Indicates. In particular, the compounds described in WO00 / 59902 are not considered part of the invention.
[38] WO01 / 32628 describes factor Xa inhibitors cyano-pyrrole, cyano-imidazole, cyano-pyrazole and cyano-triazole. In particular, the compounds described in WO01 / 32628 are not considered part of the invention.
[39] WO01 / 05784 describes factor Xa inhibitors of the formula:
[40]
[41] Wherein Z is C or N, G is a monocyclic or bicyclic ring M, A is a linker and B is a basic or cyclic group. In particular, the compounds described in WO01 / 05784 are not considered part of the invention.
[42] WO00 / 39108 describes Factor Xa inhibitors of the formula:
[43]
[44] In the above formula, Ring M may be a variety of heterocycles, and Ring D-E represents a heterobicyclic group. In particular, the compounds described in WOOO / 39108 are not considered part of the invention.
[45] WOO1 / 19798 describes factor Xa inhibitors of the formula:
[46] A-Q-D-E-G-J-X
[47] Wherein A, D, G and X may be phenyl or heterocycle. However, none of the compounds claimed in the present invention are illustrated or suggested in WOO1 / 19798.
[48] Activated factor Xa, whose main playing role is the production of thrombin by limited proteolysis of prothrombin, maintains a pivotal position that links intrinsic and extrinsic activation mechanisms in the final general pathway of blood coagulation. The production of thrombin, the final serine protease in this pathway for producing fibrin clots, from its precursors is amplified by the formation of prothrombinase complexes (factor Xa, factor V, Ca ²⁺ and phospholipids). One molecule of factor Xa is calculated to be capable of producing thrombin 138 molecules (Elodi, S., Varadi, K .: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation.Thromb. Res. 1979, 15, 617-629]), inhibition of factor Xa may be more efficient than inactivating thrombin in stopping the blood coagulation system.
[49] Therefore, efficient and specific inhibitors of factor Xa are needed as potentially useful therapeutics for the treatment of thromboembolic disorders. Therefore, it is desirable to find new factor Xa inhibitors. In addition, it is also desirable to find new compounds with improved pharmacological properties compared to known Factor Xa inhibitors. For example, it is desirable to find new compounds with improved Factor Xa inhibitory activity and selectivity for Factor Xa versus other serine proteases (ie trypsin). It is also valid and desirable to find compounds having advantageous and improved characteristics in, but not limited to, one or more of the following categories: (a) Pharmaceutical properties (eg, solubility, permeability to sustained release formulations) And compliant); (b) dosage requirements (eg, lower dose and / or once daily dose); (c) factors that reduce blood concentration peak-to-trough properties (eg, cleansing rate and / or volume of distribution); (d) factors that increase the concentration of active drug at the receptor (eg, protein binding, volume of distribution); (e) factors that reduce the tendency for clinical drug-drug interactions (eg, inhibit or induce cytochrome P450 enzymes); (f) factors that reduce the potential for adverse reactions (eg, pharmacological selectivity other than serine proteases, possible chemical or metabolic reactivity, and limited CNS permeability); And (g) factors that improve manufacturing cost or validity (eg, difficulty in synthesis, number of chiral centers, chemical stability and ease of operation).
[50] Summary of the Invention
[51] Accordingly, the present invention provides novel lactam-containing compounds and derivatives thereof or pharmaceutically acceptable salts or prodrugs thereof useful as Factor Xa inhibitors.
[52] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount in one or more of the compounds of the present invention or in the form of a pharmaceutically acceptable salt or prodrug thereof.
[53] The present invention provides a method of treating a thromboembolic disorder comprising administering to a host in need thereof a therapeutically effective amount of one or more of the compounds of the invention or a pharmaceutically acceptable salt or prodrug form thereof.
[54] The present invention provides a novel method of treating a patient in need of treatment of a thromboembolic disorder comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt form thereof to treat a thromboembolic disorder. .
[55] The present invention provides a novel method comprising administering a compound of the invention or a pharmaceutically acceptable salt form thereof in an effective amount for treating a thromboembolic disorder.
[56] The present invention provides novel lactam-containing compounds and derivatives thereof for use in therapy.
[57] The present invention provides the use of a novel lactam-containing compound for the manufacture of a medicament for the treatment of thromboembolic disorders.
[58] These and other objects, which will become apparent in the detailed description, have been achieved by the inventors of the present invention in the discovery of lactam-containing compounds of formula (I) or pharmaceutically acceptable salts or prodrug forms thereof, which are effective factor Xa inhibitors.
[59]
[60] In the formula, P ₄ , P, M, and M ₄ are defined below.
[1] The present invention relates generally to trypsin-like serine protease enzymes, in particular lactam-containing compounds and derivatives thereof which are inhibitors of factor Xa, pharmaceutical compositions containing them and methods of using such materials as anticoagulants for the treatment of thromboembolic disorders.
[61] <Detailed Description of the Preferred Embodiments>
[62] [1] In one embodiment, the present invention provides novel compounds or stereoisomers or pharmaceutically acceptable salts thereof of formula (I)
[63] <Formula I>
[64]
[65] In the above formula,
[66] M is a 4-10 membered heterocycle consisting of 3 to 10 membered carbocycles or carbon atoms and 1 to 3 heteroatoms selected from 0, S (O) _p , N and NZ ² ;
[67] Ring M is substituted with 0-3 R ^1a and 0-2 carbonyl groups, and there are 0-3 ring double bonds present;
[68] P is a 5, 6 or 7 membered heterocycle fused on ring M and consists of 5, 6 or 7 membered carbocycles or carbon atoms and 1 to 3 heteroatoms selected from 0, S (O) _p and N ;
[69] Ring P is substituted with 0-3 R ^1a and 0-2 carbonyl groups, and 0-3 ring double bonds are present;
[70] Alternatively, ring P is absent and P ₄ is directly attached to ring M, provided that if ring P is absent, P ₄ and M ₄ are 1,2, 1,3 or 1,4 positions of ring M Attached to;
[71] One of P ₄ and M ₄ is -ZAB, and the other is -G ₁ -G;
[72] G is a group of formula IIa or IIb;
[73]
[74]
[75] here,
[76] Ring D is a 5-6 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O and S (O) _p , including the two atoms of ring E to which it is attached;
[77] Ring D is substituted with 0-2 R, and 0-3 ring double bonds are present;
[78] E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl and is substituted with 1 to 2 R;
[79] Alternatively, ring D is absent and ring E is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl and Thiazolyl, ring E is substituted with 1 to 2 R;
[80] Alternatively, ring D is absent and ring E is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl and Selected from thiazolyl, wherein ring E is substituted with a 5-6 membered heterocycle consisting of 1 R and a carbon atom and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p , wherein A 5-6 membered heterocycle is substituted with 0-1 carbonyl and 1-2 R, and 0-3 ring double bonds are present;
[81] R is H, C _1-4 alkyl, F, Cl, Br, I, OH, OCH ₃ , OCH ₂ CH ₃ , OCH (CH ₃ ) ₂ , OCH ₂ CH ₂ CH ₃ , CN, C (= NR ⁸ ) NR ⁷ R ⁹ , NHC (= NR ⁸ ) NR ⁷ R ⁹ , ONHC (= NR ⁸ ) NR ⁷ R ⁹ , NR ⁸ CH (= NR ⁷ ), NH ₂ , NH (C _1-3 alkyl), N ( C _1-3 alkyl) ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NH (C _1-3 alkyl), CH ₂ N (C _1-3 alkyl) ₂ , CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ NH (C _1-3 alkyl), CH ₂ CH ₂ N (C _1-3 alkyl) ₂ , (CR ⁸ R ⁹ ) _t C (O) H, (CR ⁸ R ⁹ ) _t C ( O) R ^2c , (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ , (CR ⁸ R ⁹ ) _t C (O) NR ⁷ R ⁸ , (CR ⁸ R ⁹ ) _t NR ⁷ C (O) R ⁷ , ( CR ⁸ R ⁹ ) _t OR ³ , (CR ⁸ R ⁹ ) _t S (0) _p NR ⁷ R ⁸ , (CR ⁸ R ⁹ ) _t NR ⁷ S (0) _p R ⁷ , (CR ⁸ R ⁹ ) _t SR ³ , (CR ⁸ R ⁹ ) _t S (0) R ³ , (CR ⁸ R ⁹ ) _t S (0) ₂ R ³ and OCF ₃ ;
[82] Alternatively, when two R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
[83] A is
[84] C _3-10 carbocycle substituted with 0 to 2 R ⁴ , and
[85] Is selected from a carbon atom and a 5-12 membered heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ⁴ ;
[86] Provided that A is other than dihydro-benzopyran;
[87] B is or; Provided that Z and B are attached to different atoms on A, and the AXN moiety forms something other than an NNN group;
[88] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[89] Q ₁ is selected from C═O and SO ₂ ;
[90] Ring Q is a 4-8 membered monocyclic or bicyclic group consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the NQ ₁ group shown above Ring, where
[91] 0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
[92] Alternatively, ring Q is a 4-8 membered monocyclic or bicyclic ring to which another ring is fused, wherein
[93] The 4 to 7 membered ring consists of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 2 double bonds. Present in this ring;
[94] The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of carbon atoms and 1 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ ;
[95] remind Ring Q comprising 4 to 7 membered rings and the fused ring is 0 to 3 R^4aSubstituted with;
[96] Alternatively, two nonadjacent atoms in one of the rings of ring Q are bridged with 1 to 2 atoms selected from carbon atoms, NR ^4C , O, S, S (O) and S (O) ₂ , with 0 being There are bonds other than -0, S (O) _p -O, S (O) _p -S (O) _p , NO and NS (O) _p ;
[97] X is not present or _{^{- (CR 2 R 2a) 1-4}} -, -CR 2 (CR 2 R 2b) (CH 2) t -, -C (O) -, -C (= NR 1c) -, - ^{CR 2 (NR 1c R 2)} -, -CR 2 (OR 2) -, -CR 2 (SR 2) -, -C (O) CR 2 R 2a -, -CR 2 R 2a C (O), - S (O) -, -S ( O) 2 -, -SCR 2 R 2a -, -S (O) CR 2 R 2a -, -S (O) 2 CR 2 R 2a -, -CR 2 R 2a S ^{(O) -, -CR 2 R} 2a S (O) 2 -, -S (O) 2 NR 2 CR 2 R 2a -, -NR 2 S (O) 2 -, -CR 2 R 2a NR 2 S ( ^{_{O) 2 -, -NR 2 S}} (O) 2 CR 2 R 2a -, -NR 2 C (O) -, -C (O) NR 2 CR 2 R 2a -, -NR 2 C (O) CR 2 R ^2a - is selected ^{from, -CR 2 R 2a NR 2 C} (O) -, -NR 2 CR 2 R 2a - - , and -OCR ² R ^2a;
[98] G ₁ is absent or (CR ³ R ^3a ) _1-5 , (CR ³ R ^3a ) _0-2 CR ³ = CR ³ (CR ³ R ^3a ) _0-2 , (CR ³ R ^3a ) _0-2 C (C (CR ³ R ^3a ) _0-2 , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u OC (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u OC (O) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (O) O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (O ) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (S) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b S (O) ₂ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b S (O) ₂ N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3e (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O ) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) NR ^3b C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) NR ^3b S (O) ₂ ( CR ³ R ^3a ) _w and (CR ³ R ^3a ) _u S (O) ₂ NR ^3b C (O) NR ^3b (CR ³ R ^3a ) _w , wherein the sum of u + w is 0, 1, 2, 3 or 4, provided that G ₁ does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
[99] Z is a bond,-(CR ³ R ^3e ) _1-4- , (CR ³ R ^3e ) _q O (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b (CR ³ R ^3e ) _q1 , ( CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) 0 (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q OC (O) ( CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) (CR ³ R ^3e ) _q1 , ( CR ³ R ^3e ) _q OC (O) O (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q OC (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) O (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (O) ₂ (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q SO ₂ NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b SO ₂ (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (O) NR ^3b C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) NR ^3b S (O) ₂ (CR ³ R ^3e ) _q1 and (CR ³ R ^3e ) _q NR ^3b SO ₂ NR ^3b (CR ³ R ^3e ) _q1 wherein q + q1 sum is 0, 1, 2, 3 or 4, provided Z is NS, NCH and other groups to which it is attached Does not form ₂ N, NCH ₂ 0 or NCH ₂ S bonds;
[100] Provided that BAZ forms other than pyridone-phenyl-CH ₂ , pyridone-pyridyl-CH ₂ or pyridone-pyrimidyl-CH ₂ , wherein the pyridone, phenyl, pyridyl and pyrimidyl groups are substituted or substituted Without;
[101] Z ² is H, S (O) ₂ NHR ^3b , C (O) R ^3b , C (O) NHR ^3b , C (O) OR ^3f , S (O) R ^3f , S (O) ₂ R ^3f , 0 or two R ^{1a-substituted} C _1-6 alkyl, 0-2 R ^1a a C _2-6 alkenyl substituted with 0 to 2 R ^1a substituted C _2-6 alkynyl, a 0 to a 3 substituted by R ^1a - (C _O-4 alkyl) -C _3-10 carbonyl which is substituted by cycle and 0-3 R ^1a carbon atoms, and N, O, and S (O) selected from the group consisting of _p Is selected _from- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms;
[102] R ^1a is, in each case, H,-(CR ³ R ^3a ) _r -R ^1b ,-(CR ³ R ^3a ) _r -CR ³ R ^1b R ^1b ,-(CR ³ R ^3a ) _r -O- ( CR ³ R ^3a ) _r -R ^1b , -C _2-6 alkenylene-R ^1b , -C _2-6 alkynylene-R ^1b ,-(CR ³ R ^3a ) _r -C (= NR ^1b ) NR ³ R ^1b , NR ³ CR ³ R ^3a R ^1c , OCR ³ R ^3a R ^1c , SCR ³ R ^3a R ^1c , NR ³ (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , C (O) NR ² (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , CO ₂ (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , O (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , S (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , S (O) _p (CR ³ R ^3a ) _r R ^1d , O (CR ³ R ^3a ) _r R ^1d , NR ³ (CR ³ R ^3a ) _r R ^1d , OC (O) NR ³ (CR ³ R ^3a ) _r R ^1d , NR ³ C (O) NR ³ (CR ³ R ^3a ) _r R ^1d , NR ³ C (O) 0 (CR ³ R ^3a ) _r R ^1d and NR ³ C (O) (CR ³ R ^3a ) _r R ^1d , provided that R ^1a is other than N-halo, NS, 0-0 or N-CN bond To form one;
[103] Alternatively, when two R ^1a groups are attached to an adjacent atom, the groups together with the atoms to which they are attached are selected from the group consisting of carbon atoms, and from 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p ; Forms a seven membered ring, wherein the ring is substituted with 0-2 R ^4b and 0-3 ring double bonds are present;
[104] R ^1b is H, C _1-3 alkyl, F, Cl, Br, I, -CN, -NO ₂ , -CHO, (CF ₂ ) _r CF ₃ , (CR ³ R ^3a ) _r OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC (O) R ² , (CF ₂ ) _r CO ₂ R ^2a , S (O) _p R ^2b , NR ² (CH ₂ ) _r OR ² , C (= NR ^2c ) NR ² R ^2a , NR ² C (O) R ^2b , NR ² C (O) NHR ² , NR ² C (O) ₂ R ^2a , OC (O) NR ² R ^2a , C (O ) NR ² R ^2a , C (O) NR ² (CH ₂ ) _r OR ² , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , C (O) NR ² SO ₂ R ² , 0 to 2 R C _3-6 carbocycle substituted with ^4b , and carbon atoms, and 5 to 5 substituted with 0 to 2 R ^4b and consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p Selected from a 10 membered heterocycle, provided that R ^1b forms other than 0-0, N-halo, NS or N-CN bond;
[105] R ^1c is H, CH (CH ₂ OR ² ) ₂ , C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ² , S (O) ₂ R ² and SO ₂ NR ² R ^Is selected from ^2a ;
[106] R ^1d is C _3-6 carbocycle substituted with 0 to 2 R ^4b and a carbon atom and 1 to 4 heteroatoms selected from the group consisting of N, O, and S (O) _p and 0 to Selected from 5 to 10 membered heterocycles substituted with two R ^4b , provided that R ^1d forms other than NS bonds;
[107] R ² is, at each occurrence, H, CF ₃ , C _1-6 alkyl, benzyl, — (CH ₂ ) _r —C _3-10 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and Is selected ^from- (CH ₂ ) _r -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ^4b ;
[108] R ^2a is, at each occurrence, H, CF ₃ , C _1-6 alkyl, benzyl, — (CH ₂ ) _r —C _{3-10 carbocycle} substituted with 0 to 2 R ^4b , and a carbon atom, and Is selected ^from- (CH ₂ ) _r -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ^4b ;
[109] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and consist of 0 to 1 additional heteroatoms selected from the group consisting of N, O, and S (O) _p or 5 or To form a six-membered saturated, partially saturated or unsaturated ring;
[110] R ^2b is, the in each case, optionally substituted with CF _3, 0-2 R ^4b a C _1-4 alkoxy, 0-2 R ^4b a C _1-6 alkyl, substituted with 0-2 R ^4b substituted with — (CH ₂ ) _r —C _3-10 carbocycle, and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O, and S (O) _p and substituted with 0 to 2 R ^4b -(CH ₂ ) _r -5 to 10 membered heterocycle;
[111] R ^2c is, in each case, CF ₃ , OH, C _1-4 alkoxy, C _1-6 alkyl, — (CH ₂ ) _r —C _3-10 carbocycle substituted with 0 to 2 R ^4b , and Is selected ^from- (CH ₂ ) _r -5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ^4b ;
[112] R ³ is in each case H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl and phenyl;
[113] R ^3a in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl and phenyl;
[114] Alternatively, R ³ and R ^3a may be combined with the nitrogen atom to which they are attached to 0 to 1 selected from the group consisting of carbon atoms, nitrogen atoms to which R ³ and R ^3a are attached, and N, O, and S (O) _p . To form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring of two additional heteroatoms;
[115] The R ^3b is substituted in each case, in H, 0 to 2 R ^1a a C _1-6 alkyl, 0-2 R a C _2-6 alkenyl, substituted with 0-2 R ^{1a 1a} substituted with C _2-6 alkynyl, 0-3 R ^1a is substituted with - (C _0-4 alkyl) -5 to 10-carbonyl which is substituted by-cycle, and 0-3 R ^1a carbon atoms, and N, O _And- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of S (O) _p ;
[116] R ^3c in each case is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ( CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl and phenyl;
[117] R ^3d is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C _1-4 alkyl-phenyl and C ( ^═O ) R ^3c ;
[118] R ^3e is, in each case, H, SO ₂ NHR ³ , S0 ₂ NR ³ R ³ , C (O) R ³ , C (O) NHR ³ , C (O) OR ^3f , S (O) R ^3f , S (O) ₂ R ^3f, 0-2 R ^1a is substituted with a C _1-6 C alkyl, 0-2 C _2-6 alkenyl substituted with R ^1a, the 0-2 R ^1a is substituted by _{2 -6} alkynyl, 0-3 R ^1a is substituted by - (C _O-4 alkyl) -5 to 10-carbonyl which is substituted by-cycle, and 0-3 R ^1a carbon atoms, and N, O and S (O) _p is selected _from- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of _p ;
[119] R ^3f is, in each case, 0-2 C _2-6 alkenyl substituted with R ^1a to a C _1-6 alkyl, substituted with 0-2 R ^1a, 0-2 R ₂ substituted with a C ^1a _-6 alkynyl, 0 to 3 of R ^1a is substituted by - (C _0-4 alkyl) -5 to 10-carbonyl which is substituted by-cycle, and 0-3 R ^1a carbon atoms, and N, O and S (O) _p is selected _from- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of _p ;
[120] R ⁴ is in each case H, = 0, (CR ³ R ^3a ) _r OR ² , F, Cl, Br, I, C _1-4 alkyl, (CR ³ R ^3a ) _r CN, (CR ³ R ^3a ) _r NO ₂ , (CR ³ R ^3a ) _r NR ² R ^2a , (CR ³ R ^3a ) _r C (O) R ^2c , (CR ³ R ^3a ) _r NR ² C (O) R ^2b , (CR ³ R ^3a ) _r C (O) NR ² R ^2a , (CR ³ R ^3a ) _r NR ² C (O) NR ² R ^2a , (CR ³ R ^3a ) _r C (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r C (= NS (O) ₂ R ⁵ ) NR ² R ^2a , (CR ³ R ^3a ) _r NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r C ( O) NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r S0 ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r NR ² SO ₂ R ⁵ , (CR ³ R ^3a ) _r S (O) _p R ^5a , (CR ³ R ^3a ) _r (CF ₂ ) _r CF ₃ , NHCH ₂ R ^1c , OCH ₂ R ^1c , SCH ₂ R ^1c , NH (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , O (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , S ( CH ₂ ) ₂ (CH ₂ ) _t R ^1b , (CR ³ R ^3a ) _r -5 to 6-membered carbocycle substituted with 0 to 1 R ⁵ , and a carbon atom, and N, O and S (O) _p comprises one to four heteroatoms selected from the group consisting of zero to one R ⁵ Substituted (CR ³ _R ^3a) _r -5 to 6 membered heterocycle is selected from;
[121] R ^4a is, in each case, H, = 0, (CR ³ R ^3a ) _r OR ² , (CR ³ R ^3a ) _r F, (CR ³ R ^3a ) _r Br, (CR ³ R ^3a ) _r Cl, C _1-4 alkyl, (CR ³ R ^3a ) _r CN, (CR ³ R ^3a ) _r NO ₂ , (CR ³ R ^3a ) _r NR ² R ^2a , (CR ³ R ^3a ) _r C (O) R ^2c , (CR ³ R ^3a ) _r NR ² C (O) R ^2b , (CR ³ R ^3a ) _r C (O) NR ² R ^2a , (CR ³ R ^3a ) _r N = CHOR ³ , (CR ³ R ^3a ) _r C (O) NH (CH ₂ ) ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² C (O) NR ² R ^2a , (CR ³ R ^3a ) _r C (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r C (O) NHS0 ₂ -C _1-4 alkyl, (CR ³ R ^3a ) NR ² SO ₂ R ⁵ , (CR ³ R ^3a ) _r S (O) _p R ^5a , (CR ³ R ^3a ) _r (CF ₂ ) _r CF ₃ , (CR ³ R ^3a ) _r -5 substituted with 0 to 1 R ⁵ (CR ³ R ^3a ) _r consisting of from 6 to 6 membered carbocycles and carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ -5 to 6 membered heterocycle Is selected from;
[122] R ^4b is in each case H, ═O, (CH ₂ ) _r OR ³ , (CH ₂ ) _r F, (CH ₂ ) _r Cl, (CH ₂ ) _r Br, (CH ₂ ) _r I, C _1-4 alkyl, (CH ₂ ) _r CN, (CH ₂ ) _r NO ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , (CH ₂ ) _r C (O ) OR ^3c , (CH ₂ ) _r NR ³ C (O) R ^3a , (CH ₂ ) _r -C (O) NR ³ R ^3a , (CH ₂ ) _r NR ³ C (O) NR ³ R ^3a , ( CH ₂ ) _r -C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r NR ^3C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r S0 ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ SO ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ SO ₂ -C _1-4 alkyl, (CH ₂ ) _r NR ³ SO ₂ CF ₃ , (CH ₂ ) _r NR ³ SO ₂ -phenyl, ( CH ₂ ) _r S (O) _p CF ₃ , (CH ₂ ) _r S (O) _p -C _1-4 alkyl, (CH ₂ ) _r S (O) _p -phenyl and (CH ₂ ) _r (CF ₂ ) _r CF ₃ ;
[123] R ^4c is, in each case, H, C _1-4 alkyl, (CR ³ R ^3a ) _r1 OR ² , (CR ³ R ^3a ) _r1 F, (CR ³ R ^3a ) _r1 Br, (CR ³ R ^3a ) _r1 Cl, (CR ³ R ^3a ) _r1 CN, (CR ³ R ^3a ) _r1 NO ₂ , (CR ³ R ^3a ) _r1 NR ² R ^2a , (CR ³ R ^3a ) _r C (O) R ^2c , (CR ³ R ^3a ) _r1 NR ² C (O) R ^2b , (CR ³ R ^3a ) _r C (O) NR ² R ^2a , (CR ³ R ^3a ) _r1 N = CHOR ³ , (CR ³ R ^3a ) _r C (O) NH (CH ₂ ) ₂ NR ² R ^2a , (CR ³ R ^3a ) _r1 NR ² C (O) NR ² R ^2a , (CR ³ R ^3a ) _r1 C (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r1 NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r1 NR ² S0 ₂ NR ² R ^2a , (CR ³ R ^3a ) _r1 NR ² S0 ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r C (O) NHSO ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r1 NR ² SO ₂ R ⁵ , (CR ³ R ^3a ) _r S (O) _p R ^5a , (CR ³ R ^3a ) _r (CF ₂ ) _r CF ₃ , (CR ³ R ^3a ) _r -5 to 6 substituted with 0 to 1 R ⁵ (CR ³ R ^3a ) _r -5 consisting of a circular carbocycle and a carbon atom, and from 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ To 6 yuan he It is selected from Rosa cycle;
[124] R ⁵ is in each case H, C _1-6 alkyl, = 0, (CH ₂ ) _r OR ³ , F, Cl, Br, I, -CN, N0 ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , (CH ₂ ) _r C (O) OR ^3c , (CH ₂ ) _r NR ³ C (O) R ^3a , (CH ₂ ) _r C (O) NR ³ R ^3a , (CH ₂ ) _r NR ³ C (O) NR ³ R ^3a , (CH ₂ ) _r CH (= NOR ^3d ), (CH ₂ ) _r C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r NR ³ C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r SO ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ SO ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ S0 ₂ -C _1-4 alkyl, (CH ₂ ) _r NR ³ SO ₂ CF ₃ , (CH ₂ ) _r NR ³ SO ₂ -phenyl, (CH ₂ ) _r S (O) _p CF ₃ , (CH ₂ ) _r S (O) _p -C _{1-4 alkyl, (CH 2) r S (} O) p - , phenyl-, (CF _{2) r} CF _3, 0 to 2 r ⁶ is phenyl substituted with 0 to 2 r ⁶ Substituted naphthyl and benzyl substituted with 0 to 2 R ⁶ ;
[125] R ^5a is, in each case, C _1-6 alkyl, (CH ₂ ) _r OR ³ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , (CH ₂ ) _r C (O) OR ^3c , (CH ₂ ) _r NR ³ C (O) R ^3a , (CH ₂ ) _r C (O) NR ³ R ^3a , (CF ₂ ) _r CF ₃ , substituted with 0 to 2 R ⁶ phenyl, 0 to 2 are selected from benzyl substituted by two R ⁶ and naphthyl substituted with 0-2 R ^6, with the proviso that, R ^5a is not SN forms a bond or _{S (O) p -C (O} ) Without;
[126] R ⁶ in each case is H, OH, (CH ₂ ) _r OR ² , halo, C _1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C ( O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , C (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² S0 ₂ C _1-4 alkyl;
[127] R ⁷ is in each case H, OH, C _1-6 alkyl, C _1-6 alkyl-C (O)-, C _1-6 alkyl-O-, (CH ₂ ) _n -phenyl, C _{1- 4} alkyl-OC (O)-, C _6-10 aryl-0-, C _6-10 aryl-OC (O)-, C _6-10 aryl-CH ₂ -C (O)-, C _1-4 alkyl -C (O) OC _1-4 alkyl-OC (O)-, C _6-10 aryl-C (O) OC _1-4 alkyl-OC (O)-, C _1-6 alkyl-NH ₂ -C ( O)-, phenyl-NH ₂ -C (O)-and phenyl-C _1-4 alkyl-C (O)-;
[128] R ⁸ is in each case selected from H, C _1-6 alkyl and (CH ₂ ) _n -phenyl;
[129] Alternatively, a 5-10 membered heterocyclic ring consisting of 0 to 2 additional heteroatoms selected from the group consisting of carbon atoms and N, O and S (O) _p , when R ⁷ and R ⁸ are attached to the same nitrogen, To form;
[130] R ⁹ is in each case selected from H, C _1-6 alkyl and (CH ₂ ) _n -phenyl;
[131] n is in each case selected from 0, 1, 2 and 3;
[132] p is in each case selected from 0, 1 and 2;
[133] r is in each case selected from 0, 1, 2, 3, 4, 5 and 6;
[134] r1 is, in each case, selected from 1, 2, 3, 4, 5 and 6;
[135] t is in each case selected from 0, 1, 2 and 3;
[136] only,
[137] (a) when ring M is phenyl and is substituted 1,2 by M ₄ and P ₄ and G ₁ are present, ZA is NHC (O) -thienyl, NHCH ₂ -thienyl, NHC (O) -benzo Other than thienyl and NHCH ₂ -benzothienyl;
[138] (b) when B is 2-oxo-1-pyrrolidinyl and the ring PM is 1,7-dihydro-2-methyl-6H-purin-6-one, GG ₁ is other than unsubstituted phenyl.
[139] [2] In a preferred embodiment, the present invention provides novel compounds or stereoisomers or pharmaceutically acceptable salts thereof of the following formula (II).
[140]
[141] In the above formula,
[142] Ring M comprising P ₁ , P ₂ , M ₁ and M ₂ is a 5, 6 or 7 membered carbocycle or carbon atom and 1 to 3 heteros selected from 0, S (O) _p , N and NZ ² A 5, 6 or 7 membered heterocycle consisting of atoms;
[143] Ring M is substituted with 0-2 R ^1a and 0-2 carbonyl groups and 0-3 ring double bonds are present;
[144] Ring P comprising P ₁ , P ₂ and P ₃ is a 5 or 6 membered aromatic heterocycle consisting of carbon atoms and 1 to 3 heteroatoms selected from O, S (O) _p , and N;
[145] Alternatively, ring P comprising P ₁ , P ₂ and P ₃ is a 5 or 6 membered dihydro-aromatic heterocycle consisting of carbon atoms and 1 to 3 heteroatoms selected from O, S (O) _p and N;
[146] Ring P is substituted with 0-2 R ^1a ;
[147] One of P ₄ and M ₄ is -ZAB, and the other is -G ₁ -G;
[148] G is a group of formula IIa or IIb;
[149] <Formula IIa>
[150]
[151] <Formula IIb>
[152]
[153] here,
[154] Ring D comprises two atoms of ring E to which it is attached and is a 5 to 6 membered ring consisting of carbon atoms and 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p ;
[155] Ring D is substituted with 0-2 R, and 0-3 ring double bonds are present;
[156] E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl and substituted with 1 to 2 R;
[157] Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl, pyrimidyl and thienyl, wherein Ring E is substituted with 1 to 2 R;
[158] Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl and thienyl, wherein Ring E is substituted with one R and is selected from the group consisting of carbon atoms and N, O and S (O) _p Substituted with a 5 membered heterocycle consisting of 1 to 4 heteroatoms selected, wherein the 5 membered heterocycle is substituted with 0 to 1 carbonyl and 1 to 2 R, and 0 to 3 ring double bonds are present;
[159] R is H, C _1-4 alkyl, F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CN, C (= NH) NH ₂ , C (= NH) NHOH, C ( = NH) NHOCH ₃ , NH ₂ , NH (C _1-3 alkyl), N (C _1-3 alkyl) ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NH (C _1-3 alkyl ), CH ₂ N (C _1-3 alkyl) ₂ , (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , CH ₂ C (O) NR ⁷ R ⁸ , S (O) _p NR ⁷ R ⁸ , CH ₂ S (O) _p NR ⁷ R ⁸ , SO ₂ R ³ and OCF ₃ ;
[160] Alternatively, when two R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
[161] A is
[162] C _5-10 carbocycle substituted with 0 to 2 R ⁴ , and
[163] A carbon atom, and is selected from a 5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ⁴ ;
[164] Provided that A is other than dihydro-benzopyran;
[165] B is or; Provided that Z and B are attached to different atoms on A, and that the AXN moiety forms something other than an NNN group;
[166] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[167] Q ₁ is selected from C═O and SO ₂ ;
[168] Ring Q is a 4-7 membered monocyclic or tricyclic ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown Where
[169] 0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
[170] Alternatively, ring Q is a 4-7 membered ring to which another ring is fused, wherein
[171] The 4 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
[172] The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , O, and S;
[173] The ring Q comprising the 4 to 7 membered ring and the fused ring is substituted with 0 to 3 R ^4a ;
[174] X is not present or _{^{- (CR 2 R 2a) 1-4}} -, -C (O) -, -C (O) CR 2 R 2a -, -CR 2 R 2a C (O), -S (O) _{2 -, -S (O) 2} CR 2 R 2a -, -CR 2 R 2a S (O) 2 -, -NR 2 S (O) 2 -, -NR 2 CR 2 R 2a - , and -OCR ² R ^2a- ;
[175] Z is a bond, CH ₂ , CH ₂ CH ₂ , CH ₂ 0, OCH ₂ , C (O), NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O ) NH, NHC (O), NHC (O) CH ₂ C (O) NH, S (O) ₂ , CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHS0 ₂ Provided that Z does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
[176] Z ² is selected from H, C _1-4 alkyl, phenyl, benzyl, C (O) R ^3b , S (O) R ^3f and S (O) ₂ R ^3f ;
[177] R ^1a is H,-(CH ₂ ) _r -R ^1b ,-(CH (CH ₃ )) _r -R ^1b ,-(C (CH ₃ ) ₂ ) _r -R ^1b , NHCH ₂ R ^1c , OCH ₂ R ^1c , SCH ₂ R ^1c , NH (CH ₂ ) ₂ (CH ₂ ) _t R ^1b and O (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , provided that R ^1a is N-halo, NS or N To form other than -CN bonds;
[178] Alternatively, when two R ^1a groups are attached to an adjacent atom, the groups together with the atoms to which they are attached are selected from the group consisting of carbon atoms, and from 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p ; Forms a seven membered ring, wherein the ring is substituted with 0-2 R ^4b and 0-3 ring double bonds are present;
[179] R ^1b is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , F, Cl, Br, I, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC (O) R ² , CO ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , NR ² C (O) NHR ² , NR ² C (O) ₂ R ^2a , OC (O) NR ² R ^2a , C (O) NR ² R ^2a , C (O) NR ² (CH ₂ ) _r OR ² , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 2 R ^4b , provided that R ^1b is other than OO, N-halo, NS or N-CN bond Will;
[180] R ^1c is H, CH (CH ₂ 0R ² ) ₂ , C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ² , S (O) ₂ R ² and SO ₂ NR ² R ^Is selected from ^2a ;
[181] R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH _{3 ) 2, CH (CH 3)} CH 2 CH 3, C (CH 3) 3, a C ₅ optionally substituted with benzyl, 0-2 R ^4b a C _5-6 carbocycle, 0-2 R ^4b substituted with _-6 carbocyclic -CH ₂ - group, and carbon atoms, and N, O and S (O) comprises one to four heteroatoms selected from the group consisting of a 5 to 6 _p substituted with 0-2 R ^4b Selected from circular heterocycles;
[182] R ^2a is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S ( O) a 5-6 membered heterocycle consisting of 1-4 heteroatoms selected from the group consisting of _p and substituted with 0-2 R ^4b ;
[183] Alternatively, R ² and R ^2a are taken together with the atoms to which they are attached, substituted with 0 or 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
[184] R ^2b is, in each case, CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O, and S (O) _p is selected from the 5-6 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 2 R ^4b ;
[185] R ^2c is, in each case, CF ₃ , OH, C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and N, O and Is selected from a 5-6 membered heterocycle containing 1-4 heteroatoms selected from the group consisting of S (O) _p and substituted with 0-2 R ^4b ;
[186] R ³ is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
[187] R ^3a is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
[188] Alternatively, R ³ and R ^3a join together with the nitrogen atom to which they are attached to form a five or six membered saturated, partially unsaturated or unsaturated ring consisting of a carbon atom and a nitrogen atom to which R ³ and R ^3a are attached;
[189] R ^3c is in each case selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
[190] R ^3d in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ -phenyl, CH ₂ CH ₃ -phenyl and C (═O) R Selected from ^3c ;
[191] R ⁴ is in each case H, = 0, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Cl, Br, I, C _1-4 alkyl, -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , S (O) _p R ^5a , CF ₃ , CF ₂ CF ₃ , 5-6 membered carbocycle substituted with 0-1 R ⁵ , and carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 1 R ⁵ ;
[192] R ^4a is in each case H, = 0, CH ₂ 0R ² , OR ² , CH ₂ F, F, CH ₂ Br, Br, CH ₂ Cl, Cl, C _1-4 alkyl, CH ₂ -CN, -CN, CH ₂ NO ₂ , NO ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , CH ₂ -C (O) R ^2c , C (O) R ^2c , NR ² C (O) R ^2b , ( CH ₂ ) _r C (O) NR ² R ^2a , NRC (O) NR ² R ^2a , (CH ₂ ) _r SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a , NR ² SO ₂ -C ₁ CH ₂ -5 to 6-membered carbo substituted with _-4 alkyl, NR ² SO ₂ R ⁵ , (CH ₂ ) _r S (O) _p R ^5a , CH ₂ CF ₃ , CF ₃ , 0 to 1 R ⁵ A cycle, a 5-6 membered carbocycle substituted with 0-1 R ⁵ , and a carbon atom, and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0-1 CH ₂ -5 to 6 membered heterocycle substituted with R ⁵ , and a carbon atom, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ Selected from 5-6 membered heterocycle;
[193] R ^4b in each case is H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a , CH ₂ NR ³ C (O) NR ³ R ^3a , C (= NR ³ ) NR ³ R ^3a , CH ₂ C (= NR ³ ) NR ³ R ^3a , NR ³ C (= NR ³ ) NR ³ R ^3a , CH ₂ NR ³ C (= NR ³ ) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ NR ³ R ^3a , CH ₂ NR ³ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , CH ₂ NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -Phenyl, CF ₃ and CH ₂ -CF ₃ ;
[194] R ^4c is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN, CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , CH ₂ NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ -C _1-4 alkyl, C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ NR ² SO ₂ R ⁵ , S (O) _p R ^5a , CH ₂ S (O ) _p R ^5a, CF _3, CH ₂ CF _3, 0-1 R ⁵ of the 5 to 6 membered carbocycle, 0-1 of R ⁵ the CH ₂ -5 to 6-membered carbocycle substituted with substituted with, 5 to 6 membered heterocycle consisting of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ , and carbon atoms, and N, O And S (O) _p 1 to 4 selected from the group consisting of CH ₂ -5 to 6 membered heterocycle consisting of 2 heteroatoms and substituted with 0 to 1 R ⁵ ;
[195] R⁵In each case, H, = 0, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH (CH₃)₂, CH (CH₃) CH₂CH₃, C (CH₃)₃, OR³, CH₂OR³, F, Cl, -CN, N0₂, NR³R^3a, CH₂NR³R^3a, C (O) R³, CH₂C (O) R³, C (O) OR^3c, CH₂C (O) OR^3c, NR³C (O) R^3a, C (O) NR³R^3a, NR³C (O) NR³R^3a, CH (= NOR^3d), C (= NR³) NR³R^3a, NR³C (= NR³) NR³R^3a, SO₂NR³R^3a, NR³SO₂NR³R^3a, NR³SO₂-C_1-4Alkyl, NR³SO₂CF₃, NR³SO₂-Phenyl, S (O)_pCF₃, S (O)_p-C_1-4Alkyl, S (O)_p-Phenyl, CF₃, 0 to 2 R⁶Phenyl substituted by 0 to 2 R⁶Naphthyl and 0 to 2 R substituted by⁶Benzyl substituted;
[196] R ⁶ in each case is H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CN, NO ₂ , NR ² R ^2a , CH ² NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , C (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl.
[197] [3] In another preferred embodiment, the present invention
[198] Ring M is substituted with 0-2 R ^1a and is selected from the group below;
[199]
[200]
[201]
[202]
[203]
[204] Ring P comprising P ₁ , P ₂ , P ₃ and P ₄ is selected from the following group;
[205]
[206]
[207]
[208] One of P ₄ and M ₄ is -ZAB and the other is -G ₁ -G;
[209] G is selected from the following group;
[210]
[211]
[212]
[213]
[214]
[215] G ₁ is absent or (CR ³ R ^3a ) _1-3 , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C ( O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ (CR ³ R ^3a ) _w , ( CR ³ R ^3a ) _u S (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b S (O) ₂ (CR ³ R ^3a ) _w and (CR ³ R ^3a ) _u S (O) ₂ NR ^3b (CR ³ R ^3a ) _w wherein u + w total is 0, 1 or 2, provided that G ₁ is NS, NCH ₂ N, NCH ₂ 0 or Does not form an NCH ₂ S bond;
[216] A is phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxa substituted with 0-2 R ⁴ Zolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl, indolyl, benzimida Is selected from one of a carbocyclic group and a heterocyclic group of zolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl;
[217] B is or; Provided that Z and B are attached to different atoms on A;
[218] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[219] Q ₁ is selected from C═O and SO ₂ ;
[220] Ring Q is a 5-7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
[221] 0 to 2 double bonds are present in the ring and the ring is substituted with 0 to 2 R ^4a ;
[222] Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
[223] The 5 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
[224] The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , O and S;
[225] remind Ring Q comprising a 5 to 7 membered ring and the fused ring is 0 to 3 R^4aSubstituted with;
[226] R ^1a is selected from H, R ^1b , CH (CH ₃ ) R ^1b , C (CH ₃ ) ₂ R ^1b , CH ₂ R ^1b and CH ₂ CH ₂ R ^1b , provided that R ^1a is N-halo, NS Or to form other than N-CN bonds;
[227] Alternatively, when two R ^1a groups are attached to adjacent carbons, together with the atoms to which they are attached, the groups are 5 to 5 carbon atoms and 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p Forms a six membered ring, wherein the ring is substituted with 0-2 R ^4b and 0-3 ring double bonds are present;
[228] R ^1b is H, CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC ( O) R ² , C0 ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , phenyl substituted with 0 to 2 R ^4b , and 1 to 4 heteroatoms selected from the group consisting of carbon atoms, and N, O and S (O) _p and 0 to Selected from 5-6 membered aromatic heterocycles substituted with two R ^4b , provided that R ^1b forms other than 0-0, N halo, NS, or N-CN bond;
[229] R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , phenyl substituted with 0 to 2 R ^4b , 0 to 2 5-6 membered aromatic heterocycle consisting of benzyl substituted with R ^4b and carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b Is selected from;
[230] R ^2a in each case is H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and carbon An atom and a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
[231] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
[232] R ^2b in each case is substituted with CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, 0-2 R ^4b Phenyl, and a carbon atom, and is selected from a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
[233] R ^2c is, in each case, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and 0 to 2 R ^4b containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p It is selected from a 5-6 membered aromatic heterocycle substituted with;
[234] R ⁴ is, in each case, H, CH ₂ 0R ² , (CH ₂ ) ₂ OR ² , OR ² , F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
[235] R ^4a is in each case H, = 0, CH ₂ 0R ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and -CF ₃ Become;
[236] R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , —CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ -C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ -C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -phenyl and CF ₃ ;
[237] R ^4c is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN, CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , S (O) _p R ^5a , CH ₂ S (O) _p R ^5a , CF ₃ , phenyl substituted with 0 to 1 R ⁵ and 0 to 1 R Benzyl substituted by ⁵ ;
[238] R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, S (O _{) p CF 3, S (O} ) p -C 1-4 alkyl, S (O) _p -, phenyl, CF _3, 0-2 substituted with one R ⁶ is phenyl, substituted with 0-2 R ⁶ -naphthyl And benzyl substituted with 0 to 2 R ⁶ ;
[239] R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl It provides a new compound selected from.
[240] [4] In another preferred embodiment, the present invention
[241] Ring M is substituted with 0-2 R ^1a and is selected from the group below;
[242]
[243]
[244]
[245] Ring P comprising P ₁ , P ₂ , P ₃ and P ₄ is selected from the following group;
[246]
[247] One of P ₄ and M ₄ is -AB and the other is -G;
[248] G is selected from the following group;
[249]
[250]
[251]
[252] G ₁ is absent or CH ₂ , CH ₂ CH ₂ , CH ₂ O, OCH ₂ , NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O) NH, NHC (O), CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), S0 ₂ NH and NHS0 ₂ , provided that G ₁ is NS, NCH ₂ N, NCH and the other groups to which it is attached Does not form a ₂ 0 or NCH ₂ S bond;
[253] A is selected from phenyl, pyridyl and pyrimidyl and is substituted with 0 to 2 R ⁴ ;
[254] B is or; Provided that Z and B are attached to different atoms on A;
[255] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[256] Q ₁ is selected from C═O and SO ₂ ;
[257] Ring Q is a 6-7 membered ring consisting of carbon atoms and 0-1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
[258] 0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
[259] Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
[260] The 5 to 7 membered ring is composed of carbon atoms and 0 to 1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
[261] The fused ring is phenyl;
[262] Ring Q comprising said 5-7 membered ring and said fused ring is substituted with 0-2 R ^4a ;
[263] R ^1a is selected from H, R ^1b , C (CH ₃ ) ₂ R ^1b and CH ₂ R ^1b , provided that R ^1a forms other than N-halo, NS or N-CN bonds;
[264] R ^1b is CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , CO ₂ R ^2a , S ( O) _p R ² , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , and 1 to 1 selected from the group consisting of carbon atoms, and N, O and S (O) _p . Selected from a 5-6 membered aromatic heterocycle consisting of 4 heteroatoms and substituted with 0-2 R ^4b , provided that R ^1b forms other than OO, N-halo, NS or N-CN bonds;
[265] R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a 5-6 membered aromatic heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of carbon atoms, N, O and S (O) _p and substituted with 0 to 1 R ^4b ;
[266] R ^2a in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and a carbon atom, and N, O and S (O) _p is selected from a 5-6 membered aromatic heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 1 R ^4b ;
[267] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
[268] R ^2b is, in each case, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ^4b Selected from 5 to 6 membered aromatic heterocycles;
[269] R ^2c is, in each case, OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ^4b 5 to 6 membered aromatic heterocycle;
[270] R ⁴ is, in each case, OH, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Br, Cl, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
[271] R ^4a in each case is H, ═O, CH ₂ 0R ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and CF ₃ ;
[272] R ^4b is in each case H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , NR ³ S0 ₂ -C _1-4 alkyl, NR ³ S0 ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl and CF ₃ ;
[273] R ^4c are, at each occurrence, H, CH _3, CH ₂ CH _3, 0 and is selected from benzyl substituted by one R ⁵ is phenyl and R ⁵ is substituted by from 0 to 1;
[274] R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CF ₃ , 0 to 2 R selected from benzyl substituted by phenyl, ^6, 0-2 R ^6, naphthyl, and substituted with 0-2 R ⁶ is substituted by;
[275] R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, N0 ₂ , NR ² R Novel compounds are selected from ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a .
[276] [5] In another preferred embodiment, the present invention
[277] Ring M is substituted with 0 to 1 R ^1a and is selected from the group below;
[278]
[279]
[280] Ring P, including P ₁ , P ₂ , P ₃ and P ₄ , is selected from the following group;
[281]
[282] One of P ₄ and M ₄ is -AB and the other is -G;
[283] G is selected from the following group;
[284]
[285]
[286] A is phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-amino Phenyl and 2-methoxyphenyl;
[287] B is attached to an atom different from M on A and is selected from the group below;
[288]
[289]
[290]
[291] R ^1a is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ F, CH ₂ Cl, Br, CH ₂ Br, -CN, CH ₂ CN, CF ₃ , CH ₂ CF ₃ , OCH ₃ , CH ₂ OH, C (CH ₃ ) ₂ OH, CH ₂ OCH ₃ , NH ₂ , CH ₂ NH ₂ , NHCH ₃ , CH ₂ NHCH ₃ , N (CH ₃ ) ₂ , CH ₂ N (CH ₃ ) ₂ , CO ₂ H, COCH ₃ , CO ₂ CH ₃ , CH ₂ CO ₂ CH ₃ , SCH ₃ , CH ₂ SCH ₃ , S (O) CH ₃ , CH ₂ S (O) CH ₃ , S (O) ₂ CH ₃ , CH ₂ S (O) ₂ CH ₃ , C (O) NH ₂ , CH ₂ C (O) NH ₂ , SO ₂ NH ₂ , CH ₂ SO ₂ NH ₂ , NHSO ₂ CH ₃ , CH ₂ NHSO ₂ CH ₃ , pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N- Oxide, imidazol-1-yl, CH ₂ -imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N, N-dimethylaminomethyl-oxazol-2-yl, 1, 2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH ₂ -1,2,3,4-tetrazol-1-yl and CH ₂ -1 , 2,3,4-tetrazol-5-yl, provided that R ^1a forms other than N-halo, NS or N-CN bonds;
[292] R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a carbon atom, and selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of N, O, and S (O) _p and substituted with 0 to 1 R ^4b and a 5-membered aromatic heterocycle;
[293] R ^2a is in each case selected from H, CH ₃ and CH ₂ CH ₃ ;
[294] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p Selected from saturated, partially saturated or unsaturated rings of the circle;
[295] R ^2b is in each case selected from OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
[296] R ^2c is in each case selected from OH, OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
[297] R ^4a in each case is H, ═O, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ and C (CH ₃ ) ₃ ;
[298] R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -phenyl, S (O) ₂ CH ₃ , S (O) ₂ -phenyl and CF ₃ ;
[299] R ⁵ is in each case H, ═O, CH ₃ , CH ₂ CH ₃ , OR ³ , CH ₂ 0R ³ , F, Cl, NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO _{2- phenyl, S (O) 2 -CH 3} , S (O) 2 - , phenyl, CF _3, 0-2 R ⁶ substituted by phenyl, 0-2 R ⁶ substituted naphthyl, and 0-2 R Benzyl substituted by ⁶ ;
[300] R ⁶ is in each case H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C ( O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a .
[301] [6] In another preferred embodiment, the present invention
[302] P ₄ is -G;
[303] M ₄ is -AB;
[304] G is selected from;
[305]
[306] A-B is selected from the following;
[307]
[308]
[309] It provides a novel compound selected from the following.
[310]
[311]
[312]
[313] [7] In another preferred embodiment, the present invention
[314] P ₄ is -G;
[315] M ₄ is -AB;
[316] A-B is selected from the following;
[317]
[318] It provides a novel compound selected from the following.
[319]
[320] [8] In another preferred embodiment, the present invention is
[321] 3-methoxy-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7-H-pyra Zolo [3,4-c] pyridin-7-one;
[322] 1- (4-methoxyphenyl) -3-[(methylamino) methyl] -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one;
[323] 1- (3-chloro-4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6- Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[324] 1- [3- (aminomethyl) -4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5 , 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[325] 1- (3-amino-1, 2-benzisoxazol-5-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1, 4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[326] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
[327] 1- (4-methoxyphenyl) -6- [4- (2-oxohexahydro-1H-azin-1-yl) phenyl] -3- (trifluoromethyl) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[328] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperazinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
[329] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-imidazolidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one;
[330] 1- (4-methoxyphenyl) -6- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[331] 6- [4- (3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -3- (trifluoro Methyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[332] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carbonitrile;
[333] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (1H-tetrazol-5-yl) -1,4,5,6- Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[334] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl-4,5,6,7-tetrahydro-1H-pyrazole- [3 , 4-c] pyridine-3-carboxamide;
[335] 3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [ 3,4-c] pyridin-7-one;
[336] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (4-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
[337] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (4-pyridinyl-N-oxide) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[338] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (3-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
[339] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (3-pyridinyl-N-oxide) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[340] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (2-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] -7-one;
[341] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c ] Pyridin-7-one;
[342] 1- (4-methoxyphenyl) -7-oxo-6- [5- (2-oxo-1-piperidinyl) -2-pyridinyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide;
[343] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
[344] 1- (4-methoxyphenyl) -3- (methylsulfonyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H- Pyrazolo [3,4-c] pyridin-7-one;
[345] 1- (4-methoxyphenyl) -6- (4- (2-oxo-1 (2H) -pyridinyl) phenyl-3- (2-pyridinyl) -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one;
[346] 1- [3- (aminomethyl) phenyl] -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro -7H-pyrazolo [3,4-c] pyridin-7-one;
[347] 3- [7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-1-yl] benzamide;
[348] 1- (3-chlorophenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide;
[349] 1- (3-chlorophenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [ 3,4-c] pyridine-3-carboxamide;
[350] 1- (3-chlorophenyl) -N, N-dimethyl-7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H -Pyrazolo [3,4-c] pyridine-3-carboxamide;
[351] 1- (3-chloro-4-fluorophenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide;
[352] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carbonitrile;
[353] 1- (3-amino-1 H-indazol-5-yl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
[354] 1- (3-amino-1, 2-benzisoxazol-5-yl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7 -Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
[355] 1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (trifluoromethyl) -1 , 4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[356] 1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4 , 5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[357] 1- (2,3-dihydro-1H-isoindol-5-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) phenyl] -3-trifluoromethyl-1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[358] 1- (4-methoxyphenyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -3- (2-pyrrolidin-1-ylmethyl-phenyl) -1 , 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[359] Ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyra Solo [3,4-c] pyridine-3-carboxylate;
[360] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid;
[361] 1- (4-methoxyphenyl) -N, N-dimethyl-7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl-4,5,6,7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
[362] N-({1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro- 1H-pyrazolo [3,4-c] pyridin-3-yl} carbonyl) methanesulfonamide;
[363] 1- (4-hydroxy-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxylic acid amide;
[364] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (1H-tetrazol-5-yl) -1,4,5, 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[365] 3- {4-[(dimethylamino) methyl] -1,3-oxazol-2-yl} -1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H)- Pyridinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[366] 3- {4- [dimethylamino) methyl] -1,3-oxazol-2-yl} -1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) Phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
[367] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperazinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
[368] 1- (4-methoxyphenyl) -3- (methylsulfonyl) -6- [4- (2-oxo-1-piperazinyl) phenyl] -1,4,5,6-tetrahydro-7H- Pyrazolo [3,4-c] pyridin-7-one;
[369] 1- (4-methoxy-phenyl) -3- (4-methyl-oxazol-2-yl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[370] 1- (4-methoxy-phenyl) -3- (4-methyl-oxazol-2-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[371] 3-acetyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one;
[372] 3- (4,5-dihydro-1H-imidazol-2-yl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl)- Phenyl] -1,4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[373] 1- (4-methoxy-phenyl) -3- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -6- [4- (2-oxo-piperidine-1 -Yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one;
[374] 1- (4-methoxy-phenyl) -3- (1-methyl-1H-imidazol-2-yl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl]- 1,4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[375] 1- (4-methoxy-phenyl) -3-methyl-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one;
[376] 3-hydroxymethyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro- Pyrazolo [3,4-c] pyridin-7-one;
[377] 3- (1-hydroxy-1-methyl-ethyl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[378] 3- (1-hydroxy-1-methyl-ethyl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
[379] 2-dimethylamino-N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7- Tetrahydro-1H-pyrazolo [3,4-c] pyridin-3-ylmethyl} -N-methylacetamide;
[380] 2-dimethylamino-N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-3-ylmethyl} acetamide;
[381] N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl-4,5,6,7-tetrahydro-1H-pyra Zolo [3,4-c] pyridin-3-ylmethyl} -2-pyridin-2-yl-acetamide;
[382] N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridin-3-ylmethyl} -2- (1-oxypyridin-2-yl) acetamide;
[383] 6- [4- (1,1-Dioxo-116-isothiazolidin-2-yl) -phenyl] -1- (4-methoxy-phenyl) -7-oxo-4,5,6,7 -Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide;
[384] N-hydroxy-3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetra Hydro-pyrazolo [3,4-c] pyridin-1-yl} -benzamidine;
[385] N-methoxy-3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetra Hydro-pyrazolo [3,4-c] pyridin-1-yl} -benzamidine;
[386] 1- (3-cyano-4-fluorophenyl-7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide;
[387] 1- (3-Aminomethyl-4-fluoro-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7- Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide;
[388] 2- {7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzenesulfonamide;
[389] 2- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzenesulfonamide;
[390] N-acetyl-2- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro -Pyrazolo [3,4-c] pyridin-1-yl} -benzenesulfonamide;
[391] 1- (3-Chloro-phenyl) -3-methanesulfonyl-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra Zolo [3,4-c] pyridin-7-one;
[392] 1- (3-Chloro-phenyl) -3-methanesulfonyl-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra Zolo [3,4-c] pyridin-7-one;
[393] 1- (3-Chloro-phenyl) -3- (1-hydroxy-1-methyl-ethyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4 , 5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one; And
[394] 3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzamide is provided in the form of a novel compound or a pharmaceutically acceptable salt thereof.
[395] [9] In another preferred embodiment, the present invention provides a compound which is a novel compound or stereoisomer or pharmaceutically acceptable salt thereof, of formula IIIa, IIIb or IIIc below.
[396]
[397]
[398]
[399] In the above formula,
[400] Ring M comprising M ₁ , M ₂ and M ₃ , if present, is phenyl or a 1 to 4 heteroatom selected from 3 to 10 membered carbocyclic or carbon atoms and O, S (O) _p , N and NZ ² 4 to 10 membered heterocyclic ring;
[401] Ring M is substituted with 0-3 R ^1a and 0-2 carbonyl groups, and there are 0-3 ring double bonds present;
[402] One of P ₄ and M ₄ is -ZAB, and the other is -G ₁ -G;
[403] G is a group of formula IIa or IIb;
[404] <Formula IIa>
[405]
[406] <Formula IIb>
[407]
[408] here,
[409] Ring D is a 5-6 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O and S (O) _p , including the two atoms of ring E to which it is attached;
[410] Ring D is substituted with 0-2 R, and 0-3 ring double bonds are present;
[411] E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl and substituted with 1 to 2 R;
[412] Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl, pyrimidyl and thienyl, wherein Ring E is substituted with 1 to 2 R;
[413] Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl and thienyl, wherein Ring E is substituted with one R and is selected from the group consisting of carbon atoms and N, O and S (O) _p A 5 membered heterocyclosubstituted consisting of 1 to 4 heteroatoms selected, wherein the 5 membered heterocycle is substituted with 0 to 1 carbonyl and 1 to 2 R and 0 to 3 ring double bonds are present;
[414] R is H, C _1-4 alkyl, F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CN, C (= NH) NH ₂ , C (= NH) NHOH, C ( = NH) NHOCH ₃ , NH ₂ , NH (C _1-3 alkyl), N (C _1-3 alkyl) ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NH (C _1-3 alkyl ), CH ₂ N (C _1-3 alkyl) ₂ , (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , CH ₂ C (O) NR ⁷ R ⁸ , S (O) _p NR ⁷ R ⁸ , CH ₂ S (O) _p NR ⁷ R ⁸ , SO ₂ R ³ and OCF ₃ ;
[415] Alternatively, when two R groups are attached to adjacent carbons, they combine to form methylenedioxy or ethylenedioxy;
[416] A is
[417] C _5-10 carbocycle substituted with 0 to 2 R ⁴ , and
[418] A carbon atom and a 5-10 membered heterocycle consisting of 1-4 heteroatoms selected from N, O and S (O) _p and substituted with 0-2 R ⁴ ;
[419] Provided that A is other than dihydro-benzopyran;
[420] B is or; Provided that Z and B are attached to different atoms on A, and that the AXN moiety forms something other than an NNN group;
[421] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[422] Q ₁ is selected from C = 0 and SO ₂ ;
[423] Ring Q is a 4-7 membered monocyclic or tricyclic ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , 0, S, S (O) and S (O) ₂ , in addition to the NQ ₁ group shown Where,
[424] 0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
[425] Alternatively, ring Q is a 4-7 membered ring to which another ring is fused, wherein
[426] The 4 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
[427] The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , 0 and S;
[428] The ring Q comprising the 4 to 7 membered ring and the fused ring is substituted with 0 to 3 R ^4a ;
[429] X is not present or _{^{- (CR 2 R 2a) 1-4}} -, -C (O) -, -C (O) CR 2 R 2a -, -CR 2 R 2a C (O), -S (O) _{2 -, -S (O) 2} CR 2 R 2a -, -CR 2 R 2a S (O) 2 -, -NR 2 S (O) 2 -, -NR 2 CR 2 R 2a - , and -OCR ² R ^2a- ;
[430] Z is a bond, CH ₂ , CH ₂ CH ₂ , CH ₂ 0, OCH ₂ , C (O), NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O ) NH, NHC (O), NHC (O) NH, NHC (O) CH ₂ C (O) NH, C (O) NHS (O) ₂ , S (O) ₂ , CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHSO ₂ , provided that Z does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
[431] Z ² is selected from H, C _1-4 alkyl, phenyl, benzyl, C (O) R ^3b , S (O) R ^3f and S (O) ₂ R ^3f ;
[432] R ^1a is H,-(CH ₂ ) _r -R ^1b ,-(CH (CH ₃ )) _r -R ^1b ,-(C (CH ₃ ) ₂ ) _r -R ^1b , NHCH ₂ R ^1c , OCH ₂ R ^1c , SCH ₂ R ^1c , NH (CH ₂ ) ₂ (CH ₂ ) _t R ^1b and O (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , provided that R ^1a is N-halo, NS or N To form other than -CN bonds;
[433] Alternatively, when two R ^1a groups are attached to adjacent carbons, together with the atoms to which they are attached, the groups are 5 to 5 carbon atoms and from 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p Forms a seven membered ring, which is substituted with 0-2 R ^4b , and there are 0-3 ring double bonds present;
[434] R ^1b is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , F, Cl, Br, I, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC (O) R ² , CO ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , NR ² C (O) NHR ² , NR ² C (O) ₂ R ^2a , OC (O) NR ² R ^2a , C (O) NR ² R ^2a , C (O) NR ² (CH ₂ ) _r OR ² , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 2 R ^4b , provided that R ^1b is other than OO, N-halo, NS or N-CN bond To form one;
[435] R ^1c is H, CH (CH ₂ 0R ² ) ₂ , C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ² , S (O) ₂ R ² and SO ₂ NR ² R ^Is selected from ^2a ;
[436] R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH _{3 ) 2, CH (CH 3)} CH 2 CH 3, C (CH 3) 3, a C ₅ optionally substituted with benzyl, 0-2 R ^4b a C _5-6 carbocycle, 0-2 R ^4b substituted with _-6 carbocyclic -CH ₂ - group, and carbon atoms, and N, O and S (O) comprises one to four heteroatoms selected from the group consisting of a 5 to 6 _p substituted with 0-2 R ^4b Selected from circular heterocycles;
[437] R ^2a is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S ( O) a 5-6 membered heterocycle consisting of 1-4 heteroatoms selected from the group consisting of _p and substituted with 0-2 R ^4b ;
[438] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a circular saturated, partially saturated or unsaturated ring;
[439] R ^2b is, in each case, CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p is selected from 5-6 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 2 R ^4b ;
[440] R ^2c is, in each case, CF ₃ , OH, C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and N, O and Is selected from a 5-6 membered heterocycle containing 1-4 heteroatoms selected from the group consisting of S (O) _p and substituted with 0-2 R ^2b ;
[441] R ³ is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
[442] R ^3a is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
[443] Alternatively, R ³ and R ^3a join together with the nitrogen atom to which they are attached to form a five or six membered saturated, partially unsaturated or unsaturated ring consisting of a carbon atom and a nitrogen atom to which R ³ and R ^3a are attached;
[444] R ^3c is in each case selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
[445] R ^3d in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ -phenyl, CH ₂ CH ₂ -phenyl and C (═O) R Selected from ^3c ;
[446] R ⁴ is in each case H, = 0, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Cl, Br, I, C _1-4 alkyl, -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , S (O) _p R ^5a , CF ₃ , CF ₂ CF ₃ , 5-6 membered carbocycle substituted with 0-1 R ⁵ , and carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 1 R ⁵ ;
[447] R ^4a in each case is H, = 0, CH ₂ OR ² , OR ² , CH ₂ F, F, CH ₂ Br, Br, CH ₂ Cl, Cl, C _1-4 alkyl, CH ₂ -CN, -CN, CH ₂ NO ₂ , NO ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , CH ₂ -C (O) R ^2c , C (O) R ^2c , NR ² C (O) R ^2b , ( CH ₂ ) _r C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , (CH ₂ ) _r SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a , NR ² SO _2- C _{1-4 ^{alkyl, NR 2 SO 2 R 5,}} (CH 2) r S (O) p R 5a, CH 2 CF 3, CF 3, 0 to CH substituted with 1 to 6 R ⁵ ₂ -5 Carbocycle, 5-6 membered carbocycle substituted with 0-1 R ⁵ , and carbon atoms, and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0- CH ₂ -5 to 6 membered heterocycle substituted with 1 R ⁵ , and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0 to 1 R ⁵ Is selected from a 5-6 membered heterocycle substituted with;
[448] R ^4b in each case is H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a , CH ₂ NR ³ C (O) NR ³ R ^3a , C (= NR ³ ) NR ³ R ^3a , CH ₂ C (= NR ³ ) NR ³ R ^3a , NR ³ C (= NR ³ ) NR ³ R ^3a , CH ₂ NR ³ C (= NR ³ ) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ NR ³ R ^3a , CH ₂ NR ³ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , CH ₂ NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -Phenyl, CF ₃ and CH ₂ -CF ₃ ;
[449] R ^4c in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , CH ₂ NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ -C _1-4 alkyl, C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ NR ² SO ₂ R ⁵ , S (O) _p R ^5a , CH ₂ S (O) _{^{p R 5a, CF 3, CH}} 2 CF 3, 0 to 1 of the R ⁵ substituted with a 5 to 6 membered carbocycle, substituted with 0-1 of R ⁵ CH ₂ -5 to 6 membered carbocycle, carbon 5-6 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of atoms, and N, O and S (O) _p and substituted with 0 to 1 R ⁵ , and a carbon atom, and N, O and 1 to 4, selected from the group consisting of S (O) _p The hetero atom is made is selected from a CH ₂ -5 to 6 membered heterocycle substituted with 0-1 of R ^5;
[450] R ⁵ is in each case H, ═O, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, N0 ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a , CH (= NOR ^3d ), C (= NR ³ ) NR ³ R ^3a , NR ³ C (= NR ³ ) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , S (O) _p -C _{1- 4} alkyl, S (O) _p -, phenyl, CF _3, 0 and is selected from benzyl substituted by two R ⁶ is phenyl, 0-2 R ⁶ naphthyl and 0-2 R ⁶ substituted with substituted with ;
[451] R ⁶ in each case is H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , C (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl.
[452] [10] In another preferred embodiment, the present invention
[453] Ring M comprising M ₁ , M ₂ and M ₃ , if present, is phenyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3- Triazole, 1,2,4-triazole, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole , 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-tetazole, 1,2,3,5- Tetrazole, pyran, thiopyran, thiopyran = 1,1-dioxide, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2, 3,4-tetrazine, dihydro-pyrrole, dihydro-furan, dihydro-thiophene, dihydro-pyrazole, dihydro-imidazole, dihydro-isoxazole, dihydro-oxazole, dihydro- Isothiazole, dihydro-thiazole, dihydro-1,2,3-triazole, dihydro-1,2,4-triazole, dihydro-1,3,4-triazole, dihydro-1 , 2,3-oxadiazole, dihydro-1,2,4-oxadiazole, dihydro-1,3,4-jade Diazole, dihydro-1,2,3-thiadiazole, dihydro-1,2,4-thiadiazole, dihydro-1,3,4-thiadiazole, dihydro-1,2,3 , 4-tetrazole, dihydro-1,2,3,5-tetrazole, dihydro-pyran, dihydro-thiopyran, dihydro-thiopyran = 1,1-dioxide, dihydro-pyridine, di Hydro-pyrimidine, dihydro-pyridazine, dihydro-pyrazine, dihydro-1,2,3-triazine, dihydro-1,2,4-triazine, dihydro-1,2,3,4 -Tetrazine, cyclopentene, cyclopentane, cyclohexene, cyclohexane, tetrahydro-pyrrole, tetrahydro-furan, tetrahydro-thiophene, tetrahydro-thiophene-1,1-dioxide, tetrahydro-pyrazole , Tetrahydro-imidazole, tetrahydro-isoxazole, tetrahydro-oxazole, tetrahydro-isothiazole, tetrahydro-thiazole, tetrahydro-1,2,3-triazole, tetrahydro-1,2 , 4-triazole, tetrahydro-1,3,4-triazole, tetra Hydro-1,2,3-oxadiazole, tetrahydro-1,2,4-oxadiazole, tetrahydro-1,3,4-oxadiazole, tetrahydro-1,2,3-thiadiazole , Tetrahydro-1,2,4-thiadiazole, tetrahydro-1,3,4-thiadiazole, tetrahydro-1,2,3,4-tetazole, tetrahydro-1,2,3, 5-tetrazole, tetrahydro-pyran, tetrahydro-thiopyran, tetrahydro-thiopyran-1,1-dioxide, tetrahydro-pyridine, tetrahydro-pyrimidine, tetrahydro-pyridazine, tetrahydro-pyrazine , Tetrahydro-1,2,3-triazine, tetrahydro-1,2,4-triazine and tetrahydro-1,2,3,4-tetraazine;
[454] Ring M is substituted with 0-3 R ^1a and 0-1 carbonyl group;
[455] G is selected from the group below;
[456]
[457]
[458]
[459]
[460]
[461]
[462] G ₁ is absent or (CR ³ R ^3a ) _1-3 , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C ( O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ (CR ³ R ^3a ) _w , ( CR ³ R ^3a ) _u S (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b S (O) ₂ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ NR ^3b (CR ³ R ^3a ) _w and (CR ³ R ^3a ) _u C (O) NR ^3b S (O) ₂ (CR ³ R ^3a ) _w , wherein the sum of u + w is 0 , 1 or 2, provided that G ₁ does not form an NS, NCH ₂ N, NCH or NCH ₂ S bond with another group to which it is attached;
[463] A is phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxa substituted with 0-2 R ⁴ Zolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl, indolyl, benzimida Is selected from one of carbocyclic and heterocyclic groups of zolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl;
[464] B is or; Provided that Z and B are attached to different atoms on A;
[465] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[466] Q ₁ is selected from C═O and SO ₂ ;
[467] Ring Q is a 5-7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
[468] 0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
[469] Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
[470] The 5 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
[471] The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , 0 and S;
[472] Ring Q comprising said 5-7 membered ring and said fused ring is substituted with 0-3 R ^4a ;
[473] R ^1a is selected from H, R ^1b , CH (CH ₃ ) _r R ^1b , C (CH ₃ ) ₂ R ^1b , CH ₂ R ^1b and CH ₂ CH ₂ R ^1b , provided that R ^1a is N-halo, Other than NS or N-CN bonds;
[474] Alternatively, when two R ^1a groups are attached to an adjacent atom, the groups together with the atoms to which they are attached are selected from the group consisting of 5 to 5 heteroatoms selected from the group consisting of carbon atoms and N, O and S (O) _p Forms a 6-membered ring, which ring is substituted with 0-2 R ^4b , and 0-3 ring double bonds are present;
[475] R ^1b is H, CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC ( O) R ² , C0 ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , phenyl substituted with 0 to 2 R ^4b , and 1 to 4 heteroatoms selected from the group consisting of carbon atoms, and N, O and S (O) _p and 0 to Selected from 5-6 membered aromatic heterocycles substituted with two R ^4b , provided that R ^1b forms other than OO, N-halo, NS or N-CN bonds;
[476] R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , phenyl substituted with 0 to 2 R ^4b , 0 to 2 5-6 membered aromatic heterocycle consisting of benzyl substituted with R ^4b and carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b Is selected from;
[477] R ^2a in each case is H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and carbon An atom and a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
[478] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p Selected from circle saturated, partially saturated or unsaturated rings;
[479] R ^2b in each case is substituted with CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, 0-2 R ^4b Phenyl, and a carbon atom, and is selected from a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
[480] R ^2c is, in each case, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and 0 to 2 R ^4b containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p It is selected from a 5-6 membered aromatic heterocycle substituted with;
[481] R ⁴ is in each case H, CH ₂ OR ² , (CH ₂ ) ₂ 0R ² , OR ² , F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, NO ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
[482] R ^4a is in each case H, = 0, CH ₂ 0R ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and -CF ₃ Become;
[483] R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , —CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ -C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ -C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -phenyl and CF ₃ ;
[484] R ^4c is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN, CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , S (O) _p R ^5a , CH ₂ S (O) _p R ^5a , CF ₃ , phenyl substituted with 0 to 1 R ⁵ and 0 to 1 R Benzyl substituted by ⁵ ;
[485] R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) _r R ^3a , C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, S ( _{O) p CF 3, S (} O) p -C 1-4 alkyl, S (O) _p -, phenyl, CF _3, 0-2 substituted with one R ⁶ is phenyl, substituted with 0-2 R ⁶ naphthyridin Butyl and benzyl substituted with 0-2 R ⁶ ;
[486] R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl It provides a new compound selected from.
[487] [11] In another preferred embodiment, the present invention
[488] J is selected from 0, S, NH and NR ^1a ;
[489] G is selected from the group below;
[490]
[491]
[492]
[493] G ₁ is absent or CH ₂ , CH ₂ CH ₂ , CH ₂ 0, OCH ₂ , NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O) NH, NHC (O), NHC (O) NH, C (O) NHS (O) ₂ , CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), S0 ₂ NH and NHS0 ₂ , but , G ₁ does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
[494] A is selected from indolinyl, phenyl, pyridyl and pyrimidyl and is substituted with 0 to 2 R ⁴ ;
[495] B is or; Provided that Z and B are attached to different atoms on A;
[496] Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
[497] Q ₁ is selected from C═O and SO ₂ ;
[498] Ring Q is a 6-7 membered ring consisting of carbon atoms and 0-1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
[499] 0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
[500] Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
[501] The 5 to 7 membered ring is composed of carbon atoms and 0 to 1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
[502] The fused ring is phenyl;
[503] remind Ring Q comprising 5-7 membered rings and said fused ring is 0-2 R^4aSubstituted with;
[504] R ^1a is selected from H, R ^1b , C (CH ₃ ) ₂ R ^1b and CH ₂ R ^1b , provided that R ^1a forms other than N-halo, NS or N-CN bonds;
[505] R ^1b is CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , C0 ₂ R ^2a , S ( O) _p R ² , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , and 1 to 1 selected from the group consisting of carbon atoms, and N, O and S (O) _p . Selected from a 5-6 membered aromatic heterocycle consisting of 4 heteroatoms and substituted with 0-2 R ^4b , provided that R ^1b forms other than OO, N-halo, NS or N-CN bonds;
[506] R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a carbon atom, and from 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and selected from 5 to 6 membered aromatic heterocycles substituted with 0 to 1 R ^4b and ;
[507] R ^2a in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and a carbon atom, and N, O and S (O) _p is selected from a 5-6 membered aromatic heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 1 R ^4b ;
[508] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a circular saturated, partially saturated or unsaturated ring;
[509] R ^2b is, in each case, OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0 to 1 R ^4b It is selected from a 5-6 membered aromatic heterocycle substituted with;
[510] R ^2c is, in each case, OH, OCH ₃ , OCH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ^4b 5 to 6 membered aromatic heterocycle;
[511] R ⁴ is, in each case, OH, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Br, Cl, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₃ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
[512] R ^4a in each case is H, = 0, CH ₂ OR ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and CF ₃ ;
[513] R ^4b is in each case H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl and CF ₃ ;
[514] R ^4c are, at each occurrence, H, CH _3, CH ₂ CH _3, 0 and is selected from benzyl substituted by one R ⁵ is phenyl and R ⁵ is substituted by from 0 to 1;
[515] R ⁵ , in each case, is H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CF ₃ , 0 to 2 R selected from benzyl substituted by phenyl, ^6, 0-2 R ^6, naphthyl, and substituted with 0-2 R ⁶ is substituted by;
[516] R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a ;
[517] It provides a novel compound selected from the following.
[518]
[519]
[520]
[521]
[522] [12] In another preferred embodiment, the present invention
[523] J is selected from O, S, NH and NR ^1a ;
[524] P ₄ is G ₁ -G;
[525] M ₄ is -ZAB;
[526] G is selected from;
[527]
[528]
[529] G ₁ is absent or CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O) NH, NHC (O), NHC (O) NH, CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHS0 ₂ , provided that G ₁ does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached ;
[530] A is indolinyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, It is selected from the group of 2-aminophenyl and 2-methoxyphenyl;
[531] B is attached to an atom different from M on A and is selected from the group below;
[532]
[533]
[534]
[535] R ^1a is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ F, CH ₂ Cl, Br, CH ₂ Br, -CN, CH ₂ CN, CF ₃ , CH ₂ CF ₃ , OCH ₃ , CH ₂ OH, C (CH ₃ ) ₂ 0H, CH ₂ OCH ₃ , NH ₂ , CH ₂ NH ₂ , NHCH ₃ , CH ₂ NHCH ₃ , N (CH ₃ ) ₂ , CH ₂ N (CH ₃ ) ₂ , CO ₂ H, COCH ₃ , C0 ₂ CH ₃ , CH ₂ CO ₂ CH ₃ , SCH ₃ , CH ₂ SCH ₃ , S (O) CH ₃ , CH ₂ S (O) CH ₃ , S (O) ₂ CH ₃ , CH ₂ S (O) ₂ CH ₃ , C (O) NH ₂ , CH ₂ C (O) NH ₂ , S0 ₂ NH ₂ , CH ₂ SO ₂ NH ₂ , NHSO ₂ CH ₃ , CH ₂ NHSO ₂ CH ₃ , pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N- Oxide, imidazol-1-yl, CH ₂ -imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N, N-dimethylaminomethyl-oxazol-2-yl, 1, 2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH ₂ -1,2,3,4-tetrazol-1-yl and CH ₂ -1 , 2,3,4-tetrazol-5-yl, provided that R ^1a forms other than N-halo, NS or N-CN bonds;
[536] R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a carbon atom, and from 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and selected from 5 membered aromatic heterocycles substituted with 0 to 1 R;
[537] R ^2a is in each case selected from H, CH ₃ and CH ₂ CH ₃ ;
[538] Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
[539] R ^2b is in each case selected from OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
[540] R ^2c is in each case selected from OH, OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
[541] R ^4a in each case is H, ═O, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ and C (CH ₃ ) ₃ ;
[542] R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -phenyl, S (O) ₂ CH ₃ , S (O) ₂ -phenyl and CF ₃ ;
[543] R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , OR ³ , CH ₂ 0R ³ , F, Cl, NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO _{2- phenyl, S (O) 2 -CH 3} , S (O) 2 - , phenyl, CF _3, 0-2 R ⁶ substituted by phenyl, 0-2 R ⁶ substituted naphthyl, and 0-2 R Benzyl substituted by ⁶ ;
[544] R ⁶ is in each case H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C ( O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a ,
[545] It provides a novel compound selected from the following.
[546]
[547]
[548] [13] In another preferred embodiment, the present invention
[549] G is selected from;
[550]
[551]
[552] A-B is selected from the following;
[553]
[554]
[555] It provides a novel compound selected from the following.
[556]
[557] [14] In another preferred embodiment, the present invention
[558] P ₄ is -G;
[559] A-B is selected from the following;
[560]
[561] It provides a novel compound selected from the following.
[562]
[563] [15] In another preferred embodiment, the present invention
[564] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1-piperidinyl) -2,3-dihydro-1 H-indole-1 -Yl] carbonyl} -1 H-pyrazole-3-carboxamide;
[565] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[6- (2-oxo-1-piperidinyl-2,3-dihydro-1H-indole-1- Il] carbonyl} -1H pyrazole-3-carboxamide;
[566] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxohexahydro-1 H-azin-1-yl) -2,3-dihydro- 1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide;
[567] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[6- (2-oxohexahydro-1 H-azin-1-yl) -2,3-dihydro- 1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide;
[568] 2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] benzamide;
[569] 2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] benzamide;
[570] 2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] benzamide;
[571] 5-chloro-N- [2-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide;
[572] 5-chloro-N- [2-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide;
[573] 5-chloro-N- [2-({[4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide;
[574] 4-chloro-2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] benzamide;
[575] 4-chloro-2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] benzamide;
[576] 4-chloro-2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] benzamide;
[577] 2-[(4-chlorobenzoyl) amino] -4-[(methylsulfonyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] benzamide;
[578] 2-[(4-chlorobenzoyl) amino] -4-[(methylsulfonyl) amino] -N- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] benzamide;
[579] 2-[(4-chlorobenzoyl) amino] -4-[(methylsulfonyl) amino] -N- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] benzamide;
[580] 5-chloro-N- [5-[(methylsulfonyl) amino] -2-({4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarbox amides;
[581] 2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] nicotinamide;
[582] 3-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] isonicotinamide;
[583] 4-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] nicotinamide;
[584] 5-chloro-N- [3-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) -4-pyridinyl] -2-pyridinecarboxamide;
[585] 5-chloro-N- [3-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) -4-pyridinyl] -2-pyridinecarboxamide;
[586] 5-chloro-N- [5-chloro-3-methoxy-2-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) phenyl] -2-pyridincar Boxamide;
[587] 5-chloro-N- [5-chloro-3-methoxy-2-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide ;
[588] Methyl 2- [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H -Pyrazol-5-yl] -3-oxopropanoate;
[589] 1- (3-fluoro-4- {2- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2-oxoethyl} phenyl) -2 (1H) -pyridinone;
[590] 1- (4- {2- [1- (3-amino-1, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2- Oxoethyl} -3-fluorophenyl) -2 (1H) -pyridinone;
[591] 5-{[2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] acetyl} -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxamide;
[592] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1 (2H) -pyridinyl) -2,3-dihydro-1H-indole -1-yl] carbonyl} -1 H-pyrazole-3-carboxamide;
[593] 5-chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) benzamide;
[594] 5-chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) benzamide;
[595] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) -5-methoxybenzamide;
[596] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5-methoxybenzamide;
[597] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl) amino) -5-methylbenzamide;
[598] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5-methylbenzamide;
[599] 2- (5-chloro-pyridin-2-yl) -7-methoxy-3- [4- (2-oxo-piperidin-1-yl) -phenyl] -2H-isoquinolin-1-one;
[600] 2- (5-chloro-pyridin-2-yl) -7-methoxy-3- [4- (2-oxo-pyridin-1-yl) -phenyl] -2H-isoquinolin-1-one;
[601] 5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-2- [4- (2-oxopiperidin-1-yl) -benzoylamino] benzamide;
[602] 5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-2- [4- (2-oxo-2H-pyridin-1-yl) -benzoylamino] benzamide;
[603] 3-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[604] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[605] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[606] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[607] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[608] 3-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[609] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[610] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[611] 3-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[612] 3-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[613] 3-chloro-N- (2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[614] 3-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[615] 3-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[616] 3-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[617] 3-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
[618] 3-chloro-N- (3-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} tetrahydro-2H-pyran-4-yl) -1H-indole-6-carboxamide ;
[619] 3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} tetrahydro-2H-pyran-3-yl) -1H-indole-6-carboxamide ;
[620] 3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} piperidin-3-yl) -1H-indole-6-carboxamide;
[621] 3-chloro-N- (3-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} piperidin-4-yl) -1H-indole-6-carboxamide;
[622] 3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} pyrrolidin-3-yl) -1H-indole-6-carboxamide;
[623] 3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} tetrahydrofuran-3-yl) -1H-indole-6-carboxamide;
[624] 3-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -1H-indole-6-carboxamide;
[625] 3-chloro-N- (1,1-dioxido-4-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} tetrahydro-3-thienyl) -1H-indole -6-carboxamide;
[626] 3-chloro-N- (1,1-dioxido-4-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} tetrahydro-2H-thiopyran-3-yl) -1H-indole-6-carboxamide;
[627] 3-chloro-N- (1,1-dioxido-3-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} tetrahydro-2H-thiopyran-4-yl) -1H-indole-6-carboxamide;
[628] N- (2-{[(3-chloro-1H-indol-6-yl) sulfonyl] methyl} cyclohexyl) -4- (2-oxopiperidin-1-yl) benzamide;
[629] N- (2-{[(6-chloro-2-naphthyl) sulfonyl] methyl} cyclohexyl) -4- (2-oxopiperidin-1-yl) benzamide;
[630] 5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[631] 5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophen-2-carboxamide;
[632] 5-chloro-N- (2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[633] 5-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[634] 5-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[635] 5-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[636] 5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) thiophene-2-carboxamide;
[637] 5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thiophene-2-carboxamide;
[638] 5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[639] 5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[640] 5-chloro-N- (2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[641] 5-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[642] 5-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[643] 5-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
[644] 5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -1H-indole-2-carboxamide;
[645] 5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) -1H-indole-2-carboxamide;
[646] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
[647] 6-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
[648] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
[649] 6-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
[650] 6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
[651] 6-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
[652] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) -2-naphtamide;
[653] 6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -2-naphtamide;
[654] 2-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
[655] 2-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
[656] 2-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
[657] 2-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
[658] 2-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
[659] 2-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} pentyl) quinoline-6-carboxamide;
[660] 2-chloro-N- (2-{[4- (2-oxopyridin-1-yl) benzoyl] amino} cyclopentyl) quinoline-6-carboxamide;
[661] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
[662] 6-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
[663] 6-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
[664] 6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
[665] 6-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
[666] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) -1-benzothiophene-2-carboxamide;
[667] 6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -1-benzothiophene-2-carboxamide;
[668] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
[669] 6-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
[670] 6-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-car Boxamide;
[671] 6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
[672] 6-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
[673] 6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thieno [2,3-b] pyridine-2-carboxamide;
[674] 6-chloro-N- (2-{[4- (2-oxopiperidin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thieno [2,3-b] pyridine-2-carbox amides;
[675] 5-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[676] 5-methoxy-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[677] 5-methoxy-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[678] 5-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[679] 5-methoxy-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[680] 5-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thiophene-2-carboxamide;
[681] 5-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
[682] 4-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) benzamide;
[683] 4-methoxy-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) benzamide;
[684] 4-methoxy-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) benzamide;
[685] 4-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) benzamide;
[686] 4-methoxy-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) benzamide;
[687] 4-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) benzamide;
[688] Novel compounds or pharmaceutically acceptable salt forms thereof selected from the group of 4-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) benzamide It provides a phosphorus compound.
[689] In a preferred embodiment, when ring M is 1,2 substituted by M ₄ and P ₄ , there is no G ₁ or Z.
[690] In another preferred embodiment, ring M is 1,2 substituted by M ₄ and P ₄ and G ₁ is (CR ³ R ^3a ) _u NR ³ (CR ³ R ^3a ) _w (u + w is 1, 2, 3 or 4), (CR ³ R ^3a ) _u C (O) NR ³ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ³ C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) NR ³ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ NR ³ (CR ³ R ^3a ) _w or (CR ³ R ^3a ) _u NR ³ When S (O) ₂ (CR ³ R ^3a ) _w ;
[691] Z is (CH ₂ ) NR ³ , NR ³ (CH ₂ ), (CH ₂ ) NR ³ (CH ₂ ), (CH ₂ ) (CH ₂ ) NR ³ , NR ³ (CH ₂ ) (CH ₂ ), ( CH ₂ ) _q C (O) NR ³ (CH ₂ ) _q1 , (CH ₂ ) _q NR ³ C (O) (CH ₂ ) _q1 , (CH ₂ ) _q SO ₂ NR ³ (CH ₂ ) _q1 or (CH ₂ ) _q Other than NR ³ SO ₂ (CH ₂ ) _q1 .
[692] In another preferred embodiment, ring M is substituted 1,2 by M ₄ and P ₄ , and Z is (CH ₂ ) NR ³ , NR ³ (CH ₂ ), (CH ₂ ) NR ³ (CH ₂ ), ( CH ₂ ) (CH ₂ ) NR ³ , NR ³ (CH ₂ ) (CH ₂ ), (CH ₂ ) _q C (O) NR ³ (CH ₂ ) _q1 , (CH ₂ ) _q NR ³ C (O) ( CH ₂ ) _q1 , (CH ₂ ) _q SO ₂ NR ³ (CH ₂ ) _q1 or (CH ₂ ) _q NR ³ SO ₂ (CH ₂ ) _q1 ;
[693] G ₁ is (CR ³ R ^3a ) _u NR ³ (CR ³ R ^3a ) _w (u + w is 1, 2, 3 or 4), (CR ³ R ^3a ) _u C (O) NR ³ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ³ C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) NR ³ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ NR ³ (CR ³ R ^3a ) _w or (CR ³ R ^3a ) _u NR ³ S (O) ₂ (CR ³ R ^3a ) _w .
[694] In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount in the form of a compound of the invention or a pharmaceutically acceptable salt thereof.
[695] In another embodiment, the present invention provides a novel method for treating thromboembolic disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. .
[696] In another preferred embodiment, the invention provides a novel method wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders and thromboembolic disorders in the atrioventricular chamber.
[697] In another preferred embodiment, the present invention is directed to angina in which thromboembolic disorders are unstable, acute coronary syndrome, primary myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral obstructive artery disease, venous thrombosis, Deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and (a) artificial valves or other implants, (b) indwelling catheter, (c) stent, (( d) cardiopulmonary bypass, (e) hemodialysis, or (f) thrombosis resulting from thrombosis resulting from other treatments in which the blood is exposed to an artificial surface that promotes thrombosis.
[698] In another embodiment, the present invention provides a method of treating a patient in need of treatment of a thromboembolic disorder comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt form thereof for the treatment of a thromboembolic disorder. Provide a new method
[699] In another embodiment, the present invention provides a novel method comprising administering a compound of the invention or a pharmaceutically acceptable salt form thereof in an effective amount for the treatment of a thromboembolic disorder.
[700] In another embodiment, the present invention provides a novel method of treating thromboembolic disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first therapeutic agent is provided herein. And a pharmaceutically acceptable salt thereof, and the second therapeutic agent is one or more agents selected from factor 2 Xa inhibitors, anticoagulants, antiplatelets, thrombin inhibitors, thrombolytics and fibrinolytics.
[701] In another preferred embodiment, the invention provides that the second therapeutic agent is warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrovanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, metha Phenamate, doxycam, diclofenac, sulfinpyrazone, pyroxicam, ticlopidine, clopidogrel, tyropiban, eptifivatid, abciximab, melagatran, disulfatohirin, tissue plasminogen activation First, a novel method is provided wherein the modified tissue plasminogen activator, anistreplace, urokinase and one or more agents selected from streptokinase.
[702] In another preferred embodiment, the present invention provides a novel method wherein the second therapeutic agent is at least one antiplatelet agent.
[703] In another preferred embodiment, the present invention provides a novel method wherein the antiplatelet agents are aspirin and clopidogrel.
[704] In another preferred embodiment, the present invention provides a novel method wherein the antiplatelet agent is clopidogrel.
[705] In another embodiment, the present invention
[706] (a) a first container;
[707] (b) a pharmaceutical composition located in a first container, wherein the composition comprises a first therapeutic agent comprising a compound of the invention or a pharmaceutically acceptable salt thereof; And
[708] (c) a package attachment specifying that the pharmaceutical composition can be used for the treatment of thromboembolic disorders.
[709] It provides a new product comprising a.
[710] In another preferred embodiment, the present invention
[711] (d) providing a new product further comprising a second container,
[712] Wherein elements (a) and (b) are located within the second container and element (c) is located inside or outside the second container.
[713] In another embodiment, the present invention
[714] (a) a first container;
[715] (b) a pharmaceutical composition located in a first container, wherein the composition comprises a first therapeutic agent comprising a compound of the invention or a pharmaceutically acceptable salt thereof; And
[716] (c) a package attachment specifying that the pharmaceutical composition may be used with a second therapeutic agent for the treatment of thromboembolic disorders.
[717] It provides a new product comprising a.
[718] In another preferred embodiment, the present invention
[719] (d) providing a new product further comprising a second container,
[720] Wherein elements (a) and (b) are located within the second container and element (c) is located inside or outside the second container.
[721] In another embodiment, the present invention provides novel compounds as described above for use in therapy.
[722] In another embodiment, the present invention provides the use of a novel compound as described above for the manufacture of a medicament for the treatment of a thromboembolic disorder.
[723] The invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention includes all combinations of the preferred aspects of the invention mentioned herein. It is understood that any and all embodiments of the invention may be accommodated in conjunction with any other embodiment or embodiments to describe further more preferred embodiments. It is also understood that each individual element of the preferred embodiment is individually accepted as its own independent preferred embodiment. In addition, any element of the embodiment can be any and all from any embodiment. By combining with other elements it is meant to describe further embodiments.
[724] <Definition>
[725] The compounds described herein can have an asymmetric center. Compounds of the invention containing asymmetrically substituted atoms can be isolated either optically active or racemic. Methods of preparing optically active forms, for example by cleavage of racemic forms or synthesis from optically active starting materials, are well known in the art. Numerous geometric isomers such as olefins, C═N double bonds and the like may also be present in the compounds described herein, and all such stable isomers are included in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated in the form of mixtures or isolated isomers of isomers. Unless specific stereochemical or isomeric forms are specifically mentioned, all chiral, diastereomeric, racemic and all geometric isomeric forms of the structure are intended. All methods used to prepare the compounds of the invention and the intermediates produced therein are contemplated as part of the invention. All tautomers of the compounds shown or described are also contemplated as part of the present invention.
[726] The molecular weight of the compounds of the present invention is preferably less than about 500, 550, 600, 650, 700, 750 or 800 grams per mole. The molecular weight is preferably less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.
[727] As used herein, the term "substituted" means that any one or more hydrogens on a specified atom are substituted with a group selected from the groups mentioned, provided that the compound does not exceed the general valence of the specified atom and that a substitutionally stable compound is obtained. . When the substituent is keto (ie = 0), two hydrogens on the atom are substituted. Keto substituents are not present on the aromatic moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (eg, C═C, C═N or N═N). In general, the present invention does not include groups such as N-halo, S (O) H and SO ₂ H.
[728] The present invention includes all isotopes of atoms found in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of non-limiting general example, the isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
[729] If any variable (eg R ⁶ ) appears one or more times in any constituent or formula of a compound, the definition in each case is independent of the definition in each other case. Thus, for example, when a group is shown to be substituted with 0 to 2 R ⁶ , the group may be optionally substituted with up to 2 R ⁶ , in which case R ⁶ is independently selected from the definition of R ⁶ . In addition, combinations of substituents and / or variables may only be tolerated if stable combinations result.
[730] If a bond to a substituent is shown to intersect a bond connecting two atoms in the ring, such substituent may be attached to any atom on the ring. If such substituents are listed and do not represent atoms bonded to the rest of the compound of a given formula, then these substituents may be bonded via any atom in the substituent. Combinations of substituents and / or variables can be tolerated only if stable compounds are obtained by such combinations.
[731] If an amine is present on the compound of the present invention, the amine can be converted to the amine N-oxide by treatment with an oxidizing agent (eg, MCPBA and / or hydrogen peroxide) to produce another compound of the present invention. Accordingly, all the amines shown and claimed are considered to include both the amines shown and their N-oxide (N-O) derivatives.
[732] As used herein, "alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C _1-6 alkyl includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl groups. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl and s-pentyl. "Haloalkyl" is a branch substituted with one or more halogens (eg -C _v F _w , where v is 1 to 3 and w is 1 to (2v + 1)) having the specified number of carbon atoms It includes both chain and straight chain saturated aliphatic hydrocarbon groups. Non-limiting examples of haloalkyl include trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl. "Alkoxy" refers to an alkyl group as defined above having the stated number of carbon atoms attached via an oxygen bridge. C _1-6 alkoxy includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and s-pentoxy . "Cycloalkyl" includes saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. C _3-7 cycloalkyl includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. "Alkenyl" includes one or more unsaturated carbon-carbon bonds which may be found at any stable point along the hydrocarbon chain and chain in a straight or branched chain arrangement, for example ethenyl and propenyl. C _2-6 alkenyl includes C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenyl groups. "Alkynyl" includes one or more triple carbon-carbon bonds that may be found at any stable point along the hydrocarbon chain and chain in a straight or branched chain arrangement, for example ethynyl and propynyl. C _2-6 alkynyl includes C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkynyl groups.
[733] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo and iodo; "Counterions" are used to denote negatively charged small species such as chlorides, bromide, hydroxides, acetates and sulfates.
[734] As used herein, a “carbocycle” or “carbocyclic moiety” is any stable 3, 4, 5, 6 or 7 membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13 Means a bicyclic or tricyclic ring, either of which may be saturated, partially unsaturated or unsaturated (aromatic). Non-limiting examples of such carbocycles include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cycloocta Tenyl, cyclooctadienyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naph Butyl, indanyl, adamantyl and tetrahydronaphthyl. As indicated above, crosslinked rings are also included in the definition of carbocycles (eg [2.2.2] bicyclooctane). Crosslinked rings are observed when one or more carbon atoms are connected to two nonadjacent carbon atoms. Preferred crosslinking is 1 or 2 carbon atoms. Note that crosslinking always converts monocyclic rings into tricyclic rings. If the ring is crosslinked, the substituents listed for the ring may also be present on the crosslinking phase.
[735] As used herein, the term “heterocycle” or “heterocyclic group” is saturated, partially unsaturated or unsaturated (aromatic), 1, independently selected from the group consisting of carbon atoms, and N, O and S, Stable 5, 6 or 7 membered monocyclic or bicyclic or 7 consisting of 2, 3 or 4 ring heteroatoms and wherein any heterocyclic ring as defined above comprises any bicyclic group fused to a benzene ring , 8, 9 or 10 membered bicyclic heterocyclic ring. Nitrogen and sulfur heteroatoms may be optionally oxidized (ie, N → O and S (O) _p ). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents if defined). The heterocyclic ring can be attached to a group suspended from any heteroatom or carbon atom to obtain a stable structure. Heterocyclic rings as defined herein may be substituted on carbon or nitrogen atoms when the resulting compound is stable. Nitrogen in a heterocycle may optionally be quaternized. If the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle is 1 or less. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" refers to a stable 5, consisting of 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of carbon atoms and N, O and S. 6 or 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic aromatic ring. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents if defined). Nitrogen and sulfur heteroatoms may be optionally oxidized (ie, N → O and S (O) _p ). It should be noted that the total number of S and O in the aromatic heterocycle is 1 or less. Crosslinked rings are also included in the definition of heterocycle. Crosslinked rings are observed when one or more atoms (ie, C, O, N or S) connect two nonadjacent carbon or nitrogen atoms. Non-limiting examples of preferred crosslinks include one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and carbon-nitrogen groups. Note that crosslinking always converts monocyclic rings into tricyclic rings. If the ring is crosslinked, the substituents listed for the ring may also be present on the crosslinking phase.
[736] Non-limiting examples of heterocycles include acridinyl, azosinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl , Benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzamidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromamanyl, chromaenyl, cinnaolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H- Indazolyl, indolenyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolinyl, isoquinolin Neyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadi Zolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, auxin Dolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl , Piperonyl, putridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyrimidimidazole, pyridothiazole, pyridinyl , Pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinucridinyl, tetrahydrofuranyl , Tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1 , 2,5-thiadiazolyl, 1,3,4-thiadia Reel, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl , 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. For example, fused rings and spiro compounds containing such heterocycles are also included.
[737] As used herein, the phrase “pharmaceutically acceptable” is intended for use in contact with tissues of humans and animals, with appropriate benefit / risk ratios, without undue toxicity, irritation, allergic reactions, or other problems or complications within the scope of normal medical judgment. Suitable compounds, materials, compositions and / or dosage forms.
[738] As used herein, “pharmaceutically acceptable salts” means derivatives of the compounds described, wherein the parent compound is modified by forming acid or base salts thereof. Non-limiting examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic residues such as amines; Alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; And organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanic acid, 2 Salts prepared from acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isetionic acid and the like.
[739] Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, these salts are capable of stoichiometric free acid or base forms of these compounds in water or organic solvents, or mixtures thereof (typically non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile). It can be prepared by reacting with a suitable base or acid of Ron. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418.
[740] Since prodrugs are known to enhance various desirable properties of pharmaceuticals (eg, solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be delivered in prodrug form. Accordingly, the present invention includes prodrugs of the presently claimed compounds, methods of delivering them, and compositions containing them. "Prodrug" includes any covalently bound carrier that releases the active parent drug of the present invention in vivo when the prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying the functional groups present in the compound such that the modification is cleaved into the parent compound by universal manipulation or in vivo. Prodrugs include a compound of the invention, wherein a hydroxy, amino or sulfhydryl group, wherein the prodrug is cleaved when the prodrug of the invention is administered to a mammalian subject, results in free hydroxyl, free amino or free sulf It is coupled to any group to form each of the drill groups. Non-limiting examples of prodrugs include acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
[741] "Stable compound" and "stable structure" are meant to represent a compound that is strong enough to withstand the formulation of an isolated and efficacious therapeutic agent to a degree of purity from the reaction mixture. It is preferred that the presently mentioned compounds do not contain N-halo, S (O) ₂ H or S (O) H groups.
[742] "Substituted" indicates that at least one hydrogen on the atom indicated in the expression using "substituted" is replaced by a group selected from said group (s), provided that the substitution does not exceed the general valence of the indicated atom, A stable compound is obtained by this. If the substituent is a keto (ie ═O) group, two hydrogens on the atom are substituted.
[743] As used herein, “treat” or “treatment” includes the treatment of a disease state of a mammal, in particular a human, comprising (a) a condition prone to suffering from a mammal, in particular a disease state but not yet diagnosed with the disease. To prevent the development of a disease state in a mammal of; (b) inhibit the disease state, ie, stop the onset of the disease; (c) alleviating the disease state, ie regressing the disease state.
[744] A "therapeutically effective amount" includes an amount of a compound of the invention that is effective when administered alone or in combination with inhibitory factor Xa. A "therapeutically effective amount" also includes the amount of the claimed compound combination effective to inhibit Factor Xa. The combination of compounds is preferably a synergistic combination. See, eg, Chou and Talalay, Adv. Enzyme. Regul. 1984, 22: 27-55, the synergistic effect of which is greater when the compound is administered in combination (in this case inhibition of factor Xa) than the additive effect of the compound when administered alone as a single agent. Appears in large cases. In general, the synergistic effect is most clearly explained below the optimal concentration of the compound. The synergistic effect may increase the antithrombotic effect, or some other beneficial effect of the combination compared to the individual components, in terms of low cytotoxicity.
[745] <Synthesis>
[746] The compounds of the present invention can be prepared by a number of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below together with the synthesis methods known in the field of synthetic organic chemistry, or by their modifications that can be appreciated by those skilled in the art. Non-limiting examples of preferred methods include the following methods. The reaction is carried out in a solvent suitable for the modifications that are suitable and effective for the reagents and materials used. It will be understood by those skilled in the art of organic synthesis that the functional groups present on the molecule must conform to the proposed modifications. This sometimes requires the judgment of modifying the order of the synthetic steps or selecting one particular scheme over another in order to obtain the desired compound of the present invention.
[747] Another major consideration in planning any synthetic route in this field will also be appreciated as a wise choice of protecting groups used for the protection of reactive functional groups present in the compounds described herein. An authoritative technique explaining many alternatives to skilled professionals is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated by reference in their entirety.
[748] Synthesis of the compounds of the present invention, including the use of intermediates A-B, is accomplished through standard methods known in the art. A general route involving this type of method is outlined in Scheme 1 below.
[749]
[750] A-B intermediates can be obtained via the Ullman or Buchwald method outlined in the following scheme.
[751]
[752] Intermediate AB, in which the B group contains an oxidizable group, can be obtained by oxidation, for example by oxidizing S to S and SO ₂ . Pyridone analogs can also be prepared via the Ulman method. The urea analogs shown in Scheme 3 below can also be prepared by applying Ullman coupling.
[753]
[754] Piperidone A-B analogs can be prepared via the method outlined in Scheme 4 below.
[755]
[756] Aminopyridyl and aminopyrimidyl A-B analogs (see Structural Formula below) can also be prepared using routes similar to Schemes 2-4.
[757]
[758] The piperidone A-B intermediates shown above can be further treated by a number of methods known to those skilled in the art (see, eg, Scheme 5) to provide other compounds of the present invention.
[759]
[760] Another A-B intermediate can be synthesized by the chemical handwriting of the amino functional groups of the compounds described above (see Scheme 6).
[761]
[762] Other possible A-B intermediates can be synthesized by the method shown in Scheme 7. Iodo-ester intermediates can be treated with the Ulmann and / or Buchwald coupling method to prepare A-B intermediates. The intermediate may again be identified through the Arndt Eistert method to provide another A-B intermediate. Alternatively, the ester functionality can be reduced to alcohol and converted back to various A-B intermediates by methods known to those skilled in the art.
[763]
[764] Non-aromatic intermediates shown in Scheme 8 can be synthesized via methods known to those skilled in the art. These intermediates may also be further treated to incorporate R ^4a via the methods described above.
[765]
[766] Another non-aromatic intermediate can be synthesized via methods known to those skilled in the art (see, eg, Scheme 9). These intermediates may also be further treated to incorporate R ^4a via the methods described above.
[767]
[768] Schemes 2 to 9 describe methods for preparing A-B intermediates and then coupling with other suitable intermediates to form compounds of the present invention. Compounds of the invention are provided when the halogenated intermediates depicted in the schemes shown above are treated with the Ulmann or Buchwald-Goldman coupling methods.
[769] If the intermediate of the invention has a reactive group, Ullman or Buchwald-Goldman coupling is generally carried out in the early stages of the synthesis. The intermediate may then be modified by one skilled in the art to provide a compound of the present invention (see Scheme 10).
[770]
[771] Compounds of the invention can also be prepared by ulman or Buchwald coupling of compounds of the invention wherein the B subunit of the A-B substituent is a substituted cyclic amide.
[772]
[773] Likewise, compounds of the invention wherein B is a cyclic urea can also be prepared via the Ullman or Buchwald method described in Scheme 12. Further processing by those skilled in the art can provide the compounds of the present invention.
[774]
[775] Another approach to a compound of the present invention wherein the B subunit of the A-B groups of Formula I is a cycle is shown in Scheme 13. Further processing by those skilled in the art can provide the compounds of the present invention.
[776]
[777] Schemes 2 to 13 describe methods for preparing the A-B moieties of the present invention and methods for coupling the compounds of the present invention. In the above scheme, the Z groups may or may not be present depending on how the A-B groups are coupled. The coupling site of the A-B group can be substituted by (a) introducing a Z or M group, (b) becoming a Z group, or (c) incorporated into ring M.
[778] The remaining portion of _{GG 1 -PMZ, GG 1 -MPZ,} GG 1 -PM, GG 1 -MP, GG 1 -MZ and GG ₁ -M of the compounds of the invention may be prepared using methods known to those skilled in the art . All of the following patents and publications are incorporated herein by reference. For compounds in which ring P is absent and ring M is a 5, 6 or 7 membered ring, those skilled in the art will be aware of US 5,939,418, US 5,925,635, US 6,057,342, US 6,187,797, US 6,020,357, US 6,060,491, US 5,998,424, US 6,191,159, W0 98/57951, W0 99/32454, WO 00/039108, WO 00/059902, WO 01/32628, W0 01/005785, USSN 09 / 892,319, USSN 60 / 313,552, USSN 60 / 246,108, and USSN 09 / 887,936. In the case of compounds in which ring P is fused to ring M (ie, a bicyclic moiety is present), those skilled in the art will appreciate WO 00/39131, for starting materials and intermediates to which the B and / or AB groups of the present invention may be coupled. See USSN 60 / 246,125, USSN 60 / 292,665, USSN 60 / 278,173, USSN 60 / 278,165, and USSN 09 / 887,850.
[779] For compounds wherein G is a ring substituted with a basic moiety, those skilled in the art will appreciate that the GG ₁ -PMZ, GG ₁ -MPZ, GG ₁ -PMZA and / or of the invention to which the B and / or AB groups of the invention may be coupled ) US 5,939,418, US 5,925,635, US 6,057,342, US 6,187,797, US 6,020,357, US 6,060,491, US 6,191,159, W0 98/57951, W0 99/32454, WO 00/059902, for starting materials and intermediates that form GG ₁ -MPZA groups See WO 01/32628, WO 00/39131, USSN 09 / 892,319, USSN 60 / 313,552, USSN 60 / 246,108, USSN 60 / 246,125, USSN 60 / 292,665, USSN 60 / 278,173 and USSN 60 / 278,165. For compounds wherein G is a ring substituted with a non-basic group, those skilled in the art will appreciate that the G-G1-PMZ, G-G1-MPZ, GG1-PMZA of the present invention to which the B and / or AB groups of the present invention may be coupled and (Or) US 5,998,424, WO00 / 39131, WO00 / 059902, W001 / 32628, USSN 09 / 892,319, USSN 60 / 313,552, USSN 60 / 246,108, USSN 60 / for starting materials and intermediates that form G-G1-MPZA groups See 246,125, USSN 60 / 292,665, USSN 60 / 278,173 and USSN 60 / 278,165. In the case of the G moiety is bicyclic compounds, those skilled in the art of the present invention B and (or) of the invention, which groups can be coupled AB _{GG 1 -PMZ, GG 1 -MPZ,} GG 1 -PMZA and (or) ₁ GG W0 98/57951 WO 00/039108, WO 00/39131, USSN 09 / 892,319, USSN 60 / 313,552, USSN 60 / 246,108, USSN 60 / 246,125, USSN 60 / 292,665, for starting materials and intermediates forming the MPZA group. See USSN 60 / 278,173 and USSN 60 / 278,165. In the case of compounds in which A is indolin or similar bicyclic, those skilled in the art can refer to WO 01/005785 for starting materials and intermediates in which the B groups of the invention can be coupled or the AB groups of the invention can be formed. Scheme 14 depicts some of the numerous pyrrole intermediates that can be used to prepare compounds of the invention, where R ^z is the point of attachment of ZAB and can be a group H, a protecting group, Z or a group that can be modified to ZA, Z, ZA or A. . Such intermediates are described in the above patents and publications.
[780]
[781] Scheme 15 depicts some of the various imidazole, triazole and tetrazole intermediates that may be used to prepare the compounds of the present invention. These intermediates are described in the above patents and publications. In Scheme 15, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic acid ester, sulfonyl chloride, ester, acid or halide. In Scheme 15, U is an aldehyde, ester, acid, amide, amino, thio, hydroxy, sulfonic acid, sulfonic acid ester, sulfonyl chloride or methylene halide.
[782]
[783] Scheme 16 illustrates some of the numerous pyrazole intermediates that can be used to prepare the compounds of the present invention. These intermediates are described in the above patents and publications.
[784]
[785] Scheme 17 depicts some of the numerous oxazole, thiazole, isoxazole, oxadiazole and thiadiazole intermediates that can be used to prepare the compounds of the present invention. These intermediates are described in the above patents and publications. In Scheme 17, V is nitro, amino, ester or acid.
[786]
[787] Scheme 18 depicts two intermediates useful for preparing compounds of the invention wherein ring P is fused to ring M. Scheme 18 also illustrates a number of bicyclic compounds that can be prepared from these intermediates or derivatives thereof. These intermediates and variants thereof are described in the above patents and publications.
[788]
[789] Scheme 19 depicts another intermediate useful for preparing compounds of the invention wherein ring P is fused to ring M. Scheme 19 also depicts a number of bicyclic compounds that can be prepared from such intermediates or derivatives thereof (eg, the corresponding cyclohexenone). In Scheme 19, U is OH or morpholine and V is H or C (O) R ^1a . The intermediates, derivatives thereof and variants thereof are described in the above patents and publications.
[790]
[791] Scheme 20 shows another intermediate useful for preparing compounds of the invention wherein ring P is fused to ring M. Scheme 20 also depicts a number of bicyclic compounds that may be prepared from such intermediates or derivatives thereof. Such intermediates, derivatives thereof and variants thereof are described in the above patents and publications.
[792]
[793] Scheme 21 depicts a number of other bicyclic rings that are considered part of the ring P-M, which is a bicyclic group of the present invention. Scheme 21 also describes a method for converting the indicated ring to a compound of the present invention. Those skilled in the art will recognize that the method can be applied to other heterobicyclics not shown.
[794]
[795] Another useful pyrazole intermediate in which G ₁ is an amide is illustrated in Scheme 22. Compounds of the present invention wherein the G ₁ group is not an amide may be readily treated with other linker functionalities according to methods known in the art, including those outlined in W0 98/28269 and W0 98/28282, the contents of which are incorporated herein by reference. Can be.
[796]
[797] Scheme 23 depicts some of the numerous six-membered aromatic ring intermediates that may be used to prepare the compounds of the present invention. Such intermediates are described in the patents and publications. In Scheme 23, V is a nitro, protected sulfonamide or ester group and is a precursor of group Z of the present invention.
[798]
[799] The benzo-fused dihydro-pyridone intermediates of the present invention can be prepared from readily available starting materials as shown in Scheme 24.
[800]
[801] Other benzo-bicyclic compounds can be obtained as shown in Schemes 25 and 26.
[802]
[803]
[804] Intermediates A-B of the invention, wherein A is indolin, can be prepared as shown in Scheme 27. Intermediates of this type can then be attached to the rest of the desired compound as described above. Alternatively, indolin can be attached to the other half of the desired compound before forming the lactam ring.
[805]
[806] Compounds of the invention wherein Ring P is absent and Ring M is a 6-membered ring can be obtained as shown in Scheme 28. Compounds of this type can be obtained from commercially available anthranilic acid or anthranilates thereof. Anthranilic acid or a nitro precursor thereof may be coupled to a suitable B-A-V, wherein V is an amino functional group, in the presence of a base such as triethyl amine, pyridine or DMAP. Compounds of the invention should be provided with suitable acid chlorides or subsequent coupling with aniline or aminopyridyl.
[807]
[808] In a similar manner, anthranilate can be coupled with a suitable amine, aniline or aminopyrimidyl to form the corresponding benzamide. Benzamide can then be coupled with a suitable B-A-V where V is an acid chloride derivative, alkyl halide or sulfonyl chloride to provide further compounds of the present invention (see Scheme 29).
[809]
[810] In addition, commercially available ring M derivatives bearing nitro and amino functionalities can be derivatized as indicated above to provide bisamide analogs. In this case, an intermediate is obtained by coupling an aniline with BAV, where V is an acid chloride, sulfonyl chloride or alkyl halide, in which the appropriate GU in the presence of a suitable base, such as DMAP, wherein U is an acid Chloride or alkyl halide). The order of adding B-A-V and G-U may be reversed to obtain other compounds of the present invention (see Scheme 30).
[811]
[812] It should be noted that modifications to the synthesis described above can be used to employ coupling intermediates such as iodo-A-V, where V is an acid chloride, amino, alkyl halide or sulfonyl chloride. It can be coupled back to the G-U group. The iodo intermediate can then be treated by the Ullmann or Buchwald coupling method as described above to provide the compounds of the present invention. In addition, the iodo intermediates may be converted to amines via standard Buchwald conditions to provide the corresponding anilino intermediates. It can in turn be coupled as described above to provide the compounds of the invention.
[813] When M is a non-aromatic ring, the compounds of the invention of formula (I) can be synthesized by one skilled in the art using similar methods as described above. One of the diastereomers of the compound of formula (I) may exhibit better activity compared to the other. Accordingly, the following stereochemistry is considered part of the present invention.
[814]
[815] If necessary, separation of the racemic material can be carried out in enantiomeric form or by using a chiral column or enantiomers using a splitting agent such as camphoric acid chloride as in Wilen, SH Tables of Resolving Agents and Optical Resolutions 1972, 308 pp. By cleavage using pure acids and bases. Chiral compounds of formula (I) can also be used with chiral catalysts or chiral ligands (e.g. Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431) or other known to those skilled in the art of asymmetric synthesis. It can be synthesized directly using enantio- and diastereo-selective reactions and reagents.
[816] <Usability>
[817] The compounds of the present invention are inhibitors of factor Xa and are useful as anticoagulants for the treatment or prophylaxis of thromboembolic disorders (ie, factor Xa-related disorders) in mammals. In general, thromboembolic disorders are circulatory diseases caused by clots (ie, diseases including fibrin formation, platelet activation, and / or platelet aggregation). As used herein, the term "thromboembolic disorder" includes arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers. The term "thromboembolic disorder" as used herein refers to unstable angina or other acute coronary syndrome, primary or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral obstructive arterial disease, venous thrombosis, deep vein Thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and (a) artificial valves or other implants, (b) indwelling catheters, (c) stents, (d) Cardiopulmonary bypass, (e) hemodialysis, or (f) certain disorders selected from, but not limited to, thrombosis arising from other treatments in which blood is exposed to an artificial surface that promotes thrombosis. Note that thrombosis includes closure (eg after bypass) and reclosure (eg during or after percutaneous transvascular dilation). Thromboembolic disorders arise from symptoms including, but not limited to, atherosclerosis, surgical or surgical complications, sustained immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, medication or hormone effects, and pregnancy complications Can be. The anticoagulant effect of the compounds of the invention is believed to be due to the inhibition of factor Xa or thrombin.
[818] The effect of the compounds of the invention as inhibitors of Factor Xa is measured using purified human factor Xa and synthetic substrates. The factor Xa hydrolysis rate of the chromogenic substrate S2222 (Diapharma / Chromogenix, West Chester, OH) is measured both in the absence and presence of the compounds of the present invention. Hydrolysis of the substrate leads to the release of pNA, which is monitored spectrophotometrically by measuring the increase in absorbance at 405 nm. A decrease in the rate of absorbance change at 405 nm in the presence of an inhibitor indicates enzyme inhibition. The result of this analysis is represented by the inhibition constant K _i .
[819] Factor Xa measurements are performed in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl and 0.5% PEG 8000. Michaelis constant K _m for substrate hydrolysis is measured at 25 ° C. using the method of Lineweaver and Burk. K _i values are measured by reacting 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) with a substrate (0.20 mM to 1 mM) in the presence of an inhibitor. The reaction proceeds for 30 minutes and the rate (rate of absorbance change over time) is measured in a time frame of 25-30 minutes. Calculate the K _i value using the following relationship:
[820]
[821] In the formula,
[822] v _o is the speed of the control in the absence of the inhibitor;
[823] v _s is the rate in the presence of the inhibitor;
[824] I is the concentration of the inhibitor;
[825] K _i is the dissociation constant of the enzyme: inhibitor complex;
[826] S is the concentration of the substrate;
[827] K _m is the Michaelis constant.
[828] Compounds tested in this assay are considered to be active when shown as Ki <10 μM. Preferred compounds of the invention are K _i '≦ 1 μM. More preferred compounds of the invention are K _i '≦ 0.1 μM. Even more preferred compounds of the invention are K _i '≦ 0.01 μM. Even more preferred compounds of the invention are K _i ≦ 0.001 μM. Using the methods described above, it was found that many of the compounds of the present invention exhibit K _i '≦ 10 μM, thereby confirming the usefulness of the compounds of the present invention as effective Xa inhibitors.
[829] The antithrombotic effect of the compounds of the present invention can be measured in a rabbit arterial-vein (AV) short circuit thrombosis model. In this model, an anesthetized rabbit was used with a mixture of 2 to 3 kg body weight of xylazine (10 mg / kg intramuscular) and ketamine (50 mg / kg intramuscular). A saline-filled AV short device was connected between the femoral artery and the femoral venous cannula. The AV shorting device consisted of a 6 cm Tygon rubber tube containing silk threads. Blood will flow from the femoral artery to the femoral vein via the AV-short. Exposing flowing blood to silk threads induces significant thrombus formation. After 40 minutes, the shorts were separated and the silk threads covered with blood clots were weighed. The test drug or vehicle will be given (intravenous, intraperitoneal, subcutaneous or oral administration) prior to the commencement of the AV paragraph. Inhibition rate of thrombus formation was measured for each treatment group. ID ₅₀ values (dose that inhibits thrombus formation 50%) are calculated by linear regression.
[830] The compounds of the invention are also useful as inhibitors of serine proteases, in particular human thrombin, factor VIIa, factor IXa, factor XIa, urokinase, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds appear to be used for the prevention or treatment of physiological reactions, blood coagulation and inflammation catalyzed by the enzyme group. In particular, the compounds have utility as drugs for the treatment of diseases resulting from elevated thrombin activity, such as myocardial infarction, and as reagents used as anticoagulants in the treatment of blood to plasma for diagnostic and other commercial purposes.
[831] Some compounds of the present invention have been shown to act directly as inhibitors of the serine protease thrombin by the ability to inhibit degradation of small molecule substrates by thrombin in purified systems. In vitro inhibition constants are described in Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990). In this assay, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture reduces absorbance, indicating thrombin inhibition. Incubate human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer (pH 7.5), 0.20 M NaCl, and 0.5% PEG 6000 at various substrate concentrations ranging from 0.20 to 0.02 mM. It was. After incubation for 25-30 minutes, thrombin activity was analyzed by monitoring the rate of absorbance increase at 405 nm resulting from substrate hydrolysis. Inhibition constants are derived from an inverse plot of reaction rate as a function of substrate concentration using standard methods of Reineweaver and Burke. Using the methods described above, some compounds of the present invention were evaluated and observed that K _i showed less than 10 μM, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.
[832] The compound was administered to the mammal in a therapeutically effective amount. A "therapeutically effective amount" means that when the compound of the present invention is administered to a mammal alone or in combination with additional therapeutic agents, the amount of the compound is effective for treating thromboembolic symptoms or diseases.
[833] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. "Administered together" or "combination therapy" means that the compound of the invention and one or more additional therapeutic agents are administered simultaneously to the mammal to be treated. When administered together, these components may be administered sequentially, in any order, at the same time or at different time points. Thus, each component may be administered separately, but may be administered at a time close enough to provide the desired therapeutic effect.
[834] Additional therapeutic agents include other anticoagulants or anticoagulants, anti-platelet or platelet inhibitors, thrombin inhibitors, thrombolytic or fibrinolytic agents, antiarrhythmics, antihypertensives, calcium channel blockers (L-type and T-type), cardiac glycosides, diuretics , Corticosteroid receptor antagonists, phosphodiesterase inhibitors, cholesterol / lipid lowering and lipid profile therapies, antidiabetics, antidepressants, anti-inflammatory agents (steroids and nonsteroids), anti-osteoporosis, hormone replacement therapy, oral contraceptives, anti-obesity agents Anti-anxiety, anti-proliferative, anti-tumor, anti-ulcer and gastroesophageal reflux disease, growth hormone and / or growth hormone secretagogues, thyroid mimetics (including thyroid receptor antagonists), anti-infectives, antivirals, anti- Bacterial and antifungal agents.
[835] Other anticoagulants (or coagulation inhibitors) that can be used with the compounds of the present invention include directly acting thrombin, including warfarin and heparin (undivided heparin or any commercially available low molecular weight heparin), synthetic pentasaccharides, hirudin and argatrovanas. As well as inhibitors as well as other Factor Xa inhibitors as described in the publications identified above in the art.
[836] As used herein, the term antiplatelet agent (or platelet inhibitor) refers to an agent that inhibits platelet function, for example by inhibiting aggregation, adhesion or granular secretion of platelets. Numerous nonsteroidal anti-inflammatory drugs (NSAIDS) known as non-limiting examples of preparations, such as aspirin, ibuprofen, naproxen, sulindac, idometacin, mefenamate, doxycamp, diclofenac, sulfinpyrazone, pyroxam And pharmaceutically acceptable salts or prodrugs thereof. Among NSAIDS, aspirin (acetylsalicylic acid or ASA) and pyroxicam are preferred. Other suitable platelet inhibitors include IIb / IIIa antagonists (e.g. tyropiban, eptibivatid and absximab), thromboxane-A2-receptor antagonists (e.g. ifeprovane), thromboxane-A2- Synthetase inhibitors, PDE-III inhibitors (eg dipyridamole) and pharmaceutically acceptable salts or prodrugs thereof.
[837] As used herein, the term antiplatelet agent (or platelet inhibitor) also includes ADP (adenosine diphosphate) receptor antagonists, with purine receptors P ₂ Y ₁ and P ₂ Y ₁₂ preferred, and P ₂ Y ₁₂ more preferred. . Preferred P ₂ Y ₁₂ receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs. Clopidogrel is even more preferred agent. Ticlopidine and clopidogrel are also preferred because they are known to be gentle in the gastrointestinal tract in use.
[838] The term thrombin inhibitor (or antithrombin agent) as used herein means an inhibitor of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (ie, aggregation of platelets, and / or granulation of plasminogen activator inhibitor-1 and / or serotonin) Secretion) and / or fibrin formation is stopped. Many thrombin inhibitors are known to those skilled in the art, and it is contemplated that these inhibitors may be used with the compounds of the present invention. Non-limiting examples of such inhibitors include boroarginine derivatives, boropeptides, heparin, hirudin, argatroban and melagatran, including pharmaceutically acceptable salts and prodrugs. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and their corresponding isothiouronium analogues. . The term hirudin, as used herein, includes a suitable derivative or analog of hirudin, meaning a hirlog, such as disulfate hirudin.
[839] The term thrombolytic or fibrinolytic, as used herein, refers to an agent that dissolves clots (Trombi). Such agents include tissue plasminogen activators (natural or recombinant) and their modified forms, including pharmaceutically acceptable salts or prodrugs, anistreplase, urokinase, streptokinase, tenecteplase, TNK), lanoteplase (nPA), factor VIIa inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2-antiplasmin inhibitors, and anisoylated ) Plasminogen streptokinase activator complex. As used herein, the term anistreplace means an anisolyzed plasminogen streptokinase activator complex as described, for example, in EP 028,489, which is incorporated herein by reference. The term urokinase as used herein refers to both double and single chain urokinase, but a single chain is also referred to herein as prourokinase.
[840] Examples of antiarrhythmic agents suitable for use with the compounds of the present invention include Class I agents (eg, propapenone); Class II agents (eg, carbodiol and propranolone); Class III agents (eg, sotalol, dofetilide, aminodarone, azimilide and ibutylide); Class IV agents (eg, dithiazem and verapamil); K ⁺ channel openers such as I _Ach inhibitors and I _Kur inhibitors (eg, compounds as described in WO 01/40231).
[841] Examples of antihypertensive agents suitable for use with the compounds of the invention include alpha adrenergic blockers; Beta adrenergic blockers; Calcium channel blockers (eg, dithiazem, verapamil, nifedipine, amlodipine and mibepradil); Diuretics (eg, chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumetiazide, bendroflumetiazide, methylchlorothiazide, trichloromethageide, polythiazide, benzthiazide , Ethacrylic acid tricrinafen, chlortalidone, furosemide, musolimin, bumetanide, triamtrenen, amylolide, spironolactone); Renin inhibitors; ACE inhibitors (eg, captopril, jofenopril, posinopril, enalapril, serranopril, silazopril, delapril, pentopril, quinapril, ramipril, risinopril); AT-1 receptor antagonists (eg, losartan, irbesartan, valsartan); ET receptor antagonists (eg, citaxentane, atentane and compounds disclosed in US Pat. Nos. 5,612,359 and 6,043,265); Dual ET / AII antagonists (eg, compounds disclosed in WO 00/01389); Neutral endopeptidase (NEP) inhibitors; Vasopeptidase inhibitors (dual NEP-ACE inhibitors) (eg, omapatrylat, gemopatrylat and nitrate).
[842] Examples of calcium channel blockers (L-type or T-type) suitable for use with the compounds of the present invention include diltiazem, verapamil, nifedipine, amoldipine and mibepradil.
[843] Examples of cardiac glycosides suitable for use with the compounds of the present invention include digitalis and ovine.
[844] Examples of diuretics suitable for use with the compounds of the present invention include chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumetiazide, bendroflumethiazide, methylchlorothiazide, trichloromethazide , Polythiazide, benzthiazide, ethacrylic acid tricrinafen, chloritalidone, furosemide, musolimin, bumetanide, triamtrenen, amylolide and spironolactone.
[845] Examples of electrolytic corticoid receptor antagonists suitable for use with the compounds of the present invention include spironolactone and eprilinone.
[846] Examples of phosphodiesterase inhibitors suitable for use with the compounds of the invention include PDE III inhibitors (such as cilostazol); And PDE V inhibitors (such as sildenafil).
[847] Examples of cholesterol / lipid lowering agents and lipid profile therapies suitable for use with the compounds of the invention include HMG-CoA reductase inhibitors (eg, provastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 ( aka itavastatin or nyvastatin) and ZD-4522 (aka rosuvastatin, or atavastatin or bisastatin)); Squalene synthetase inhibitors; Fibrate; Bile acid sequestrant (eg, questran); ACAT inhibitors; MTP inhibitors; Lipooxygenase inhibitors; Cholesterol absorption inhibitors; And cholesterol ester transfer protein inhibitors (eg, CP-529414).
[848] Examples of antidiabetic agents suitable for use with the compounds of the invention include biguanides (eg, metformin); Glucosidase inhibitors (eg, acarbose); Insulin (including insulin secretagogues or insulin sensitizers); Meglitinide (eg, repaglinide); Sulfonylureas (eg, glymepyride, glyburide and glyphizide); Biguanide / glyburide combinations (eg glycovans), thiozolidinediones (eg troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha / gamma Dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding proteins (aP2) as disclosed in WO OO / 59506, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors .
[849] Examples of suitable antidepressants for use with the compounds of the present invention include nefazodone and sertraline.
[850] Examples of suitable anti-inflammatory agents for use with the compounds of the invention include prednisone; Dexamethasone; Enbrel; Protein tyrosine kinase (PTK) inhibitors; Cyclooxygenase inhibitors (including NSAIDs and COX-1 and / or COX-2 inhibitors); aspirin; Indomethacin; Ibuprofen; Preoxycam; Naproxen; Celecoxib and / or rofecoxib.
[851] Examples of anti-osteoporosis agents suitable for use with the compounds of the present invention include alendronates and raloxifene.
[852] Examples of hormone replacement therapies suitable for use with the compounds of the present invention include estrogens (eg, conjugated estrogens) and estradiol.
[853] Examples of anticoagulants suitable for use with the compounds of the present invention include heparin (eg, undivided low molecular weight heparins such as ethoxaparin and dalteparin).
[854] Examples of anti-obesity agents suitable for use with the compounds of the present invention include orilistat and aP2 inhibitors (eg, inhibitors disclosed in WO 00/59506).
[855] Examples of anti-anxiety agents suitable for use with the compounds of the present invention include diazepam, rolazepam, buspyrone and hydroxyzin pamoate.
[856] Examples of suitable antiproliferative agents for use with the compounds of the invention include cyclosporin A, paclitaxel, adriamycin; Epitylone, cisplatin and carboplatin.
[857] Examples of anti-ulcer agents and gastroesophageal reflux disease agents suitable for use with the compounds of the present invention include pamotidine, ranitidine and omeprazole.
[858] Administration of a compound of the invention (ie, a first therapeutic agent) with one or more additional therapeutic agents (ie, a second therapeutic agent) preferably allows each to be used at a lower dosage (ie, a synergistic effect). Combination), preferably to provide the benefit of efficacy over administration of the compound and formulation alone. Low doses minimize the potential for side effects, increasing safety. It is desirable to administer one or more therapeutic agents below a therapeutic dose. More preferably, all therapeutic agents are administered at less than a therapeutic dose. Below dosage means an amount of therapeutic agent that does not provide the desired therapeutic effect for the condition or condition to be treated by the therapeutic agent itself. Synergistic combination means that the observed effect of the combination is greater than the sum of the individual agents administered alone.
[859] The compounds of the present invention may be useful as a reference or standard compound, eg, a quality standard or control, in tests or assays involving inhibition of factor Xa. Such compounds may be provided as commercial kits for use in pharmaceutical research, including, for example, Factor Xa. For example, a compound of the invention can be used as a reference in an assay that compares the known activity of a compound of the invention to a compound of unknown activity. This assures the investigator that the assay was performed appropriately, and provides a basis for comparison, especially if the test compound is a derivative of the reference compound. When developing new assays or protocols, the compounds according to the invention can be used to test their effects.
[860] In addition, the compounds of the present invention can also be used in diagnostic assays involving Factor Xa. For example, the presence of factor Xa in an unknown sample can be determined by adding the chromogenic substrate S2222 to a series of solutions containing the test sample and optionally one of the compounds of the present invention. If the production of pNA is observed in the solution containing the test sample but not in the solution in which the compound of the present invention is present, it can be concluded that factor Xa is present.
[861] Compounds of the invention may also be useful as diagnostic agents and adjuvants. For example, the compounds of the present invention may be useful for maintaining whole and divided blood in the fluid as required for analytical and biological tests.
[862] The invention also includes a product. Non-limiting examples of products as used herein include kits and packages. The product of the present invention comprises (a) a first container; (b) a pharmaceutical composition located in a first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and (c) the pharmaceutical composition (as defined above) Package attachments designated for use in the treatment of thromboembolic disorders). In other embodiments, package attachments refer to that the pharmaceutical composition can be used (as defined above) with a second therapeutic agent to treat thromboembolic disorders. The product further comprises (d) a second container, wherein elements (a) and (b) are located within the second container and element (c) is present inside or outside the second container. Positioning within the first and second containers means that each container accepts the item within its boundaries.
[863] The first container is a reservoir used to receive a pharmaceutical composition. The container may be manufactured, stored, moved and / or sold separately / whole. The first container includes a bottle, jar, vial, flask, syringe, tube (eg, for cream formulation), or any other container used for the manufacture, storage, storage, or distribution of a pharmaceutical product.
[864] The second container is used to hold the first container and is optionally a package attachment. Non-limiting examples of second containers include boxes (eg cardboard or plastic), cradles, boxes, bags (eg paper or plastic bags), pouches and bags. The package attachment may be physically attached to the outside of the first container via tape, glue, stapler or other attachment method, or may be included inside the second container without any physical attachment means to the first container. Alternatively, the package attachment is located outside of the second container. When located outside of the second container, the package attachment is preferably physically attached by tape, glue, stapler or other attachment method. Alternatively, it may be adjacent to or in contact with the outside of the second container without being physically attached.
[865] Package attachments are labels, tags, markers, and the like that enumerate information associated with pharmaceutical compositions located within a first container. The information listed will generally be determined by the regulatory agency (eg, US Food and Drug Administration) that governs the region in which the product will be sold. It is preferred that the package attachment specifically lists the indications for which the pharmaceutical composition is approved. The package attachment may be made of any material that can read information contained in or on the package. It is preferred that the package attachment is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) in which the desired information has been formed (eg, printed or applied).
[866] Dosage and Formulation
[867] The compounds of the present invention may be administered in oral dosage forms such as tablets, capsules (each comprising sustained or agonist formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsifiers. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, using all dosage forms well known to those skilled in the pharmaceutical arts. The compounds may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
[868] Dosage regimens of the compounds of the invention include, of course, known factors such as the pharmacokinetic properties and methods and routes of administration of particular agents; The species, age, sex, health, medical condition and weight of the recipient; The nature and extent of the symptoms; The current type of treatment; Frequency of treatment; The route of administration, renal and hepatic function of the patient, and the desired effect will vary. The physician or veterinarian may determine and prescribe an effective amount of the drug required to prevent, counter or arrest the progression of thromboembolic disorders.
[869] As a general guideline, the daily oral dosage of each active ingredient, when used for the mentioned effects, is about 0.001 to 1000 mg / kg body weight, preferably about 0.01 to 100 mg / kg body weight per day, and most preferred Preferably about 1.0 to 20 mg / kg / day. For intravenous administration, the most preferred dosage is in the range of about 1 to about 10 mg / kg / minute during a constant rate of infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
[870] The compounds of the present invention can be administered in intranasal form via topical use of a suitable intranasal vehicle or via the transdermal route using transdermal skin patches. When administered in the form of a transdermal delivery system, of course administration will be continuous rather than intermittent throughout the dosing regimen.
[871] Typically the compounds are suitably selected for the intended dosage form, i.e. oral tablets, capsules, elixirs, syrups and the like, and are suitable pharmaceutical diluents, excipients or carriers in accordance with conventional pharmaceutical practice (general pharmaceutical carriers herein). Is called).
[872] For example, when administered orally in the form of tablets or capsules, the active drug component is an oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, Can be combined with calcium sulfate, mannitol, sorbitol, and the like; For oral administration in liquid form, the oral drug component can be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycols, waxes and the like. Lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Non-limiting examples of disintegrants include starch, methyl cellulose, agar, bentonite, xanthine gum and the like.
[873] The compounds of the invention may also be administered in the form of liposome delivery system such as small monolayer vehicles, large monolayer vehicles, and multimodal vehicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.
[874] The compounds of the present invention may also be coupled with soluble polymers as target drug carriers. Such polymers include polyvinylpyrrolidone substituted with palmitoyl moieties, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyethyleneoxide-polylysine. In addition, the compounds of the present invention are groups of biodegradable polymers useful for achieving controlled release of drugs such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid , Polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates and hydrogels can be coupled with crosslinked or amphiphilic block copolymers.
[875] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 mg to about 100 mg of active ingredient per dosage unit. In the pharmaceutical composition, the active ingredient is generally present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.
[876] Gelatin capsules may contain active ingredients and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make extruded tablets. Both tablets and capsules can be made into sustained release products to provide sustained release of the product over several hours. Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
[877] Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase patient acceptance.
[878] Generally, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, a suitable stabilizer, and, if necessary, a buffer substance. Antioxidants alone or in combination, such as sodium bisulfite, sodium sulfite or ascorbic acid, are suitable stabilizers. Citric acid and its salts and sodium EDTA are also used. Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl- or propyl-parabens and chlorobutanol.
[879] Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, which is a standard reference in this field.
[880] Representative pharmaceutical dosage forms useful for administering a compound of the invention may be described as follows:
[881] capsule
[882] Multiple unit capsules can be prepared by filling standard two-piece hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate, respectively.
[883] Soft gelatin capsules
[884] Mixtures of the active ingredients in digestible oils such as soybean oil, cottonseed oil or olive oil can be prepared and injected into the gelatin by means of a positive displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. Capsules should be washed and dried.
[885] refine
[886] Tablets may be prepared by conventional procedures such that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings can increase taste or delay absorption.
[887] Injectable Substance
[888] Parenteral compositions suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol and water. The solution must be isotonic with sodium chloride and must be sterilized.
[889] Suspension
[890] Aqueous suspensions for oral administration include 100 mg of finely divided active ingredients in 5 ml each, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, sorbitol solution U.S.P. It may be prepared to contain 1.0 g and 0.025 ml of vanillin.
[891] When the compound of the present invention is combined with other anticoagulants, for example, the daily dosage may be about 0.1 to 100 mg of the compound of formula 1 and about 1 to 7.5 mg of the second anticoagulant per kilogram of body weight of the patient. In tablet dosage forms, the compounds of the invention may generally be present in an amount of about 5-10 mg per dosage unit and the second anticoagulant may be present in an amount of about 1-5 mg per dosage unit.
[892] If, according to general guidelines, a compound of the present invention is administered with an antiplatelet agent, a typical daily dosage is about 0.01 to 25 mg of the compound of formula I and about 50 to 150 mg of the antiplatelet agent, preferably per kilogram of body weight of the patient. About 0.1 to 1 mg of the compound of formula I and about 1-3 mg of the antiplatelet agent.
[893] When the compound of formula (I) is administered in conjunction with a thrombolytic agent, a typical daily dosage may be about 0.1 to 1 mg of the compound of formula (I) per kilogram of body weight of the patient, and in the case of thrombolysis, Typical dosages can be reduced by about 70 to 80% when administered with a compound of formula (I).
[894] When two or more such second therapeutic agents are administered in combination with a compound of formula (I), the usual daily dosage and the amount of each component in the conventional dosage form are solely in terms of the additive or synergistic effect of the therapeutic agent when administered in combination When administered as compared to the usual dosage of the formulation.
[895] In particular, when provided in a single dosage unit, there may be chemical interactions between the combined active ingredients. For this reason, when the compound of formula (I) and the second therapeutic agent are combined in a single dosage unit, even if the active ingredients are combined in a single dosage unit, they are formulated to minimize (ie, reduce) physical contact between the active ingredients. For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is not only possible to minimize contact between the combined active ingredients, but also to control the release of one of these ingredients from the gastrointestinal tract so that one of these ingredients is not released from the stomach but rather is released from the intestine. It is possible. In addition, one of the active ingredients may be coated with a material that renders it sustained throughout the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. In addition, these components may be further enteric coated such that release of sustained release components occurs only in the intestine. Another approach is that in order to further separate the active ingredient, one component is coated with a sustained release polymer and / or enteric release polymer, and the other component is also a polymer such as low viscosity grade hydroxypropyl methylcellulose (HPMC) or Formulation of a combination product coated with other suitable materials known in the art. The polymer coating allows to form additional barriers to interaction with other components.
[896] Whether administered in a single dosage form or in separate forms at the same time in the same manner, the above methods as well as other methods of minimizing contact between the components of the combination product of the present invention supported by the present disclosure are apparent to those skilled in the art. something to do.
[897] Other features of the invention will be apparent from the following illustrative embodiments which illustrate, but are not limited to, the invention.
[898] Example 1
[899] 3-methoxy-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7-H-pyra Solo [3,4-c] pyridin-7-one
[900] Part A. To a solution of 1.91 g of DMAP in 10 mL of methylene chloride, 1.45 mL of trichloroacetyl chloride was added at 0 ° C. After stirring for 30 minutes at room temperature, 1.0 g of 1- (4-iodophenyl) -3- (4-morpholinyl) -5,6-dihydro-2 (1H) -pyridinone was added. The reaction mixture was refluxed overnight, then quenched with water and extracted with ether. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to afford the crude product used in the next step without further purification.
[901] Part B. The crude obtained above in a mixture of 20 mL ether, 1 mL water and 1 mL concentrated HCl was heated to reflux (oil bath 65 ° C.) for 3 h. The mixture was then cooled to rt and filtered to collect the product as a solid (0.97 g, 81% in two steps).
[902]
[903] Part C. A mixture of the above prepared “trione” (0.5 g, 1.09 mmol), p-methoxyphenylhydrazine HCl salt (0.152 g, 1.09 mmol) in 20 mL THF overnight at room temperature with 0.30 mL triethylamine Treated. 20 mL of 1N HCl was added to the reaction mixture. The resulting mixture was refluxed for 2 hours. After cooling to room temperature, the compound was collected by filtration (0.42 g, 84%).
[904]
[905] Part D. To a solution of hydroxy compound (1.78 g, 3.86 mmol) in 20 mL of DMF was added sodium hydride (232 mg, 60%, 5.79 mmol) at 0 ° C. The mixture was stirred at rt for 30 min. To the reaction mixture was added MeI (0.36 mL, 5.79 mmol). The reaction was stirred at rt overnight, then quenched with water and extracted with ether. The organic layer was dried over Na ₂ S0 ₄ and concentrated to dryness. The residue was purified by column chromatography to give 6- (4-iodophenyl) -3-methoxy-1- (4-methoxyphenyl) -1,4,5,6-tetrahydro-7H-pyrazolo [ 3,4-c] pyridin-7-one (1.67 g, 91%) was obtained.
[906]
[907] Part E. Oven-dried flask was charged with 6- (4-iodophenyl) -3-methoxy-1- (4-methoxyphenyl) -1,4,5,6-tetrahydro-7H-pyrazolo [ 0.28 g of 3,4-c] pyridin-7-one, 90 mg of δ-valerolactam and 70 mg of anhydrous (powdered) potassium carbonate. The solid was dissolved in 3 mL of degassed DMSO, then 20 mg of copper (I) iodide was added. The flask was equipped with a reflux condenser and heated to 120 ° C. with stirring for 12 hours. The reaction was cooled to room temperature and then quenched by addition of water. The product was extracted with ethyl acetate, then dried over Na ₂ SO ₄ and concentrated to give a yellow solid. The residue was purified by HPLC to give 50 mg of the title compound as TFA salt (15% yield).
[908]
[909] Example 2
[910] 1- (4-methoxyphenyl) -3-[(methylamino) methyl] -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one
[911] Part A. An oven-dried flask with a stir bar was charged with vacuum-oven dried lithium chloride (1.6 g, 38 mmol) and potassium borohydride (2.1 g, 38 mmol). While the system was flushed with N ₂ , the solids were dissolved in 60 mL dry THF. The mixture was stirred at rt for 30 min and then cooled to 0 ° C. Ethyl 6- (4-iodophenyl) -1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,] dissolved in 40 mL of dry THF. A solution of 4-c] pyridine-3-carboxylate (9 g, 17 mmol) was added slowly to the stirring suspension and the reaction continued for 12 hours starting at 0 ° C. and gradually warming to room temperature. The reaction was quenched by addition of water and a small amount of 1N HCl aqueous solution was added until pH was 7.0. When the product was broken up from the solution it was filtered off and dried in vacuo to give 6.9 g (83% yield) of the corresponding alcohol. LRMS (ES +) 476 (M + H) &lt; + &gt;.
[912] Part B. A vacuum-dried flask with a stir bar containing the synthesized alcohol (850 mg, 1.8 mmol) was charged with 10 mL of dichloromethane, purged with N ₂ and cooled to 0 ° C. Phosphorous tribromide (0.170 mL, 1.8 mmol) was added dropwise to the stirred solution. The reaction was started at 0 ° C. and then stirred for 12 hours while gradually warming to room temperature. The reaction was diluted with dichloromethane and then quenched with aqueous NaHC0 ₃ solution. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to yield 1 g (quantitative yield) of the corresponding bromide. LRMS (ES &lt; + &gt;) 538,540 (M, M + 2) &lt; + &gt;.
[913] Part C. The bromide (1 g, 2 mmol) obtained from the above reaction was added to an oven-dried flask as a solution in 10 mL of dry THF. A stir bar and a solution of methylamine (5 mL, 10 mmol in THF) were added. The reaction was stirred overnight at room temperature. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organics were concentrated to give 850 mg (85% yield) of the desired compound as an oil. LRMS (ES +) 489 (M + H) &lt; + &gt;.
[914] Part D. Vacuum dried flask with stir bar containing 850 mg (1.7 mmol) of amine obtained by the above reaction was added with di-tert-butyl dicarbonate (860 mg, 3.5 mmol), 4-DMAP (10 mg, 0.09 mmol), triethylamine (1.2 mL, 8.7 mmol) and 10 mL dichloromethane. The reaction was stirred at room temperature for 10 minutes and another 1.2 mL of triethylamine was added to the reaction and then stirred for 12 hours. The reaction was quenched by addition of dichloromethane and 1N HCl aqueous solution. The organics were separated and washed with brine and then dried over Na ₂ SO ₄ . The solution was filtered and concentrated to rotovap to give 490 mg (48% yield) of Boc-protected amine.
[915]
[916] Part E. Oven-dried flasks with stir bar were pre-synthesized N-Boc amino compound (100 mg, 0.17 mmol), δ-valerolactam (20 mg, 20 mmol), 4,5-bis- (di Charged with phenylphosphino) -9,9-dimethylxanthene (30 mg, 50 mmol), palladium (II) acetate (8 mg, 30 mmol) and cesium carbonate (80 mg, 30 mmol). The solid was dissolved in pre-gassed 1,4-dioxane (6 mL). The flask was equipped with a reflux condenser and heated to 80 ° C. with stirring for 12 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The organic solution was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to yield 45 mg (47% yield) of the corresponding lactam. LRMS (ES +) 560 (M + H) +,
[917] Part F. A solution of lactam (45 mg, 80 mmol) dissolved in chloroform (4 mL) was transferred to an oven-dried flask with a stir bar and purged with N ₂ , followed by TFA (1 mL, 13 mmol) via syringe. ) Was added dropwise. The reaction was stirred at rt for 12 h and then diluted with dichloromethane and aqueous NaHCO ₃ . The organic solution was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by HPLC to give 13 mg as TFA salt (26% yield).
[918]
[919] Example 3
[920] 1- (3-chloro-4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6- Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[921] Part A. 3-Chloro-4-fluorophenyl hydrazine (5.00 g, 31.14 mmol) and 1- (4-iodophenyl) -4- (trifluoroacetyl) -2,3-piperidinedione (12.8 g, 31.14 mmol) was added together with 120 mL of ethanol and 4 mL of hydrochloric acid (12 M). The mixture was stirred at reflux overnight under N ₂ . The reaction was cooled to room temperature. The solvent was removed and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL x 2) and brine (50 mL). Then dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel using 4: 1 hexanes: ethyl acetate to give 1- (3-chloro-4-fluorophenyl) -6- [4-iodophenyl] -3- (tri Fluoromethyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one was obtained as a brown solid (12.5 g, 75% yield).
[922]
[923] Part B. 1- (3-Chloro-4-fluorophenyl) -6- [4-iodophenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H-pyra Zolo [3,4-c] pyridin-7-one (0.54 g, 1.0 mmol), δ-valerolactam (0.12 g, 1.2 mmol), 1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), K ₃ PO ₄ (0.42 g, 2 mmol) and CuI (2 mg, 0.01 mmol) were added to 5 mL of 1,4-dioxane. The mixture was degassed under argon and stirred for 48 h at 110 ° C. under N ₂ . The mixture was then cooled to room temperature. Dioxane was removed. The residue was dissolved in EtOAc (100 mL) and washed with HCl (1N, 30 mL), water (50 mL × 2) and brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel using 1: 2 hexanes: ethyl acetate to afford the desired product (0.41 g, 80% yield).
[924]
[925] Example 4
[926] 1- [3- (aminomethyl) -4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5 , 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[927] Part A. 1- (3-Chloro-4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5 , 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one (0.35 g, 0.69 mmol), Zn (CN) ₂ (81 mg, 0.69 mmol), Pd ₂ (dba) ₃ ( 63 mg, 0.07 mmol), dppf (77 mg, 0.14 mmol) and Zn (9 mg, 0.14 mmol) were added to 15 mL of DMAC. The mixture was degassed under argon and stirred at 140 ° C. for 12 h under N ₂ . The reaction was cooled to room temperature and ethyl acetate (75 mL) was added and the mixture was filtered through Celite®. The filtrate was washed with saturated NaHC0 ₃ solution (30 mL), water (30 mL x 3) and brine (20 mL). It was then dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel using 10% methanol in dichloromethane to afford 2-fluoro-5- [7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-1-yl] benzonitrile (0.17 g, 50% yield) Obtained.
[928]
[929] Part B. The product from Part A (50 mg) was dissolved in 20 mL of MeOH in a hydrogenation vessel. To the solution was added 5% Pd / C (20 mg) and 1 drop of TFA. The reaction mixture was placed on a hydrogenated Parr shaker at 50 psi for 5 hours at room temperature. The reaction mixture was filtered through Celite (R). The filtrate was concentrated and purified via HPLC (C18 RP., 0.5% TFA, H ₂ O / MeCN gradient) to give 40 mg of the title compound as its TFA salt (65%).
[930]
[931] Example 5
[932] 1- (3-amino-1, 2-benzisoxazol-5-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1, 4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[933] Acetohydroxamic acid (54 mg, 0.72 mmol) and K ₂ CO ₃ (0.2 g, 1.45 mmol) were added to 8 mL of DMF and 4 mL of H ₂ O. The mixture was stirred at rt for 15 min, then 2-fluoro-5- [7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -3- in DMF (2 mL). A solution of (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-1-yl] benzonitrile (0.12 g, 0.24 mmol) was added. The mixture was stirred at rt overnight. The mixture was then partitioned between ethyl acetate (40 mL) and water (20 mL), washed with H ₂ O (20 mL × 3) and brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated It was. HPLC (C18 RP., 0.5% TFA, H ₂ O / MeCN gradient) purification gave 100 mg (67% yield) of the title compound as its TFA salt.
[934]
[935] Example 6
[936] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one
[937] Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved in THF (800 mL) and cooled to 0 ° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was allowed to warm to rt and stirred overnight. The reaction was cooled to 0 ° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was added slowly. The reaction was allowed to warm to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2 x 250 mL), washed with 1N HCl (3 x 250 mL) and brine (1 x 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 51.03 g (81%):
[938]
[939] Part B. The product from part A (85.17 g, 282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) were dissolved in CHCl ₃ (750 mL) and refluxed for 3½ hours. The reaction was poured onto ice, then quenched further with water and extracted with CHCl ₃ (3 × 400 mL), washed with brine (1 × 400 mL), dried (MgSO ₄ ) and concentrated. The residue was dissolved in morpholine (400 mL) and refluxed overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent to give 68 g (63%):
[940]
[941] Part C. 4-Dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved in CH ₂ Cl ₂ (130 mL) and cooled to 0 ° C. Trifluoroacetic anhydride (4.54 g, 32.01 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. The morpholine-enamine (10.25 g, 26.68 mmol) obtained from Part B dissolved in CH ₂ Cl ₂ (370 mL) was added slowly and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -50% ethyl acetate / hexanes gradient to isolate the intermediate. The intermediate was dissolved in 20% HCl (50 mL) and diethyl ether (200 mL) and stirred at rt overnight. The reaction was quenched with water, extracted with ether (3 × 100 mL), washed with brine (1 × 100 mL) and dried (Na ₂ SO ₄ ). The residue was redissolved in petroleum ether and the solid was filtered off. The filtrate was concentrated to give 9.99 g (78%):
[942]
[943] Part D. The product obtained from part C (10.0 g, 24.3 mmol) and 4-methoxyhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in 1N HCl (200 mL) and methanol (400 mL) and refluxed overnight. The reaction was cooled to rt and quenched with water, extracted with ethyl acetate (3 × 250 mL), washed with brine (1 × 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 9.28 g (74%);
[944]
[945] Part E. δ-valerolactam (0.023 g, 0.214 mmol), cesium carbonate (0.095 g, 0.292 mmol), palladium (II) acetate (0.004 g, 0.019 mmol) and 9,9-dimethyl-4,5-bis (Diphenylphosphino) xanthene (0.015 g, 0.029 mmol) was charged to the flask and flushed with N ₂ . The trifluoromethyl intermediate (0.100 g, 0.195 mmol) dissolved in 1,4-dioxane (2 mL) was added via syringe and the flask was flushed with N ₂ . The reaction was heated at 100 ° C. overnight. The reaction was cooled to rt and diluted with ethyl acetate (25 mL) and water (25 mL), extracted with ethyl acetate (3 x 25 mL), washed with brine (1 x 25 mL) and dried (Na ₂ SO). ₄ ). Purification by HPLC and freeze-drying gave 32.4 mg (34%);
[946]
[947] Example 7
[948] 1- (4-methoxyphenyl) -6- [4- (2-oxohexahydro-1H-azin-1-yl) phenyl] -3- (trifluoromethyl) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[949] The title compound was synthesized according to the method of Example 6.
[950]
[951] Example 8
[952] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperazinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one
[953] Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved in THF (800 mL) and cooled to 0 ° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to room temperature and stirred overnight. The reaction was cooled to 0 ° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was added slowly. The reaction was allowed to warm to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2 x 250 mL), washed with 1N HCl (3 x 250 mL), brine (1 x 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 51.03 g (81%):
[954]
[955] Part B. The product from part A (85.17 g, 282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) were dissolved in CHCl ₃ (750 mL) and refluxed for 3½ hours. The reaction was poured onto ice and then quenched further with water, extracted with CHCl ₃ (3 × 400 mL), washed with brine (1 × 400 mL), dried (MgSO ₄ ) and concentrated. The residue was dissolved in morpholine (400 mL) and refluxed overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent to give 68 g (63%):
[956]
[957] Part C. 4-dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved in CH ₂ Cl ₂ (130 mL) and cooled to 0 ° C. Trifluoroacetic anhydride (4.54 g, 32.01 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. The morpholine-enamine product (10.25 g, 26.68 mmol) obtained from Part B dissolved in CH ₂ Cl ₂ (370 mL) was added slowly and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -50% ethyl acetate / hexanes gradient to isolate the intermediate. The intermediate was dissolved in 20% HCl (50 mL) and diethyl ether (200 mL) and stirred at rt overnight. The reaction was quenched with water, extracted with ether (3 × 100 mL), washed with brine (1 × 100 mL) and dried (Na ₂ SO ₄ ). The residue was redissolved in petroleum ether and the solid was filtered off. The filtrate was concentrated to give 9.99 g (78%):
[958]
[959] Part D. The product obtained from part C (10.0 g, 24.3 mmol) and 4-methoxyhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in 1N HCl (200 mL) and methanol (400 mL) and refluxed overnight. The reaction was cooled to rt and quenched with water, extracted with ethyl acetate (3 × 250 mL), washed with brine (1 × 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 9.28 g (74%);
[960]
[961] Part E. 4-Benzyloxycarbonylpiperazin-2-one (0.050.214 mmol), cesium carbonate (0.095 g, 0.292 mmol), palladium acetate (II) (0.004 g, 0.019 mmol) and 9,9-dimethyl -4,5-bis (diphenylphosphino) xanthene (0.015 g, 0.029 mmol) was charged to the flask and flushed with N ₂ . The trifluoromethyl intermediate (0.100 g, 0.195 mmol) dissolved in 1,4-dioxane (2 mL) was added via syringe and the flask was flushed with N ₂ . The reaction was heated at 100 ° C. overnight. The reaction was cooled to rt, diluted with ethyl acetate (25 mL) and water (25 mL), extracted with ethyl acetate (3 x 25 mL), washed with brine (1 x 25 mL) and dried (Na ₂ SO). ₄ ). Lactam (0.091 g, 0.146 mmol) was dissolved in 6N HCl (20 mL) and MeOH (5 mL) and refluxed for 2 hours. The reaction was quenched with water (20 mL) and washed with ether (3 x 20 mL), basified to pH 12 with 1N NaOH, extracted again with ether (3 x 20 mL), brine (1 x 20 mL) Washed with and dried (Na ₂ SO ₄ ). Purification and freeze-drying by HPLC gave 1 mg (1% total);
[962]
[963] Example 9
[964] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-imidazolidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one
[965] Pre-made trifluoromethyl intermediate (part D, Example 6, 0.120 g, 0.234 mmol), 2-imidazolidone (0.025 g, 0.281 mmol), potassium carbonate (0.081 g, 0.257 mmol), 1 , 10-phenanthralline (0.006 g, 0.012 mmol) and DMSO (6 mL) were charged to the flask and degassed for 15 minutes. Copper iodide (I) (0.007 g, 0.012 mmol) was added and the reaction was heated to 130 ° C. overnight. The reaction was cooled to rt and quenched with H ₂ O (20 mL) and ethyl acetate (20 mL), washed with H ₂ O (3 × 20 mL), washed with brine (1 × 30 mL) and dried (Na ₂ SO ₄ ). Purification and freeze-drying with HPLC gave 29.1 mg (2. 6%);
[966]
[967] Example 10
[968] 1- (4-methoxyphenyl) -6- [4- (2-oxo-tetrahydro-1 (2H) -pyrimidinyl) phenyl] -3- (trifluoromethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[969] The title compound was synthesized according to the method of Example 6.
[970]
[971] Example 11
[972] 6- [4- (3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -3- (trifluoro Methyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[973] The title compound was synthesized according to the method of Example 6.
[974]
[975] Example 12
[976] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carbonitrile
[977] Part A. 4-iodoaniline (45.82 g, 209. 2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved in THF (800 mL) and cooled to 0 ° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was allowed to warm to rt and stirred overnight. The reaction was cooled to 0 ° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was added slowly. The reaction was allowed to warm to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2 x 250 mL), washed with 1N HCl (3 x 250 mL), brine (1 x 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 51.03 g (81%):
[978]
[979] Part B. The product from part A (85.17 g, 282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) were dissolved in CHCl ₃ (750 mL) and refluxed for 3½ hours. The reaction was poured onto ice, then quenched further with water, extracted with CHCl ₃ (3 × 400 mL), washed with brine (1 × 400 mL), dried (MgSO ₄ ) and concentrated. The residue was dissolved in morpholine (400 mL) and refluxed overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent to give 68 g (63%):
[980]
[981] Part C. and concentrated HCl (40 mL) of p- anisidine (16 g, 0.129 mol), a sodium nitrite (9.4 g, 0.136 in H ₂ O 100 mL and H ₂ O (60 mL) was cooled to -5 ℃ mol) was added. The diazohydrate is stirred cold for 20 minutes and a mixture of ethylchloroacetoacetate (22 g, 0.133 mol), ethanol (100 mL), sodium acetate (32 g, 0.389 mol) and H ₂ O (400 mL) is added. It was. The reaction was allowed to warm to rt and stirred for 2 h. The product precipitated as a black solid (30 g), which was collected and dried in vacuo.
[982]
[983] Part D. Crude chloro ester hydrazone (30 g, 0.117 mol) obtained from part C, iodo-morpholine enamine (29.9 g, 0.078 mol) and triethylamine (74 mL, 0.53 mol) obtained from Example 6 Was heated to reflux in toluene (400 mL) for 24 h. The reaction was cooled, washed with water and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using 1: 1 hexanes / ethyl acetate as eluent gave morpholine intermediates. The morpholine intermediate was treated with trifluoroacetic acid (50 mL) in CH ₂ Cl ₂ (500 mL) for 24 hours, then washed with water and dried (Na ₂ SO ₄ ) ester / iodo 28.8 g (71%) Obtained; Mass Spectrometry (M + H) + 517.9
[984] To ammonium chloride (1 g, 19 mmol) in part E. xylene (250 mL) was added trimethyl ammonium (2M heptane, 19.3 mL, 38 mmol) and stirred for 20 minutes. The ester (9.1 g, 17.6 mmol) obtained from part D was added and the reaction heated to reflux for 3 hours. The reaction was cooled to 0 ° C., quenched with HCl, extracted with ethyl acetate, washed with brine and dried (Na ₂ SO ₄ ). The resulting amide / nitrile mixture was treated with 30% H ₂ O ₂ (70 mL), 10% NaOH (150 mL) in CH ₂ Cl ₂ (400 mL) for 24 hours. The aqueous layer was extracted with CH ₂ Cl ₂ , washed with water and dried to give 6.18 g (72%) of (Na ₂ SO ₄ ) amide;
[985]
[986] Part F. To DMF (4.28 mL, 55.3 mmol) dissolved in 150 mL acetonitrile was added oxalyl chloride (3.99 mL, 46.1 mmol) at 0 ° C. and stirred until all gas evolution ceased. The amide (9.0 g, 18.4 mmol) obtained from part E was added and stirred until a homogeneous mixture was formed. Pyridine (7.45 mL, 92.2 mmol) was added and the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched with 1N HCl, extracted with ether, washed with brine and dried to give 6.54 g (75%) of (Na ₂ SO ₄ ) nitrile;
[987]
[988] Partial G. δ-valerolactam (0.127 g, 1.276 mmol), cesium carbonate (0.520 g, 1.595 mmol), palladium (II) acetate (0.024 g, 0.106 mmol) and 9,9-dimethyl-4,5-bis (Diphenylphosphino) xanthene (0.092 g, 0.159 mmol) was charged to the flask and flushed with N ₂ . The trifluoromethyl intermediate (0.500 g, 1.063 mmol) obtained from Part F dissolved in 1,4-dioxane (10 mL) was added via syringe and the flask was flushed with N ₂ . The reaction was heated at 100 ° C. overnight. The reaction was cooled to rt and diluted with ethyl acetate (25 mL) and water (25 mL), extracted with ethyl acetate (3 x 25 mL), washed with brine (1 x 25 mL) and dried (Na ₂ SO). ₄ ). Purification and freeze-drying with HPLC gave 104.2 mg (22%);
[989]
[990] Example 13
[991] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (1H-tetrazol-5-yl) -1,4,5,6- Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[992] Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved in THF (800 mL) and cooled to 0 ° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was allowed to warm to rt and stirred overnight. The reaction was cooled to 0 ° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was added slowly. The reaction was allowed to warm to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2 x 250 mL), washed with 1N HCl (3 x 250 mL), brine (1 x 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 51.03 g (81%):
[993]
[994] Part B. The lactam intermediate (85.17 g, 282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) obtained from Part A were dissolved in CHCl ₃ (750 mL) and refluxed for 3½ hours. The reaction was poured onto ice and then quenched further with water, extracted with CHCl ₃ (3 × 400 mL), washed with brine (1 × 400 mL), dried (MgSO ₄ ) and concentrated. The residue was dissolved in morpholine (400 mL) and refluxed overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent to give 68 g (63%):
[995]
[996] Part C. 100 mL of H ₂ O cooled to −5 ° C. in p-anisidine (16 g, 0.129 mol) in concentrated HCl (40 mL) and sodium nitrite (9.4 g, 0.136 mol in H ₂ O (60 mL)) ) Was added. The diazohydrate is stirred cold for 20 minutes and a mixture of ethylchloroacetoacetate (22 g, 0.133 mol), ethanol (100 mL), sodium acetate (32 g, 0.389 mol) and H ₂ O (400 mL) is added. It was. The reaction was allowed to warm to rt and stirred for 2 h. If the product precipitated as a black solid (30 g) it was collected and dried in vacuo.
[997]
[998] Part D. Crude chloro ester hydrazone (30 g, 0.117 mol) obtained from part C, iodo-morpholine (29.9 g, 0.078 mol) and triethylamine (74 mL, 0.53 mol) obtained from part B are 24 hours Heated to reflux in toluene (400 mL). The reaction was cooled, washed with water and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using 1: 1 hexanes / ethyl acetate as eluent gave morpholine intermediates. The morpholine intermediate was treated with trifluoroacetic acid (50 mL) in CH ₂ Cl ₂ (500 mL) for 24 hours, then washed with water and dried (Na ₂ SO ₄ ) ester / iodo 28.8 g (71%) Obtained; Mass Spectrometry (M + H) + 517.9
[999] To ammonium chloride (1 g, 19 mmol) in part E. xylene (250 mL) was added trimethyl ammonium (2M heptane, 19.3 mL, 38 mmol) and stirred for 20 minutes. The ester (9.1 g, 17.6 mmol) was added and the reaction heated to reflux for 3 hours. The reaction was cooled to 0 ° C., quenched with HCl, extracted with ethyl acetate, washed with brine and dried (Na ₂ SO ₄ ). The resulting amide / nitrile mixture was treated with 30% H ₂ O ₂ (70 mL), 10% NaOH (150 mL) in CH ₂ Cl ₂ (400 mL) for 24 hours. The aqueous layer was extracted with CH ₂ Cl ₂ , washed with water and dried to give 6.18 g (72%) of (Na ₂ SO ₄ ) amide;
[1000]
[1001] Part F. To DMF (4.28 mL, 55.3 mmol) dissolved in 150 mL acetonitrile was added oxalyl chloride (3.99 mL, 46.1 mmol) at 0 ° C. and stirred until gas evolution ceased. The amide (9.0 g, 18.4 mmol) was added and stirred until a homogeneous mixture was formed. Pyridine (7.45 mL, 92.2 mmol) was added and the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched with 1N HCl, extracted with ether, washed with brine and dried (Na ₂ SO ₄ ) nitrile 6.54 g (75%);
[1002]
[1003] Part G. Tributyltin chloride (0.142 g, 1.06 mmol) was added dropwise to a solution of THF (2 mL) sodium bizide (0.553 g, 8.51 mmol) at 0 ° C. The nitrile (0.500 g, 1.06 mmol) was added and the reaction was refluxed overnight. The reaction was cooled to room temperature and quenched slowly with 6N HCl (4 mL), diluted with H ₂ O (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (3 x 20 mL) and brine (1 x 25). mL) and dried to give 455 mg (83%) (Na ₂ SO ₄ );
[1004]
[1005] Part H. Triphenylmethyl chloride (0.230 g, 0.826 mmol) and 10N NaOH (0.10 mL, 0.991 mmol) were added to the tetrazole (0.424 g, 0.826 mmol) dissolved in toluene (10 mL) and room temperature Stir overnight at. The reaction was quenched with water (50 mL), extracted with ethyl acetate (3 x 75 mL), washed with brine (1 x 50 mL) and dried to give (Na ₂ SO ₄ ) protected tetrazole intermediate. δ-valerolactam (0.106 g, 1. 07 mol), cesium carbonate (0.437 g, 1.34 mmol), palladium (II) acetate (0.020 g, 0.089 mmol) and 9,9-dimethyl-4,5-bis ( Diphenylphosphino) xanthene (0.123 g, 0.134 mmol) was charged to the flask and flushed with N ₂ . Protected tetrazole / iodo intermediates (0.676 g, 0.895 mmol) dissolved in 1,4-dioxane (10 mL) were added via syringe and the flask was flushed with N ₂ . The reaction was heated at 60 ° C. overnight. The reaction was cooled to rt and diluted with ethyl acetate (75 mL) and water (75 mL), extracted with ethyl acetate (3 x 100 mL), washed with brine (1 x 75 mL) and dried (Na ₂ SO). ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave a protected tetrazole / lactam intermediate. Protected tetrazole / lactam intermediate (0.249 g, 0.322 mmol), trifluoroacetic acid (5 mL), water (5 mL) and THF (30 mL) were charged to the flask and stirred at room temperature for 2 hours. Additional trifluoroacetic acid (20 mL) and water (20 mL) were added and the reaction was stirred at rt overnight. The reaction was basified to pH 10 with 10N NaOH and washed with CH ₂ Cl ₂ (3 × 75 mL). The aqueous layer was acidified to pH 3 with 1N HCl, extracted with ethyl acetate (3 × 75 mL), washed with brine (1 × 50 mL) and dried (MgSO ₄ ). Purification and freeze-drying by HPLC gave 13.4 mg (4% total);
[1006]
[1007] Example 14
[1008] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1-piperidinyl) -2,3-dihydro-1 H-indole-1 -Yl] carbonyl} -1H-pyrazole-3-carboxamide
[1009] Part A. A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to −78 ° C. and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 minutes di-tert-butyl oxalate was added dropwise over 1 hour as a solution in 100 mL of ether. The resulting mixture was warmed to 23 ° C. over 3 hours and kept at room temperature for 20 hours. The mixture was then filtered and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was then dried in a vacuum oven for 1 hour to yield lithium 1-tert-butoxy-4- (2-furyl) -1,4-dioxo-2-butene-2-oleate (25 g, 83% ) Was obtained as a creamy solid.
[1010]
[1011] Part B. To the product obtained from Part A (13 g, 54 mmol) was added 2-fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250 mL of acetic acid. The resulting orange mixture was kept at room temperature for 20 hours and then concentrated to dryness. The resulting residue was taken up in 30% CHCl ₃ in hexanes and filtered to tert-butyl 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) -1H-pyrazole-3-carboxyl Yield (18 g, 95%) was obtained as a light brown solid.
[1012]
[1013] Part C. To the product obtained from part B (10 g, 28 mmol) was added 125 mL of CH ₂ Cl _{2 and} 125 mL of trifluoroacetic acid. The resulting black solution was kept at room temperature under N ₂ for 2 hours and then concentrated to dryness. The resulting solid was dried in a vacuum oven for 4 hours to give 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) -1H-pyrazole-3-carboxylate (8.4 g, 99 %) Was obtained as a brown solid.
[1014]
[1015] Section D. The product obtained from part C was added 2.0 M oxalyl chloride (10 mL, 21 mmol) in CH ₂ Cl ₂ and 23 mL CH ₂ Cl ₂ in (4.1 g, 14 mmol). DMF (10 drops) was added dropwise to the brown mixture, then all solids were dissolved over 30 minutes. When no more gas was generated, the brown solution was concentrated. The resulting residue was redissolved in 100 mL of CH ₂ Cl ₂ and 0.5 M ammonia in dioxane (110 mL, 55 mmol) was added via cannula. After 30 minutes, the resulting suspension was concentrated and poured into H ₂ O. The aqueous layer was washed with ethyl acetate (3 × 70 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was dissolved in 10 mL of CH ₂ Cl ₂ and 50 mL of hexanes were added. The resulting suspension was filtered and the filter cake was washed with 50 mL of hexanes. The filter cake was dried in a vacuum oven to give 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) -1H-pyrazole-3-carboxamide (2.5 g, 62%) Obtained as a solid.
[1016]
[1017] Part E. To the product obtained from part D (2.5 g, 8.3 mmol) was added H ₂ O (51 mL), 5% aqueous NaH ₂ PO ₄ (35 mL) and tert-butanol (51 mL). The resulting mixture was warmed to 60 ° C. and KMnO ₄ (8.0 g, 51 mmol) was added over 10 minutes. After an additional 10 minutes, the resulting purple slurry was cooled to 0 ° C. and 200 mL of saturated aqueous sodium bisulfite was added to quench the reaction. The resulting mixture was filtered, washed with 300 mL of H ₂ O and the filtrate was acidified with concentrated HCl. The aqueous layer was extracted with EtOAc (6 × 100 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. Concentration gave 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid (1.6 g, 71%) as a yellow solid.
[1018]
[1019] Part F. 5-nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol) and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF. The solution was stirred at rt for 12 h under N ₂ and then concentrated. The residue was taken up in EtOAc and the mixture was filtered. The filtered solid was washed with 100 mL of hexane and dried to afford tert-butyl-5-nitro-1H-indole-1-carboxylate as off white solid (3.1 g, 78%).
[1020]
[1021] Part G. The product obtained from part F (1.0 g, 4.3 mmol) was dissolved in 100 mL of MeOH. Palladium hydroxide, 20 wt% Pd, Degussa type (100 mg) was added and the resulting mixture was vigorously shaken under hydrogen atmosphere (50 psi). After 5 hours the black mixture was filtered and concentrated to afford tert-butyl-5-amino-1-indolincarboxylate as a brown oil (0.98 g, 98%).
[1022]
[1023] To part H. tert-butyl-5-amino-1-indolincarboxylate (1.90 g, 8.2 mmol) was added 5-bromovaleric chloride (1.4 mL, 9.0 mmol) and 18 mL of THF. After stirring for 5 minutes at room temperature under N ₂ , potassium tert-butoxide (9 mL, 9 mmol; 1.0 M in THF) was added in one portion and the resulting brown solution was stirred for 30 minutes under N ₂ . A second portion of potassium tert-butoxide (9 mL) was added and the resulting brown suspension was stirred for 15 minutes. An additional 0.10 mL portion of 5-bromovaleric chloride and 4.5 mL portion of potassium tert-butoxide were added and the mixture was stirred for 30 minutes. The reaction was then poured into H ₂ O (80 mL). The aqueous layer was washed with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated and the resulting residue was purified by radial chromatography (50% EtOAc in hexane) to give tert-butyl-5- (2-oxo-1-piperidinyl) -1-indolincarboxylate as a pink solid Obtained as (1.30 g, 50%).
[1024]
[1025] Part I. The product obtained from part H (1.30 g, 4.2 mmol) was dissolved in 30 mL of CH ₂ Cl ₂ and stirred at room temperature under N ₂ . Trifluoroacetic acid (30 mL) was added and the reaction stirred for 2 hours. The yellow solution was concentrated and the resulting residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO ₃ . The aqueous layer was washed with EtOAc (2 × 50 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 1- (2,3-dihydro-1H-indol-5-yl) -2-piperidinone ( 740 mg, 81%) was obtained as a beige solid (LC / MS (ESI +): 217.2 (M + H) &lt; + &gt;). To the solid was added 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid (1.00 g, 3.8 mmol) (see Part E above). After addition, 28 mL of pyridine and 6.8 mL of DMF were added. 1,3-Diisopropyl-carbodiimide (0.59 mL, 3.8 mmol) was added and the resulting solution was stirred for 14 h. The reaction was then poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to give crude 1- (3-cyano-4-fluorophenyl) -5-{[5- (2-oxo-1-piperidinyl) -2,3-dihydro-1H-indole-1 -Yl] carbonyl} -1 H-pyrazole-3-carboxamide (1.20 g; LC / MS (ESI +): 473.2 (M + H) &lt; + &gt;) was obtained as a brown residue. The residue was dissolved in 18 mL of DMF and 3 mL of H ₂ O. Potassium carbonate (1.70 g, 13 mmol) and acetohydroxysamic acid (470 mg, 6.2 mmol) were added and the resulting mixture was warmed to 50 ° C. under N ₂ atmosphere. After 2 hours, the reaction was cooled to room temperature and poured into EtOAc (60 mL). The organic layer was washed with H ₂ O (2 × 50 mL), brine and dried over Na ₂ SO ₄ . Filtration and concentration gave a brown oily residue which was purified by preparative LC / MS (C18 reverse phase, eluted with 0.05% TFA in CH ₃ CN / H ₂ O) to give the TFA salt of the final product. The salt was dissolved in saturated aqueous NaHCO ₃ (15 mL) and the aqueous layer was washed with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo- 1-piperidinyl) -2,3-dihydro-1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide as a white solid (150 mg in 2 steps, 7.3%) Obtained.
[1026]
[1027] Example 15
[1028] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[6- (2-oxo-1-piperidinyl) -2,3-dihydro-1H-indole-1 -Yl] carbonyl} -1H-pyrazole-3-carboxamide trifluoroacetate
[1029] The title compound was prepared in the same manner using 6-nitro-1H-indole according to the general method described above. LC / MS (ESI &lt; + &gt;): 486.2 (M + H-TFA) &lt; + &gt;.
[1030] Example 16
[1031] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxohexahydro-1 H-azin-1-yl) -2,3-dihydro- 1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide
[1032] Part A. tert-Butyl 5- (2-oxohexahydro-1H-azepine- prepared as in part C of Example 15 using 6-bromohexanoyl chloride instead of 5-bromovaleryl chloride To 1-yl) -1-indolincarboxylate (140 mg, 0.42 mmol) was added 10 mL of 4.0 M HCl in dioxane. The resulting solution was maintained at rt for 2 h under N ₂ and then concentrated. The resulting residue was dissolved in 25 mL of EtOAc and the organic layer was washed with saturated aqueous NaHCO ₃ . The aqueous layer was washed with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to 1- (2,3-dihydro-1H-indol-5-yl) hexa. Hydro-2H-azin-2-one (96 mg, 100%) was obtained as a brown oil.
[1033]
[1034] Part B. In the product obtained from Part A (95 mg, 0.41 mmol) 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ( 94 mg, 0.34 mmol), 3.3 mL of pyridine and 0.70 mL of DMF were added. 1,3-Diisopropylcarbodiimide (0.059 mL, 0. 38 mmol) was added and the resulting solution was stirred for 1 h. The red mixture was then poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated and the resulting residue was purified by radial chromatography (1-5% MeOH in CH ₂ Cl ₂ ) to give 1- (3-cyano-4-fluorophenyl) -5-{[5- (2 -Oxohexahydro-1H-azin-1-yl) -2,3-dihydro-1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide (98 mg, 49% ) Was obtained as a brown residue.
[1035]
[1036] Part C. To the product obtained from part B (92 mg, 0.19 mmol) was added 8.8 mL of DMF and 3.4 mL of H ₂ . Potassium carbonate (130 g, 0.95 mmol) and acetohydroxysamic acid (36 mg, 0.47 mmol) were added and the resulting mixture was warmed to 50 ° C. under N ₂ atmosphere. After 2 h the reaction was cooled to rt and poured into EtOAc (50 mL). The organic layer was washed with H ₂ O (2 × 15 mL), brine and dried over Na ₂ SO ₄ . Filtration and concentration afforded a brown oily residue which was purified by radial chromatography (10% MeOH in CH ₂ Cl ₂ containing 2% NH ₄ 0H) to give 1- (3-amino-1,2-benzisoxazole -5-yl) -5-{[5- (2-oxohexahydro-1H-azin-1-yl) -2,3-dihydro-1H-indol-1-yl] carbonyl} -1H- Pyrazole-3-carboxamide (11 mg, 12%) was obtained as a white solid. LC / MS (ESI &lt; + &gt;): 500.1 (M + H) &lt; + &gt;.
[1037] Example 17
[1038] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[6- (2-oxohexahydro-1 H-azin-1-yl) -2,3-dihydro- 1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide
[1039] Part A. tert-butyl-6-nitro-1H-indole-1-carboxylate prepared according to part F of Example 14 using 6-nitro-1H-indole as starting material (3.80 g, 14 mmol) To 150 mL of MeOH and 150 mL of EtOAc were added. To the solution was applied an N ₂ stream and 10 wt% Pd / C (100 mg) was added in one portion. The mixture was left for 14 hours in a hydrogen atmosphere (50 psi), then filtered and concentrated. The resulting brown residue (3.34 g, 100%) was analyzed (LC / MS) to give tert-butyl 6-amino-1-indolincarboxylate: tert-butyl-6-amino-1H-indole-1-car It was found to be a 20:80 mixture of carboxylates. LC / MS (ESI &lt; + &gt;): 233.1 (indole M + H) &lt; + &gt;, 235.1 (indoline M + H) &lt; + &gt;.
[1040] Part B. To the mixture obtained from Part A (400 mg, 1.7 mmol) was added 6-bromohexanoyl chloride (0.26 mL, 1.7 mmol) and 15 mL of THF. Potassium tert-butoxide (1.90 mL, 1.9 mmol; 1.0 M in THF) was added and the cloudy mixture was stirred for 10 minutes. A second 1.90 mL portion of potassium tert-butoxide was added and the reaction maintained at room temperature for 1 hour. The reaction was then poured into 1N HCl (70 mL) and the aqueous layer washed with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by radial chromatography to give tert-butyl 6- (2-oxohexahydro-1H-azin-1-yl) -1-indolincarboxylate and tert-butyl 6- (2-oxo A mixture of hexahydro-1H-azin-1-yl) -1H-indole-1-carboxylate (340 mg, 60%) was obtained as a red oil. LC / MS (ESI &lt; + &gt;): 329.3 (Indole M + H) &lt; + &gt;, 331.2 (Indolin M + H) &lt; + &gt;.
[1041] Part C. To the product obtained from part B, 5 mL of trifluoroacetic acid and NaBH ₃ CN (260 mg, 4.1 mmol) were added. After 2 hours, an additional 100 mg portion of boron hydride salt was added. The mixture was stirred for 14 hours and another 100 mg portion was added. After the reaction was kept at rt for 24 h under N ₂ , the mixture was concentrated and poured into 1N NaOH (25 mL). The aqueous layer was washed with EtOAc (3 × 25 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by radial chromatography (5% MeOH in CH ₂ Cl ₂ ) to give 1- (2,3-dihydro-1H-indol-5-yl) hexahydro-2H-azin-2-one Was obtained alone as a yellow foam (90 mg, 38%).
[1042]
[1043] Part D. In the product obtained from part C (90 mg, 0.39 mmol) 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ( 89 mg, 0.33 mmol), 3.0 mL of pyridine and 1.0 mL of DMF were added. 1,3-Diisopropylcarbodiimide (0.056 mL, 0.36 mmol) was added and the resulting solution was stirred for 14 hours. The red mixture was poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated and the resulting residue was purified by preparative LC / MS (C18 reverse phase, eluted with 0.05% TFA in CH ₃ CN / H ₂ O) to give 1- (3-cyano-4-fluorophenyl)-. 5-{[6- (2-oxohexahydro-1H-azin-yl) -2,3-dihydro-1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide (67 mg, 29%) was obtained as a white foam. LC / MS (ESI &lt; + &gt;): 487.2 (M + H) &lt; + &gt;.
[1044] Part E. To the product obtained from part D (67 mg, 0.11 mmol), 6.3 mL of DMF and 2.5 mL of H ₂ O were added. Potassium carbonate (95 g, 0.69 mmol) and acetohydroxysamic acid (26 mg, 0.34 mmol) were added and the resulting mixture was warmed to 50 ° C. under N ₂ atmosphere. After 2 h, the reaction was cooled to rt and poured into EtOAc (50 mL). The organic layer was washed with H ₂ O (2 × 15 mL), brine and dried over Na ₂ SO ₄ . Filtration and concentration gave a brown oily residue which was purified by preparative LC / MS (C18 reverse phase, eluted with 0.05% TFA in CH ₃ CN / H ₂ O) to 1- (3-amino-1,2- Benzisoxazol-5-yl) -5-{[6- (2-oxohexahydro-1H-azin-1-yl) -2,3-dihydro-1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide trifluoroacetate (33 mg, 40%) was obtained as a white solid. LC / MS (ESI &lt; + &gt;): 500.2 (M + H-TFA) &lt; + &gt;.
[1045] Example 18
[1046] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl-4,5,6,7-tetrahydro-1H-pyrazole- [3 , 4-c] pyridine-3-carboxamide
[1047] Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved in THF (800 mL) and cooled to 0 ° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was allowed to warm to rt and stirred overnight. The reaction was cooled to 0 ° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was added slowly. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2 x 250 mL), washed with 1N HCl (3 x 250 mL), brine (1 x 250 mL) and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent gave 51.03 g (81%):
[1048]
[1049] Part B. The lactam intermediate (85.17 g, 282.8 mmol) and phosphorus pentachloride (205.91 g, 990.0 mmol) obtained from part A were dissolved in CHCl ₃ (750 mL) and refluxed for 3½ hours. The reaction was poured onto ice and then quenched further with water, extracted with CHCl ₃ (3 × 400 mL), washed with brine (1 × 400 mL), dried (MgSO ₄ ) and concentrated. The residue was dissolved in morpholine (400 mL) and refluxed overnight. The reaction was concentrated and purified by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent to give 68 g (63%):
[1050]
[1051] Part C. To p-anisidine (16 g, 0.129 mol) in concentrated HCl (40 mL) and water (100 mL) was slowly added sodium nitrite (9.4 g, 0.136 mol) in water (60 mL) at 0 ° C. . The reaction was stirred cold for 0.5 h. To the reaction was poured a mixture of ethylchloroacetoacetate (22 g, 0.133 mol), ethanol (100 mL), sodium acetate (32 g, 0.389 mmol) and water (400 mL). The reaction was stirred at rt for 2 h. The precipitate was filtered off and dried to give hydrazone as red gum (30.3 g, 91%):
[1052]
[1053] Triethylamine (2 mL, 14.2 mmol) in hydrazone (0.7 g, 2.7 mmol) from part C and morpholine compound (0.7 g, 1. 8 mol) from part B in part D. toluene (25 mL). Was added and the reaction was heated to reflux for 6 hours. The reaction was cooled to rt and water was added. The mixture was extracted with ethyl acetate, washed with water, 1N HCl, saturated NaHCO ₃ and dried (Na ₂ SO ₄ ). Purification on silica gel with 3: 2 hexanes / ethyl acetate gave the morpholine intermediate, which was dissolved in CH ₂ Cl ₂ (50 mL) and TFA (2 mL). After 24 hours the reaction was diluted with CH ₂ Cl ₂ , washed with water and saturated NaHC0 ₃ and dried to give 0.17 g (18%) of (Na ₂ SO ₄ ) foam:
[1054]
[1055] Part E. Iodo compound obtained from Part D (25 g, 0.048 mol) to γ-valerolactam (6.7 g, 0.067 mol), K ₂ CO ₃ (8 g, 0.058 mol), degassed DMSO (100 mL) And CuI (1.84 g, 0.009 mol). The reaction was heated to 130 ° C. for 24 h. The reaction was cooled, partitioned with EtOAc / H ₂ O, extracted and dried (MgSO ₄ ). Purified by silica gel chromatography using 0-10% MeOH / CH ₂ Cl ₂ as eluent to ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-pipe 5 g (21%) of ridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylate as a tan foam;
[1056]
[1057] Part F. To ester (4.8 g, 0.009 mol) obtained from part E, 5% NH ₃ in ethylene glycol (40 mL) was added and the mixture was heated to 120 ° C. in a sealed container for 4 hours. Water was added and the resulting solid collected. Purification by silica gel chromatography using 0-10% MeOH / CHCl as eluent gave 3.5 g of a white solid. Some solid was recrystallized from CH ₂ Cl ₂ / EtOAc to give 2.5 g of the title compound. Residual solids and filtrate material were recrystallized from isopropyl alcohol to give an additional 0.57 g to 3.07 g (68%) in total:
[1058]
[1059] Example 19
[1060] 3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [ 3,4-c] pyridin-7-one
[1061] Part A. 4-methoxyphenyl hydrazine hydrochloride (3 g, 17 mmol) was treated with glyoxylic acid monohydrate (1.6 g, 17 mmol) in H ₂ O containing concentrated HCl (1 mL). After 3 hours the red precipitate was filtered off and dried to give 3.13 g (93%) of hydrazone.
[1062] Part B. Hydrazone (3.13 g, 16.1 mmol) from Part A was placed in DMF (20 mL) and cooled to -5 ° C and NBS (5.7 g, 32 mmol) in DMF (20 mL) was added slowly. The reaction was left at room temperature for 15 minutes before 3- (4-morpholinyl) -1- (4-nitrophenyl) -5,6-dihydro-2 (1H) -pyridinone (Example 1 Part A) (4.8 g, 16 mmol) was added. TEA (4.5 mL, 32 mmol) in toluene (50 mL) was added dropwise and the reaction was stirred at rt for 24 h. The morpholine intermediate was extracted with EtOAc, washed with H ₂ O, dried (Na ₂ SO ₄ ) and purified by silica gel chromatography using 1: 1 hexanes / EtOAc as eluent to give a foam.
[1063] Part C. The morpholine intermediate obtained from part B was treated with TFA (5 mL) in CH ₂ Cl ₂ (30 mL) for 24 hours. Diluted with CH ₂ Cl ₂ , washed with H ₂ O, saturated NaCl and dried (Na ₂ SO ₄ ) to give 2.29 g (32%) of a tan foam;
[1064]
[1065] Part D. The nitro compound (0.67 g, 1.5 mmol) obtained from part C was heated at reflux for 24 h in MeOH (25 mL) containing 5% Pt / C (0.1 g) and ammonium formate (0.25 g). The reaction was cooled, filtered and concentrated to give 0.61 g (98%) of aniline; Mass spectrometry (M + H) + (413-415).
[1066] Part E. Example 1 As described above for aniline in part D, the aniline obtained from part D was converted to lactam to afford the title compound.
[1067]
[1068] Example 20
[1069] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (4-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1070] Crude 3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] 1,4,5,6-tetrahydro-7H-pyrazolo [ 3,4-c] pyridin-7-one (Example 19) (0.19 g, 0.4 mmol) in toluene (25 mL), ethanol (10 mL), 2M Na ₂ CO ₃ (1 mL) and pyridin-4- Boronic acid (60 mg, 0.48 mmol) was added. The mixture was degassed with N ₂ and tetrakistriphenylphosphine palladium (25 mg) was added and the reaction heated to reflux for 24 hours. The reaction was filtered, concentrated, extracted with EtOAc and dried (MgSO ₄ ). Purification by HPLC and freeze-drying gave 10 mg (4%) of the title compound; HRMS (M + H) &lt; + &gt; for C ₂₉ H ₂₈ N ₅ O ₃ was 494.2183;
[1071]
[1072] Example 21
[1073] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (4-pyridinyl-N-oxide) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[1074] The pyridine compound TFA salt of Example 20 (40 mg, 0.065 mmol) was free-based with saturated aqueous NaHCO ₃ , extracted with ethyl acetate and dried (MgSO ₄ ). The pyridine compound was dissolved in CH ₂ Cl ₂ and excess 50% 3-chloroperbenzoic acid (50 mg) was added. The reaction was stirred for 3 hours, washed with saturated aqueous NaHCO ₃ and dried (Na ₂ SO ₄ ). Purification and freeze-drying with HPLC gave 16 mg (48%) of the title compound; HRMS (M + H) + for C ₂₉ H ₂₈ N ₅ 0 ₄ was 510.2145;
[1075]
[1076] Example 22
[1077] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (3-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1078] 3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] 1,4,5,6-tetrahydro-7H-pyrazolo [3 To 3-, 4-c] pyridin-7-one (Example 19) (0.23 g, 0.46 mmol) was added 3-tributylstannylpyridine (0.222 g, 0.61 mmol) and toluene (25 mL). The mixture was degassed with N ₂ for 10 minutes, then tetrakistriphenylphosphine palladium (10 mg) was added. The reaction was heated to reflux for 3 hours. The cooled reaction was diluted with ethyl acetate, then washed successively with saturated aqueous KF, brine and dried (MgSO ₄ ). Purification by silica gel chromatography using 0-5% MeOH / CH ₂ Cl ₂ (1% NH ₃ ) as eluent, conversion to TFA salt and freeze-drying gave 0.28 g (81%) of the title compound: HRMS (M + H) &lt; + &gt; for C ₂₉ H ₂₈ N ₅ O ₃ was 494.2191;
[1079]
[1080] Example 23
[1081] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (3-pyridinyl-N-oxide) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[1082] The compound was prepared in the same manner as in Example 21: HRMS (M + H) &lt; + &gt; for C ₂₉ H ₂₈ N ₅ 0 ₄ was 510.2121;
[1083]
[1084] Example 24
[1085] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (2-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] -7-one trifluoroacetic acid salt
[1086] 3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] 1,4,5,6-tetrahydro-7H-pyrazolo [3 To 2-, 4-c] -7-one (Example 21) (0.21 g, 0.43 mmol) was added 2-tributylstannylpyridine (0.26 g, 0.55 mmol) and toluene (25 mL). The mixture was degassed with N ₂ for 10 minutes, then tetrakistriphenylphosphine palladium (10 mg) was added. The reaction was heated to reflux for 24 hours. The cooled reaction was diluted with ethyl acetate, then washed successively with saturated aqueous KF, brine and dried (MgSO ₄ ). Silica gel chromatography using 0-5% MeOH / CH ₂ Cl ₂ (1% NH ₃ ) as eluent, then purified by HPLC and freeze-dried to give 0.26 g (58%) of the title compound: C ₂₉ H ₂₈ N HRMS (M + H) &lt; + &gt; for ₅ 0 ₃ was 494.2192;
[1087]
[1088] Example 25
[1089] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] 1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] Pyridin-7-one
[1090] 3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] 1,4,5,6-tetrahydro-7H-pyrazolo [3 , 4-c] pyridin-7-one (Example 21) (0.15 g, 0.3 mmol), dimethylamine (2M THF, 1.5 mL, 3 mmol), sodium t-butoxide (88 mg, 0.9 mmol), 2 Toluene / dioxane (1: 1) (15 mL) was added to -dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl (7 mg) and the mixture was degassed with N ₂ . Pd ₂ (dba) ₃ was added and the reaction heated to 85 ° C. for 24 h. The reaction was cooled, diluted with ethyl acetate and filtered over Celite®. Purification and freeze-drying by HPLC gave 25 mg (18%) of the title compound; HRMS (M + Na) + for C ₂₄ H ₂₄ NaN ₄ 0 ₃ was 439.1726;
[1091]
[1092] Example 26
[1093] 1- (4-methoxyphenyl) -7-oxo-6- [5- (2-oxo-1-piperidinyl) -2-pyridinyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide, trifluoroacetic acid salt
[1094] Part A. PCl ₅ (34.6 g, 166 mmol) was added to valerolactam (5.6 g, 55 mmol) in CHCl ₃ and the reaction was heated to reflux for 24 h. The reaction was cooled, quenched with H ₂ O, extracted with CHCl ₃ and dried (MgSO ₄ ) to afford crude 3,3-dichloro-2-piperidinone.
[1095] Part B. To 3,3-dichloro-2-piperidinone (55 mmol) obtained from part A, CCl ₄ (250 mL), AlCl ₃ (22 g, 166 mmol) were added and the reaction heated to reflux for 24 hours. . The reaction was cooled and added to 3N NaOH (200 mL) and NH ₄ Cl (40 g). The resulting emulsion was filtered through Celite (R) and the aqueous layer was extracted with CH ₂ Cl ₂ and dried (MgSO ₄ ) 3-chloro-5,6-dihydro-2 (1H) -pyridinone 3.4 g ( 46%) was obtained;
[1096]
[1097] Part C. 3-Chloro-5,6-dihydro-2 (1H) -pyridinone (1.5 g, 11.4 mmol) was dissolved in toluene (50 mL) TEA (5 mL, 34 mmol) and ethyl (2Z) -chloro It was heated to reflux for 24 hours with [4-methoxyphenyl) hydrazono] ethanoate (Example 19 Part B) (4 g, 15.6 mmol). The tan precipitate was filtered off and the filtrate was purified via silica gel using 1: 1 hexanes / EtOAc as eluent to give ethyl 1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetra A total of 1.4 g (38%) of hydro-1H-pyrazolo [3,4-c] pyridine-carboxylate was obtained;
[1098]
[1099] Part D. Ethyl 1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-carboxylate (0.49 g, 1.55 mmol) in CsCO ₃ (0.76 g, 2.3 mmol), 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (70 mg, 0.11 mmol) and palladium (II) acetate (18 mg, 0.08 mmol) was added and the mixture was flushed with N ₂ . Dioxane (15 mL) and 2-bromo-5-nitropyridine (0.315 g, 1.55 mmol) were added and the reaction was heated to 75 ° C. for 24 h. The reaction was filtered, partitioned between EtOAc and H ₂ O and extracted. The organic layer was dried (MgSO ₄ ). Purification by chromatography on silica gel using 2: 1 hexanes / EtOAc as eluent gave 0.62 g (92%) of nitro compounds; Mass spectrometry (M + H) + 438.1.
[1100] Part E. The nitro compound (0.61 g, 1.4 mmol) obtained from part D was reduced with iron powder (0.9 g, 16 mmol) in acetic acid (15 mL) at 90 ° C. for 1.5 h. The reaction was cooled, filtered and concentrated, dissolved in CH ₂ Cl ₂ , washed with saturated NaHCO ₃ and dried (MgSO ₄ ) aniline 0.46 g (81%) as a yellow solid; Mass spectrometry (M + H) + 408.1.
[1101] To aniline (0. 27 g, 0.66 mmol) obtained from part F. 5-bromovaleric chloride (0.16 g, 0.8 mmol) and TEA (0.23 mL, 1.65 mmol) in THF (20 mL) were added and The reaction was stirred for 24 hours. Potassium t-butoxide (0.24 g, 1.99 mmol) was added and the reaction stirred for 72 h. The reaction was quenched with water, extracted with EtOAc, dried (MgSO ₄ ) and chromatographed on silica eluting with 1: 1 hexanes / EtOAc to give 0.17 g (53%) of lactam as a white solid; Mass spectrometry (M + H) + 490.2.
[1102] Part G. To lactam (0.17 g, 0.34 mmol) obtained from part F in DMF (2.5 mL) was added formamide (0.14 mL, 3.5 mmol) and 25% NaOMe / MeOH (0.5 mL). The reaction was stirred for 24 h, concentrated, purified by HPLC and freeze-dried to give 10 mg (5%) of the title compound; HRMS (M + H) &lt; + &gt; for C ₂₄ H ₂₅ N ₆ O ₄ was 461.1918.
[1103] Example 27
[1104] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide
[1105] Part A. Ethyl 6- (4-iodophenyl) -1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] Pyridine-3-carboxylate (0.57 g, 1.1 mmol), 2-hydroxypyridine (0.125 g, 1.3 mmol), K ₂ CO ₃ (0.18 g, 1.3 mmol) was combined in DMSO (5 mL) and added with N ₂ . It was degassed. Copper (I) iodide (41 mg, 0.21 mmol) was added and the reaction was heated to 130 ° C. for 24 h. The reaction was quenched with NH ₄ 0H dilute solution and filtered. The filtrate was extracted with EtOAc and dried (MgSO ₄ ). Purification on silica gel using 0-5% MeOH / CH ₂ Cl ₂ as eluent gave 70 mg (13%) of ester; Mass spectrometry (M + H) + 485.2.
[1106] To the ester obtained from part A in part B. formamide (4 mL) and DMF (3 mL) (0.07 g, 0.144 mmol) 25% NaOMe / MeOH 1 drop was added. The reaction was stirred for 48 h and then partitioned between EtOAc and water. Extracted with EtOAc, dried (MgSO ₄ ) and purified by HPLC to give 25 mg (38%) of the title compound;
[1107]
[1108] Example 28
[1109] 1- (4-methoxyphenyl) -3- (methylsulfonyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] 1,4,5,6-tetrahydro-7H-pyra Solo [3,4-c] pyridin-7-one
[1110] Part A. To p-anisidine (4.39 g, 3.6 mmol) in concentrated HCl (9.2 mL) and water (20 mL) was slowly added sodium nitrite (2.58 g, 3.7 mmol) in water (20 mL) at 0 ° C. . The reaction was stirred cold for 0.5 h. The mixture was converted to 3-chloromethanesulfonyl acetone [Grossert et. al., Can. J. Chem. 62, 1984, 798] (6.1 g, 3.5 mmol), acetone (50 mL), sodium acetate (6.7 g, 8.2 mmol) and water (100 mL). The reaction was stirred at rt for 4 h and the precipitate was filtered off and dried to give hydrazone as a red solid (5.28 g, 57%);
[1111]
[1112] Part B. Hydrazone (0.78 g, 2.9 mmol) and 3- (4-morpholinyl) -1- (4-nitrophenyl) -5,6-dihydro-2 obtained from part A in toluene (30 mL) Triethylamine (1 mL, 7.2 mmol) was added to (1H) -pyridinone (0.9 g, 2.9 mmol) and the reaction was heated to reflux for 18 h. The reaction was cooled to room temperature and excess TFA was added. After 24 hours the reaction was diluted with ethyl acetate, washed with water and saturated NaHCO ₃ and dried (MgSO ₄ ). Purification on silica gel with 1: 1 hexanes / ethyl acetate gave 0.63 g (48%) of a tan foam;
[1113]
[1114] Part C. The nitro compound of Part B (0.63 g) was hydrogenated at 45 psi in 20 mg of ethanol / ethyl acetate / HCl and 10% palladium on carbon for 3 hours. The reaction was filtered and concentrated to afford amine. To this amine (400 mg) in THF (20 mL) was added 5-bromovaleryl chloride (0.14 mL, 1.0 mmol) and triethylamine (0.32 mL, 2.2 mmol) and stirred for 24 h. Potassium t-butoxide (0.33 g, 2.6 mmol) was added and the reaction stirred for 72 hours. The reaction was quenched with water, extracted with ethyl acetate, washed with brine and dried (MgSO ₄ ). Purification with 2% MeOH / ethyl acetate on silica gel using 1: 2 hexanes / ethyl acetate and recrystallization from isopropyl alcohol gave 0.1 g (23%):
[1115]
[1116] Example 29
[1117] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (2-pyridinyl) -1,4,5,6-tetrahydro -7H-pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1118] Part A. glyoxylic acid monohydrate in the solution of 4-methoxyphenyl hydrazine hydrochloride (3 g, 17 mmol) H 2 O (20 mL) containing concentrated HCl (1.8 mL) of H ₂ O (28 mL) ( 1.6 g, 17 mmol). After 2 hours the red precipitate was filtered off and dried to give 3 g (89%) of hydrazone.
[1119] Part B. The hydrazone (1 g, 5.0 mmol) obtained from part A was placed in DMF (10 mL), cooled to -5 ° C and NBS (1.8 g, 10 mmol) in DMF (10 mL) was added slowly. The reaction was left at room temperature for 15 minutes, then 3- (4-morpholinyl) -1- (4-iodophenyl) -5,6-dihydro-2 (1H) -pyridinone (1.97 g, 5.0 mmol) was added. TEA (1.4 mL, 32 mmol) in toluene (25 mL) was added dropwise and the reaction was stirred at rt for 24 h. The morpholine intermediate was extracted with EtOAc, washed with H ₂ O and dried (Na ₂ SO ₄ ). The morpholine intermediate was treated with TFA (5 mL) in CH ₂ Cl ₂ (30 mL) for 24 hours. Diluted with CH ₂ Cl ₂ , washed with H ₂ O, saturated NaCl and dried (Na ₂ SO ₄ ) to give a foam. Purification on silica gel with 2: 1 hexanes / ethyl acetate and recrystallization from CH ₂ Cl ₂ / hexanes gave 1.4 g (55%); Mass spectrometry (M + H) + 524-526.
[1120] Part C. Compound (0.32 g, 0.6 mmol), 2-hydroxypyridine (35 mg, 0.36 mmol), K ₂ CO ₃ (0.135 g, 0.97 mmol) obtained from part B was combined in DMSO (5 mL) and N ₂ Was degassed. Copper iodide (I) (23 mg, 0.12 mmol) was added and the reaction was heated to 130 ° C. for 24 h. The reaction was quenched with NH ₄ 0H dilute solution and filtered. The filtrate was extracted with EtOAc and dried (Na ₂ SO ₄ ). Purification on silica gel using 0-2% MeOH / CH ₂ Cl ₂ as eluent gave 130 mg (43%) of bromo compound; Mass spectrometry (M + H) + 513.3-515.2.
[1121] Part D. To compound (0.13 g, 0.26 mmol) obtained from part C, 2-tributylstannylpyridine (0.16 g, 0.34 mmol) and toluene (25 mL) were added. The mixture was degassed with N ₂ for 10 minutes, then tetrakistriphenylphosphine palladium (10 mg) was added. The reaction was heated to reflux for 24 hours. The cooled reaction was diluted with ethyl acetate, then washed successively with saturated aqueous KF, brine and dried (MgSO ₄ ). Silica gel chromatography using 0-5% MeOH / CH ₂ Cl ₂ (1% NH ₃ ) as eluent, then purified by HPLC and freeze-dried to give 0.20 mg (12%) of the title compound: C ₂₉ H HRMS (M + H) &lt; + &gt; for ₂₄ N ₅ O ₃ was 490.1880;
[1122]
[1123] Example 30
[1124] 1- [3-aminomethylphenyl] -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H- Pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1125] Nitrile precursors were prepared using the morpholine-enamine and corresponding trifluoromethyl hydrazone moieties described in Example 3 according to the general [3 + 2] method. Ullman coupling with δ-valerolactam gave the desired nitrile precursor. Example 4 The benzonitrile was reduced as in Part B and then purified via preparative HPLC to afford the desired benzylamine analog. LRMS 484 (M + H).
[1126] Example 31
[1127] 3- [7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-1-yl] benzamide
[1128] The benzonitrile precursor obtained from Example 30 was hydrolyzed with hydrogen peroxide in sodium hydroxide to afford the title compound which was purified via preparative HPLC to give pure compound. LRMS 498 (M + H).
[1129] Example 32
[1130] 1- (3-chlorophenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide
[1131] The title compound was prepared according to the general method described above.
[1132]
[1133] Example 33
[1134] 1- (3-chlorophenyl) -7-oxo-6- [4- (2-oxo-1 (2H) pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carboxamide
[1135] The title compound was prepared according to the general method described above.
[1136]
[1137] Example 34
[1138] 1- (3-chlorophenyl) -N, N-dimethyl-7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H -Pyrazolo [3,4-c] pyridine-3-carboxamide
[1139] The title compound was prepared according to the general method described above.
[1140]
[1141] Example 35
[1142] 1- (3-chloro-4-fluorophenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide
[1143] The title compound was prepared according to the general method described above.
[1144]
[1145] Example 36
[1146] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carbonitrile
[1147] To dimethylformamide (0.2 mL, 2.6 mmol) in CH ₃ CN (20 mL) was added oxalyl chloride (0.23 mL, 2.6 mmol) at 0 ° C. and the reaction stirred for 0.5 h. The amide obtained from example 27 was added and the reaction stirred cold for 0.5 h. Pyridine (0.37 mL, 4.6 mmol) was added and the reaction was allowed to warm to rt and stirred for 24 h. The solvent was stripped off and the residue was partitioned between CH ₂ Cl ₂ and 1N HCl and the layers separated. The aqueous layer was basified with 1N NaOH and extracted with EtOAc. The organic layers were combined and dried (MgSO ₄ ). CH ₂ Cl ₂ and purified by silica gel chromatography using 3% MeOH in to give a re-crystallization to 117 mg (89%) from CH ₂ Cl ₂ / hexane;
[1148]
[1149] Example 37
[1150] 1- (3-amino-1 H-indazol-5-yl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxamide
[1151] 1- (3-cyano-4-fluorophenyl) -6- [4-iodophenyl] -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4, 5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (58 mg, prepared according to the general method described for Examples 3-5) was prepared as 1-butanol. (5 mL). To the solution was added hydrazine monohydrate (0.5 mL). The reaction mixture was refluxed for 4 hours, cooled to room temperature and the solvent removed. Purification of the residue using HPLC (RP gradient) gave the title compound as its TFA salt (25 mg, 42%).
[1152]
[1153] Example 38
[1154] 1- (3-amino-1, 2-benzisoxazol-5-yl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7 -Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide
[1155] The title compound was prepared from its corresponding 4-fluoro-3-cyano intermediate (described above for Examples 3-5).
[1156]
[1157] Example 39
[1158] 5-chloro-N- [5-chloro-3-methoxy-2-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide
[1159] To Part A. 4-iodomethylbenzoate solution was added δ-valerolactam (1 equiv), cesium carbonate (1.5 equiv) followed by the catalytic amount of CuI. The reaction mixture was heated at 100 ° C. overnight, cooled and quenched with water. The organics were extracted with ethyl acetate, dried (magnesium sulfate) and evaporated to afford the crude product, which was purified via silica gel column chromatography (hexane: ethyl acetate) to give the coupled product.
[1160] Part B. LiOH (1 equivalent of excess) and water were added to the product obtained from Part A in THF. The reaction mixture was stirred at rt overnight and quenched with dilute HCl. The desired carboxylic acid intermediate was extracted with ethyl acetate, dried and evaporated to yield the product.
[1161] Part C. To the product obtained from Part B in dichloromethane was added 1 equivalent of thionyl chloride with a catalytic amount of DMF. The reaction mixture was stirred at rt overnight and concentrated to afford 4- (2-oxo-piperidin-1-yl) -benzoyl chloride.
[1162] Part D. To a solution of 2-nitro-5-chloro-benzoyl chloride in dichloromethane 2-amino-5-chloropyridine (1 equiv) and DMAP (2 equivalents excess) were added. The reaction mixture was stirred at rt overnight, quenched with water and the organics extracted with ethyl acetate and dried (magnesium sulfate). Evaporation gave the coupled product.
[1163] Part E. The product obtained from part A was dissolved in ethyl acetate. 3 equivalents of tin chloride was added to the solution, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium hydroxide solution, and the organics were extracted with ethyl acetate, dried and evaporated to yield anilino derivatives.
[1164] Part F. The product obtained from part B is dissolved in dichloromethane and to this solution 4- (2-oxo-piperidin-1-yl) -benzoyl chloride (1 equiv) and DMAP (excess 2 equivalents) are added It was. The reaction mixture was stirred at rt overnight, concentrated and purified via reverse phase preparative HPLC (acetonitrile / water / TFA) to afford the title compound.
[1165] Example 40
[1166] 5-chloro-N- [5-chloro-3-methoxy-2-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) phenyl] -2-pyridincar Voxamide
[1167] To Part A. 4-iodomethylbenzoate solution was added 2-hydroxypyridine (1 equiv), cesium carbonate (1.5 equiv) and a catalytic amount of CuI. The reaction mixture was heated at 100 ° C. overnight, cooled and quenched with water. The organics were extracted with ethyl acetate, dried and evaporated to afford the product, which was purified via silica gel column chromatography (hexane: ethyl acetate) to give the coupled product.
[1168] Part B. LiOH (1 equivalent of excess) and water were added to the product obtained from Part A in THF. The reaction mixture was stirred at rt overnight and quenched with dilute HCl. The desired carboxylic acid intermediate was extracted with ethyl acetate, dried and evaporated to yield the product.
[1169] Part C. To the product obtained from Part B in dichloromethane was added 1 equivalent of thionyl chloride with a catalytic amount of DMF. The reaction mixture was stirred at rt overnight and concentrated to afford 4- (2-oxo-pyridin-1-yl) -benzoyl chloride.
[1170] Part D. To a solution of 2-nitro-5-chloro-benzoyl chloride in dichloromethane 2-amino-5-chloropyridine (1 equiv) and DMAP (2 equivalents excess) were added. The reaction mixture was stirred at rt overnight, quenched with water, the organics extracted with ethyl acetate and dried (magnesium sulfate). Evaporation gave the coupled product.
[1171] Part E. The product obtained from part A was dissolved in ethyl acetate. 3 equivalents of tin chloride was added to the solution, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium hydroxide solution and the organics were extracted with ethyl acetate, dried and evaporated to afford the anilin product.
[1172] Part F. The product obtained from part B was dissolved in dichloromethane and 4- (2-oxo-pyridin-1-yl) -benzoyl chloride (1 equiv) and DMAP (excess 2 equivalents) were added to the solution. The reaction mixture was stirred at rt overnight, concentrated and purified via reverse phase preparative HPLC (acetonitrile / water / TFA) to afford the title compound.
[1173] Example 41-53
[1174] Examples 41-53 shown below can be prepared according to the methods of Examples 37-38.
[1175]
[1176]
[1177] Example 54-70
[1178] Examples 54-70 shown below can be prepared according to the method of Examples 37-38 using commercially available amino-nicotinic acid.
[1179]
[1180]
[1181] Example 71
[1182] Methyl 2- [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H -Pyrazol-5-yl] -3-oxopropanoate
[1183] Part A. Anhydrous methyl alcohol (1.4 L), 4-methoxyphenylhydrazine hydrochloride (25 g, 140 mmol), 4,4,4-trifluoro-1- (2 in a flame-dried 1-L flask -Furyl) -1,3-butanedione (30 g, 140 mmol) and trifluoroacetic acid (1.1 mL, 14 mmol) were combined. The resulting red slurry was kept at room temperature for 14 hours. Then a 50% solution of isopropyl alcohol / water (500 mL) was added and the mixture was stirred vigorously for 5 minutes. The mixture was filtered and left to precipitate further material from the filtrate and the new mixture was filtered. After another 3 hours, the resulting filtrate was filtered three times and the combined beige solids were oven dried under vacuum to afford 5- (2-furyl) -1- (4-methoxy-phenyl) -3- (trifluoro) Methyl) -1H-pyrazole (42 g, 96%) was obtained as a light brown solid.
[1184]
[1185] Part B. To the product obtained from Part B (20 g, 65 mmol) was added water (410 mL), 5% aqueous sodium dihydrogenphosphate (270 mL) and tert-butanol (410 mL). The resulting mixture was warmed to 60 ° C. and potassium permanganate (63,400 mmol) was added over 1.5 hours. After an additional 10 minutes, the resulting purple slurry was cooled to 0 ° C. and 400 mL of saturated aqueous sodium bisulfite was added to quench the reaction. The resulting brown slurry was filtered, washed with 500 mL of water and the filtrate was acidified to pH 1 with concentrated aqueous hydrogen chloride. The aqueous layer was extracted with ethyl acetate (6 × 150 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. Concentration gave 1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (16 g, 85%) as a light yellow solid.
[1186]
[1187] Part C. N-bromosuccinimide (42 g, 230 mmol) and 2 in a solution of 2-fluoro-4-iodo-1-methylbenzene (50 g, 210 mmol) in anhydrous acetone (490 mL) , 2'-azobisisobutyronitrile (100 mg, 0.60 mmol) was added. The resulting solution was heated to reflux and maintained for 5 hours under reflux conditions. The reaction was then cooled, concentrated and filtered. The filtrate was concentrated and the resulting dark red residue was purified by flash column chromatography (10% ethyl acetate in hexane) to give 1- (bromomethyl) -2-fluoro-4- iodobenzene (49 g, 73 %) And 4: 1 mixture (58 g) of 2-fluoro-4-iodo-1-methylbenzene (9 g, 17%) were obtained as a red solid.
[1188]
[1189] Part D. The product (58 g, 140 mmol) obtained from part C in toluene (500 mL) and water (500 mL) added sodium cyanide (34 g, 700 mmol) and tetrabutylammonium bromide (23 g, 70 mmol) Added. The resulting mixture was heated to reflux and maintained for 14 hours under reflux conditions. The dark brown mixture was then cooled and the layers separated. The aqueous layer was washed with ethyl acetate (200 mL) and the combined organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The organic layer was concentrated and the resulting residue was purified by flash column chromatography (10% ethyl acetate in hexane) to give (2-fluoro-4-iodophenyl) -acetonitrile (20 g, 54%) as yellow Obtained as a solid.
[1190]
[1191] Part E. To the product obtained from part D (20 g, 77 mmol) was added ethyl alcohol (470 mL), water (230 mL) and sodium hydroxide (31 g, 770 mmol). The resulting mixture was heated to reflux and maintained under reflux conditions for 2 hours. The reaction was then cooled and concentrated and acidified to pH 1 with concentrated aqueous hydrochloric acid. The resulting mixture was filtered and the filter cake was dried in a vacuum oven to give (2-fluoro-4-iodophenyl) acetic acid (21 g, 96%) as a yellow solid.
[1192]
[1193] Part F. To the product obtained from part E (10 g, 36 mmol) was added methyl alcohol (25 mL) and benzene (250 mL). The resulting solution was cooled to 0 ° C. and (trimethylsilyl) diazomethane (9 mL, 38 mmol; 2.0 M in hexane) was added dropwise over 15 minutes. After 1 hour, the reaction was concentrated and the resulting residue was purified by flash column chromatography (10-20% ethyl acetate in hexane) to give methyl (2-fluoro-4-iodophenyl) acetate (6.9 g, 66 %) Was obtained as a yellow oil.
[1194]
[1195] Potassium carbonate (1.9 g, 14 mmol) and 2-hydroxypyridine (650) in methyl (2-fluoro-4-iodophenyl) acetate (1.0 g, 3.4 mmol) in part G. dimethylsulfoxide (68 mL) mg, 6.8 mmol) was added. The resulting mixture was degassed (three times vacuum / nitrogen alternating) and copper iodide (I) (650 mg, 3.4 mmol) was added in one portion. The light green mixture was degassed again (vacuum / N ₂ ) and warmed to 125 ° C. After 14 hours, the brown-black mixture was cooled and poured into saturated aqueous ammonium hydroxide (50 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was washed with water (2 x 50 mL) and saturated aqueous sodium chloride. The organic layer was concentrated and the resulting residue was purified by radial chromatography (20-100% ethyl acetate in hexane) to give methyl [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] Acetate (340 mg, 39%) was obtained as a green-brown solid.
[1196]
[1197] Part H. In a flame-dried flask, 1- (4-methoxy) in a stirred solution of trimethylacetyl chloride (0.026 mL, 0.21 mmol), triethylamine (0.058 mL, 0.42 mmol) and diethyl ether (2.6 mL) Phenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (60 mg, 0.21 mmol) was added. The resulting white slurry was warmed to 23 ° C. and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated. The resulting residue was partially redissolved in diethyl ether (2 mL) and filtered again. The filtrate was concentrated to give 2,2-dimethylpropanoic 1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic anhydride as a viscous oil.
[1198] Tetrahydrofuran (0.80 mL), hexamethylphosphoramide (0.80 mL) and diisopropylamine (0.050 mL, 0.36 mmol) were combined in a flame-dried fractionation flask. The solution was cooled to -78 ° C and n-butyllithium (0.176 mL, 0.44 m mmol) was added in one portion. After 20 minutes methyl (2-fluoro-4-iodophenyl) acetate (110 mg, 0.42 mmol; part F) in tetrahydrofuran (1.0 mL) was added via cannula and the resulting red mixture was -78 ° C. It was kept for 20 minutes at. Subsequently, pre-prepared 2,2-dimethylpropanoic 1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic anhydride was added with tetrahydrofuran (1.5 mL ) Was added via cannula as a solution in) and the resulting light yellow mixture was warmed to 23 ° C. After 2 hours the reaction was poured into 1N aqueous hydrochloric acid (50 mL) and washed with ethyl acetate (3 x 50 mL), the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The resulting residue was purified by radial chromatography (1-5% methyl alcohol in dichloromethane) to give methyl 2- [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3 -[1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -3-oxopropanoate (54 mg, 49%) was obtained as a white solid. . LC / MS (ESI &lt; + &gt;): 530.1 (M + H) &lt; + &gt;.
[1199] Example 72
[1200] 1- (3-fluoro-4- {2- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2-oxoethyl} phenyl) -2 (1H) -pyridinone
[1201] Part A. Methyl 2- [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- [1- (4-methoxyphenyl) -3- (trifluoromethyl ) -1H-pyrazol-5-yl] -3-oxopropanoate (part H, Example 71) (24 mg, 0.045 mmol) with methyl alcohol (2.3 mL) and concentrated aqueous dihydrosulfate (0.048 mL) ) Was added. The reaction was then warmed to reflux. After 48 hours, monitoring by LC / MS (C18 reverse phase, eluting with 0.05% TFA in acetonitrile / water) showed 90% of starting material remaining. An additional 0.80 mL portion of 4M aqueous dihydrosulfate was added and the reaction maintained for 6 hours under reflux conditions. The reaction was cooled to 0 ° C. and the resulting white precipitate was filtered to give 1- (3-fluoro-4- {2- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H- Pyrazol-5-yl] -2-oxoethyl} phenyl) -2 (1H) -pyridinone (11 mg, 52%) was obtained as a white solid.
[1202]
[1203] Example 73
[1204] 1- (4- {2- [1- (3-amino-1, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2- Oxoethyl} -3-fluorophenyl) -2 (1H) -pyridinone trifluoroacetate
[1205] Part A. 1- (3-cyano-) in a stirred solution of trimethylacetyl chloride (0.021 mL, 0.17 mmol), triethylamine (0.071 mL, 0.51 mmol) and diethyl ether (3.4 mL) in a flame-dried flask. 4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (51 mg, 0.17 mmol) was added. The resulting white slurry was warmed to 23 ° C. and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated. The resulting residue was partially redissolved in diethyl ether (5 mL) and filtered again. The filtrate was concentrated to give 1- (3-cyano-4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic 2,2-dimethylpropanoic anhydride. .
[1206] Tetrahydrofuran (2.0 mL), hexamethylphosphoramide (1.4 mL) and diisopropylamine (0.052 mL, 0.37 mmol) were combined in a flame-dried dispense flask. The solution was cooled to -78 ° C and n-butyllithium (0.142 mL, 0.35 m mmol) was added in one portion. After 20 minutes methyl [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) -phenyl] acetate (88 mg, 0.34 mL; part G, Example 71) was added tetrahydrofuran (1.5 mL Was added via cannula as a solution in) and the resulting red mixture was kept at -78 ° C for 20 minutes. Subsequently, 1- (3-cyano-4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic 2,2-dimethylpropanoic anhydride prepared in advance The solution was added via cannula as a solution in hydrofuran (1.5 mL) and the resulting light yellow mixture was warmed to 23 ° C. After 1 hour, the reaction was poured into water (50 mL) and ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The resulting residue was purified by radial chromatography (15-40% ethyl acetate in hexane) to give methyl 3- [1- (3-cyano-4-fluorophenyl) -3- (trifluoromethyl) -1H -Pyrazol-5-yl] -2- [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3-oxopropanoate (22 mg, 23%) Obtained as an oil. LC / MS (ESI &lt; + &gt;): 543.0 (M + H) &lt; + &gt;.
[1207] Part B. To the product obtained from Part A (22 mg, 0.040 mmol) was added methyl alcohol (0.72 mL) and 4M aqueous dihydrosulfate (0.24 mL). The reaction was then heated to reflux. After 24 hours, the reaction was cooled to 0 ° C. and the resulting white precipitate was filtered to give 2-fluoro-5- [5-{[2-fluoro-4- (2-oxo-1 (2H) -pyridinyl ) Phenyl] acetyl} -3- (trifluoromethyl-1H-pyrazol-1-yl] benzonitrile (12 mg, 61%) was obtained as a white solid.
[1208]
[1209] Part C. To the product obtained from part B (10 mg, 0.040 mmol) was added N, N-dimethylformamide (0.50 mL), water (0.50 mL) and potassium carbonate (29 mg, 0.20 mmol). Acetohydroxamic acid (3.5 mg, 0.046 mmol) was added in one portion and the resulting yellow mixture was warmed to 50 ° C. After 2 hours, the reaction was cooled to room temperature and the reaction mixture was purified by preparative LC / MS (C18 reverse phase, eluted with 0.05% TFA in CH ₃ CN / H ₂ O) to 1- (4- {2- [1- (3-amino-1,2-benzisoxazol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2-oxoethyl} -3-fluorophenyl)- 2 (1H) -pyridinone trifluoroacetate (8.0 mg, 67%) was obtained as a beige solid.
[1210]
[1211] Example 74
[1212] 5-{[2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] acetyl} -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxamide
[1213] Part A. A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to −78 ° C. and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 minutes di-tert-butyl oxalate was added dropwise over 1 hour as a solution in 100 mL of ether. The resulting mixture was warmed to 23 ° C. over 3 hours and kept at room temperature for 20 hours. The mixture was then filtered and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was dried in a vacuum oven for 1 hour to obtain lithium 1-tert-butoxy-4- (2-furyl) -1,4-dioxo-2-butene-2-oleate (25 g, 83%). Obtained as a creamy solid.
[1214]
[1215] Part B. To the product obtained from Part A (1.0 g, 4.6 mmol) was added 4-methoxyphenylhydrazine hydrochloride (480 mg, 2.8 mmol) and glacial acetic acid (15 mL). The resulting orange mixture was warmed to 40 ° C. and then cooled to room temperature after 1.5 hours. The reaction was poured into saturated aqueous sodium bicarbonate (100 mL) and the aqueous layer was washed with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting red-black residue was recrystallized from hexane to give tert-butyl 5- (2-furyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (870 mg, 93%) Was obtained as a yellow-orange solid.
[1216]
[1217] Part C. tert-butyl 5- (2-furyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (1.0 g, 3.0 mmol) in dichloromethane (7 mL) and tree Fluoroacetic acid (7 mL) was added. The resulting black solution was maintained at room temperature under nitrogen for 2 hours and then concentrated to dryness. The resulting mixture was triturated with chloroform and the residual solid was washed with 50% hexanes in chloroform to give 5- (2-furyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylic acid (800 mg, 96%) was obtained as a light brown solid.
[1218]
[1219] Part D. To the product obtained from part C (800 mg, 2.8 mmol) was added dichloromethane (50 mL) and 2.0 M oxalyl chloride (2.1 mL, 4.2 mmol) in dichloromethane. N, N-dimethylformamide (2 droplets) was added dropwise to the brown mixture, followed by evolution of gas and clearing the mixture over 30 minutes. The brown solution was concentrated and the resulting residue was redissolved in dichloromethane (50 mL) and 0.5 M ammonia (23 mL, 11 mmol) in dioxane was added via cannula. After 30 minutes, the resulting beige suspension was poured into water (80 mL). The aqueous layer was washed with dichloromethane (3 x 50 mL) and the combined organic layers were dried over sodium sulfate and concentrated to give 5- (2-furyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carbox Amide (650 mg, 82%) was obtained as a beige solid.
[1220]
[1221] Part E. 5- (2-furyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxamide (2.0 g, 6.6 mmol) in pyridine (1.6 mL, 20 mmol) and dioxane (66 mL) was added. Trifluoroacetic anhydride (1.9 mL, 13 mmol) was added dropwise over 2 minutes and the resulting suspension was stirred for 40 minutes. The clear red solution was now poured into water (70 mL) and ethyl acetate (70 mL). The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid (2 × 50 mL), saturated aqueous sodium chloride and dried over sodium sulfate. The organic layer was concentrated and the resulting residue was purified by radial chromatography (20-80% ethyl acetate in hexane) to give 5- (2-furyl) -1- (4-methoxyphenyl) -1H-pyrazole-3 Carbonitrile (1.4 g, 74%) was obtained as an orange solid.
[1222]
[1223] Part F. To the product obtained from part E (1.4 g, 4.9 mmol) was added water (30 mL), 5% aqueous sodium dihydrogenphosphate (21 mL) and tert-butanol (30 mL). The resulting mixture was warmed to 60 ° C. and potassium permanganate (4.7 g, 29 mmol) was added over 5 minutes. After another 5 minutes, the resulting purple slurry was cooled to 0 ° C. and 50 mL of saturated aqueous sodium bisulfite was added to quench the reaction. The resulting brown mixture was filtered and washed with 100 mL of water and the filtrate was acidified with 6N aqueous hydrogen chloride. The resulting mixture was filtered to give 3-cyano-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid (300 mg, 25%) as a yellow solid. The aqueous layer was extracted with ethyl acetate (2 x 50 mL) to give an additional 215 mg (18%) of impure 3-cyano-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid in yellow. Obtained as an oil.
[1224]
[1225] Part G. In a flame-dried flask, 3-cyano-1- (3) was added to a stirred solution of trimethylacetyl chloride (0.087 mL, 0.70 mmol), triethylamine (0.290 mL, 2.1 mmol) and diethyl ether (14 mL). 4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid (170 mg, 0.70 mmol) was added. The resulting white slurry was warmed to 23 ° C. and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated. The resulting residue was partially redissolved in diethyl ether (15 mL) and filtered again. The filtrate was concentrated to give 3-cyano-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic 2,2-dimethylpropanoic anhydride as a viscous oil.
[1226] Tetrahydrofuran (8.0 mL), hexamethylphosphoramide (6.0 mL) and diisopropylamine (0.200 mL, 1.5 mmol) were combined in a flame-dried fractionation flask. The solution was cooled to -78 ° C and n-butyllithium (0.560 mL, 1.4 m mmol) was added in one portion. After 20 minutes, [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) -phenyl] acetate (360 mg, 1.4 mL; Part G, Example 71 in tetrahydrofuran (5 mL) ) Was added via cannula and the resulting red mixture was kept at -78 ° C for 20 minutes. Subsequently prepared 3-cyano-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic 2,2-dimethylpropanoic anhydride as a solution in tetrahydrofuran (5 mL) It was added via cannula and the resulting light yellow mixture was warmed to 23 ° C. After 12 h, the reaction was poured into water (50 mL) and ethyl acetate (75 mL) and the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The resulting residue was purified by radial chromatography (50-60% ethyl acetate in hexane) to give 3- [3-cyano-1- (4-methoxyphenyl) -1H-pyrazol-5-yl] -2 -[2-Fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3-oxopropanoate (131 mg, 40%) was obtained as an effervescent solid. LC / MS (ESI &lt; + &gt;): 487.0 (M + H) &lt; + &gt;.
[1227] Part H. 3- [3-Cyano-1- (4-methoxyphenyl) -1H-pyrazol-5-yl] -2- [2-fluoro-4- (2-oxo-1 (2H) To -pyridinyl) phenyl] -3-oxopropanoate (100 mg, 0.210 mmol) was added methyl alcohol (1.5 mL) and 4M aqueous dihydrosulfate (0.50 mL). The reaction was then warmed to reflux. After 4 days, the reaction was cooled to 23 ° C. and the resulting white suspension was poured into saturated aqueous hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to 5-{[2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] acetyl} -1- (4-meth Oxyphenyl) -1H-pyrazole-3-carbonitrile (75 mg, 85%) was obtained as a pale yellow oil. LC / MS (ESI &lt; + &gt;): 429.0 (M + H) &lt; + &gt;.
[1228] Part I. 5-{[2-Fluoro-4- (2-oxo-1 (2H) -pyridinyl) -phenyl] acetyl} -1- (4-methoxyphenyl) -1H-pyrazole-3- To carbonitrile (75 mg, 0.175 mmol) was added concentrated aqueous dihydrosulfate (4.5 mL). After 2 hours, the reaction was poured into ethyl acetate (50 mL) and water (50 mL) and the layers separated. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and concentrated to dryness. The resulting residue was purified by radial chromatography (2% methyl alcohol in dichloromethane), lyophilized from 10% acetonitrile in water and then 5-{[2-fluoro-4- (2-oxo-1 (2H) -Pyridinyl) phenyl] acetyl} -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxamide (32 mg, 41%) was obtained as a white solid.
[1229]
[1230] Example 75
[1231] 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1 (2H) pyridinyl) -2,3-dihydro-1H-indole- 1-yl] carbonyl} -1H-pyrazole-3-carboxamide
[1232] Part A. 2 in lithium 1-tert-butoxy-4- (2-furyl) -1,4-dioxo-2-butene-2-oleate (13 g, 54 mmol; Example 74, part A) -Fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250 mL glacial acetic acid were added. The resulting orange mixture was kept at room temperature for 20 hours and then concentrated to dryness. The resulting residue was taken up in 30% chloroform in hexanes and filtered to tert-butyl 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) -1H-pyrazole-3-carboxylate (18 g, 95%) was obtained as a light brown solid.
[1233]
[1234] Part B. To the product from Part A (10 g, 28 mmol) was added 125 mL of dichloromethane and 125 mL of trifluoroacetic acid. The resulting black solution was maintained at room temperature under nitrogen for 2 hours and then concentrated to dryness. The resulting solid was triturated with ethyl acetate and dried in a vacuum oven for 4 hours to give 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) -1H-pyrazole-3-car Acid (5.3 g, 63%) was obtained as a light brown solid.
[1235]
[1236] Part C. To the product obtained from part B (4.1 g, 14 mmol) was added 23 mL of dichloromethane and 2.0 M oxalyl chloride (10 mL, 21 mmol) in dichloromethane. After the dropwise addition of N, N-dimethylformamide (10 drops), the brown mixture became a clear solution over 30 minutes. The solution was concentrated, the resulting residue was redissolved in 100 mL of dichloromethane and 0.5 M ammonia (110 mL, 55 mmol) in dioxane was added via cannula. After 30 minutes the resulting suspension was concentrated and poured into water. The aqueous layer was washed with ethyl acetate (3 x 70 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The resulting residue was dissolved in 10 mL of dichloromethane and 50 mL of hexanes were added. The resulting suspension was filtered, the filter cake was washed with 50 mL of hexane and dried in a vacuum oven to give 1- (3-cyano-4-fluorophenyl) -5- (2-furyl) -1H-pyrazole-3- Carboxamide (2.5 g, 62%) was obtained as a brown solid.
[1237]
[1238] Part D. To the product obtained from part C (2.5 g, 8.3 mmol) was added water (51 mL), 5% aqueous sodium dihydrogenphosphate (35 mL) and tert-butanol (51 mL). The resulting mixture was warmed to 60 ° C. and potassium permanganate (8.0 g, 51 mmol) was added over 10 minutes. After another 10 minutes, the resulting purple slurry was cooled to 0 ° C. and 200 mL of saturated aqueous sodium bisulfite was added to quench the reaction. The resulting mixture was filtered and washed with 300 mL of water and the filtrate was acidified with concentrated hydrogen chloride. The aqueous layer was extracted with ethyl acetate (6 × 100 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. Concentration gave 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid (1.6 g, 71%) as a yellow solid.
[1239]
[1240] Part E. Sodium cyanoborohydride (1.54 g, 25 mmol) was added in one portion to an orange stirred solution of 5-iodo-1H-indole (6.0 g, 25 mmol) in glacial acetic acid (350 mL). After 24 hours, the orange solution was concentrated. To the resulting red residue, tetrahydrofuran (250 mL) and di-tert-butyl dicarbonate (16 g, 74 mmol) were added followed by saturated aqueous sodium bicarbonate (20 mL). The resulting mixture was stirred for 24 hours and then poured into aqueous 1N hydrogen chloride (70 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and concentrated. The resulting residue was dissolved in THF (100 mL) and benzyl amine (6 mL, 55 mol) was added. The resulting solution was stirred for 1.5 h and then poured into 1N hydrogen chloride (70 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography (5% ethyl acetate in hexanes) to afford tert-butyl 5-iodo-1-indolincarboxylate (3.9 g, 45%) as a white solid.
[1241]
[1242] Part F. To the product obtained from part E (1.65 g, 4.8 mmol) was added dimethylsulfoxide (59 mL), 2-hydroxypyridine (910 mg, 9.6 mmol) and potassium carbonate (2.6 g, 19 mmol). The resulting mixture was degassed (vacated & alternating three times with nitrogen) and copper (I) iodide (910 mg, 4.8 mmol) was added in one portion. The light green mixture was now degassed again (vacuum / N ₂ ) and warmed to 122 ° C. After 3 hours, the mixture was cooled and poured into saturated aqueous ammonium hydroxide (100 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer was washed with 50 mL-part ethyl acetate. The combined organic layers were then washed with water (2 x 50 mL), saturated aqueous sodium chloride and dried over sodium sulfate. The organic layer was concentrated and the resulting oil was purified by flash column chromatography (10-100% ethyl acetate in hexane) to give tert-butyl 5- (2-oxo-1 (2H) -pyridinyl) -1-indolin Carboxylate (660 mg, 44%) was obtained as a yellow solid.
[1243]
[1244] Part G. To the product obtained from part F (610 mg, 2.0 mmol) was added dichloromethane (6 mL) and trifluoroacetic acid (6 mL). After 20 minutes, the reaction was concentrated to dryness and treated with saturated aqueous sodium bicarbonate (15 mL). The layers were separated and the aqueous layer was washed with dichloromethane (2 x 50 mL). The organic layer was dried over sodium sulfate and concentrated to give 1- (2,3-dihydro-1H-indol-5-yl) -2 (1H) -pyridinone (410 mg, 99%).
[1245]
[1246] Part H. The product obtained from part G (274 mg, 1.30 mmol) was added to 3- (aminocarbonyl) -1- (3-cyano-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ( 390 mg, 1.4 mmol) was added and pyridine (11 mL) and N, N-dimethylformamide (4.0 mL) were added. Then 1,3-diisopropylcarbodiimide (0.242 mL, 1.6 mmol) was added and the resulting solution was stirred for 14 hours. The red mixture was poured into 1N aqueous hydrochloric acid (70 mL) and washed with ethyl acetate (60 mL). The organic layer was washed with 1N aqueous hydrochloric acid (3 × 25 mL), saturated aqueous sodium chloride and dried over sodium sulfate. The organic layer was concentrated and the resulting residue was purified by radial chromatography (5% methyl alcohol in dichloromethane) to partially pure 1- (3-cyano-4-fluorophenyl) -5-{[5- (2 -Oxo-1 (2H) -pyridinyl) -2,3-dihydro-1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide (620 mg, 62%) in red Obtained as an oil (LC / MS (ESI &lt; + &gt;): 469.0 (M + H) &lt; + &gt;). The material was dissolved in N, N-dimethylformamide (10 mL) and potassium carbonate (910 mg, 6.6 mmol) and water (3.0 mL) were added. Acetohydroxamic acid (110 mg, 1.5 mmol) was added in one portion and the resulting yellow mixture was warmed to 50 ° C. After 1.5 h, the reaction was cooled to rt, concentrated and diluted with ethyl acetate (10 mL). Filtration gave 1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1 (2H) -pyridinyl) -2,3-dihydro-1H -Indol-1-yl] carbonyl} -1 H-pyrazole-3-carboxamide (100 mg, 16%) was obtained as a white solid.
[1247]
[1248] Example 76
[1249] 1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (trifluoromethyl) -1 , 4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1250] Part A. 1-benzyl-6-indolinamine (2.40 g, 10.85 mmol) was stirred at 0 ° C. under N ₂ in concentrated HCl (25 mL). NaNO ₂ solution (0.749 g, 10.85 mmol) in pre-cooled H ₂ O (2 mL) was added slowly dropwise. After addition, the mixture was then stirred at 0 ° C. for 40 minutes. A solution of SnCl ₂ -2H ₂ O (6.10 g, 2.5 equiv) in concentrated HCl (7 mL) was added slowly at 0 ° C. to the stirred solution. The resulting mixture was stirred vigorously at 0 ° C. for 30 minutes. Slurry of 1- (4-iodophenyl) -4- (2,2,2-trifluoroacetyl) piperidine-2,3-trione (4.20 g, 1.02 mmol) in MeOH (30 mL) A small portion was added to the mixture at 0 ° C. The resulting mixture was gradually warmed and stirred at room temperature for 2 hours and then at 50 ° C. for 5 hours. LC-MS indicated completion of the reaction. The solvent was evaporated. The residue was basified with aqueous NaOH, extracted with EtOAc, washed with H ₂ O, brine, dried over MgSO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, CH ₂ Cl ₂ ) to give 1- (1-benzyl-2,3-dihydro-1H-indol-6-yl) -6- (4-iodo Phenyl) -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one (2.05 g, 31%)-bright orange Yellow crystals were prepared.
[1251]
[1252] Part B. The product from part A (0.33 g, 0.54 mmol), 2-hydroxypyridine (0.13 g, 1.37 mmol) and K ₂ CO ₃ (0.20 g, 1.45 mmol) were dissolved in NSO at room temperature under N ₂ (1.5 mL). Was stirred). CuI (44 mg, 0.23 mmol) and 1,10-phenanthroline (40 mg, 0.23 mmol) were added. The resulting mixture was stirred at 140 ° C. for 2.5 h under N ₂ . LC-MS showed loss of starting material from Part A. The mixture was cooled to rt and EtOAc was added. It was washed with H ₂ O, brine, dried over MgSO ₄ and concentrated. 1- (1-benzyl-2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (trifluoro The crude compound of methyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one was used directly in the next step.
[1253]
[1254] Part C. Product obtained from part B (0.33 g, 0.57 mmol), NaI (0.17 g, 1.14 mmol) and 1-chloroethyl chloroformate (0.10 mL, 1.8 equiv) at room temperature under N ₂ (2 mL) Stirred for 1.5 h. Solvent was evaporated and the residue was dissolved in MeOH (4 mL). Reflux for 1 hour. The residue was purified by preparative LC-MS (5-98% CH ₃ CN in H ₂ O, t _R = 4.18 min during 10 min operation). Fractions were collected and lyophilized to yield 1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- ( Trifluoromethyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one was obtained.
[1255]
[1256] Example 77
[1257] 1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4 , 5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1258] Part A. The product obtained from part A of Example 71 (0.89 g, 1.45 mmol), δ-valerolactam (0.20 g, 2. 02 mmol) and K ₂ CO ₃ (0.41 g, 2.97 mmol) were removed under N ₂ . Stir in DMSO (5 mL) at room temperature. CuI (86 mg, 0.45 mmol) and 1,10-phenanthroline (80 mg, 0.43 mmol) were added. The resulting mixture was stirred overnight at 130 ° C. under N ₂ . The mixture was cooled to rt and EtOAc was added. It was washed with brine (twice), dried over MgSO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, CH ₂ Cl ₂ , then CH ₂ Cl ₂ : EtOAc = 10: 3) to afford the desired product 1- (1-benzyl-2,3-dihydro-1H. -Indol-6-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H-pyra Jolo [3,4-c] pyridin-7-one (0.51 g, 68% based on recovered starting material) was prepared.
[1259]
[1260] Part B. The product obtained from part A (0.51 g, 0.87 mmol), NaI (0.26 g, 1.74 mmol) and 2-chloroethyl chloroformate (0.16 mL, 1.8 equiv) were diluted with acetone (4 hours at room temperature under N ₂ ). 5 mL). The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, CH ₂ Cl ₂ , then EtOAc, then EtOAc: MeOH = 10: 1) to give intermediate carbamate. Fractions were concentrated and dried under vacuum for 10 minutes. It was dissolved in MeOH (30 mL) and refluxed for 1 h under N ₂ . The residue was purified by preparative LC-MS (35-98% CH ₃ CN in H ₂ O, t _R = 2.24 min in 10 min operation). Fractions were collected and lyophilized to yield 1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoro Rommethyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one as a white solid.
[1261]
[1262] Example 78
[1263] 1- (2,3-dihydro-1H-isoindol-5-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) phenyl] -3-trifluoromethyl-1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt
[1264] Part A. A solution of 4-nitro-o-xylene (38.64 g, 255.9 mmol), NBS (91.1 g, 511.8 mmol), benzoyl peroxide (1.239 g, 5.118 mmol) and CCl ₄ (400 mL) was added for 1 hour. After heating to reflux, it was heated at room temperature for 2 days. The solid was filtered off and washed with CCl ₄ . The filtrate was evaporated to give crude dibromo product (80 g). A portion of the product (20 g) was dissolved in acetone (170 mL) and water (45 mL), followed by Na ₂ CO ₃ (43.1 g, 407 mmol), then BnNH ₂ (7.05 mL, in acetone (22 mL) 64.6 mmol) was added slowly. After 10 hours, the solution was concentrated to 1/4 of its volume, the solid salts were filtered off and the filtrate was evaporated. The residue was dissolved in EtOAc and washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the corresponding 2-benzyl-5-nitro-2,3-dihydro-1H-isoindole (5.41 g, 33% over 2 steps):
[1265]
[1266] Part B. To a solution of isoindoline (5.40 g, 21.3 mmol) prepared above in EtOH (266 mL) was added 20% Pd (OH) ₂ / C (3.00 g, 4.25 mmol) under N ₂ . The reaction mixture was hydrogenated at 45 psi for 1 hour. TLC analysis showed that the nitro functional group was reduced and the Bn group was still intact. Therefore, concentrated HCl (1.6 mL, 19.1 mmol) was added to the reaction mixture and hydrogenation (50 psi) was continued overnight. The mixture was filtered through Celite (R) and washed with MeOH and the filtrate was concentrated to 1/4 of volume. The precipitate was filtered to give 5-aminoisoindolin.HCl (1.32 g, 36% yield).
[1267]
[1268] Part C. The 5-aminoisoindolin (700 mg, 4.11 mmol) prepared above was dissolved in 6M HCl (4.6 mL) at room temperature and then cooled to 0 ° C. While maintaining the reaction temperature below 5 ° C., a solution of NaNO ₂ (340 mg, 4.93 mmol) in water (0.8 mL) was added dropwise. After 40 minutes, AcOH (1.4 mL) was added to the mixture, followed by dropwise addition of SnCl ₂ (1.79 g, 9.44 mmol) in concentrated HCl (2.7 mL) at 0 ° C. The mixture was warmed to 10 ° C. and stirred for 2 h, then 3-hydroxy-1- (4-iodophenyl) -4- (2,2,2-trifluoroacetyl)-in MeOH (16 mL) A solution of 5,6-dihydro-1H-pyridin-2-one (1.78 g, 4.31 mmol) was added and the reaction mixture was heated at 50 ° C. for 16 h. The methyl alcohol was removed under vacuum and the solid collected by filtration to yield 1- (2,3-dihydro-1H-isoindol-5-yl) -6-methyl-3-trifluoromethyl-1,4,5 , 6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one; The compound with iodo-benzene was obtained as AcOH salt (2.07 g, 86% yield):
[1269]
[1270] Part D. The product obtained from part C (540 mg, 1.03 mmol) was added to a stirred solution of Boc ₂ O (225 mg, 1.03 mmol) and Et ₃ N (143 mL, 1.03 mmol) in THF (5.2 mL) at room temperature. Added. After 2.5 hours, the solvent was removed in vacuo and the residue was purified by column chromatography to give the corresponding protected isoindolin 5- (6-methyl-7-oxo-3-trifluoromethyl-4,5,6 , 7-tetrahydro-pyrazolo [3,4-c] pyridin-1-yl) -1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester; Compound (272 mg, 42% yield) with iodo-benzene was prepared:
[1271]
[1272] Part E. Products obtained from part D (102 mg, 163 μmol), 2-hydroxy-pyridine (19 mg, 196 μmol), K ₂ CO ₃ (25 mg, 180 μmol), 1,10-phenanthroline ( 3 mg, 18 mmol), CuI (4 mg, 20 μmol) and DMSO (0.3 mL) were heated at 110-120 ° C. for 24 h under argon atmosphere. The mixture was diluted with CH ₂ Cl ₂ and washed with 1M HCl (twice) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography to give the corresponding biaryl lactam (17 mg), which was treated with TFA (21 mL) and purified by semi-preparative HPLC before the title compound 1- (2,3-di Hydro-1H-isoindol-5-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) phenyl] -3-trifluoromethyl-1,4,5,6-tetrahydro Pyrazolo [3,4-c] pyridin-7-one, trifluoroacetic acid salt (3.8 mg, 4% yield, 3 steps) was obtained:
[1273]
[1274] Example 79
[1275] 1- (4-methoxyphenyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -3- (2-pyrrolidin-1-ylmethyl-phenyl) -1 , 4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1276] Part A. A 250 mL flask containing a stir bar was charged with 4-methoxyphenylhydrazine HCl (3 g, 17 mmol) and 25 mL of water. A solution of glyoxylic acid monohydrate (1.6 g, 17 mmol) dissolved in 15 mL water was prepared and added dropwise to the stirred solution via an addition funnel. When the reagent solution was added, the reaction turned reddish brown and precipitated with stirring over the course of 3 hours at room temperature. The solid was filtered on a Buchner funnel and washed three times with 1N HCl and water, respectively. Hydrazone was isolated as a dark brown solid (2.7 g, 14 mmol) in 82% yield.
[1277] Part B. A 250 mL flask containing a stir bar was charged with Hydrazone (1.0 g, 5.1 mmol) and 10 mL DMF from Part A and then cooled to 0 ° C. The system was flushed with N ₂ . A solution of N-bromosuccinimide (1.8 g, 10 mmol) in 2 mL DMF was also prepared and added dropwise with a syringe to the reaction flask. When reagents were added, gas evolution was evident. The reaction was stirred at 0 ° C. for 15 minutes. A solution of iodo-morpholine enamine (3 g, 7.7 mmol) and triethylamine (1.4 mL, 10 mmol) in 20 mL toluene was added to the reaction at 0 ° C. The reaction was stirred overnight while warming to room temperature. The solution was diluted by adding water and ethyl acetate and transferred to the addition funnel. The aqueous phase was separated and extracted three times with ethyl acetate. The organics were combined, washed with brine and dried over sodium sulfate. Removal of solvent by rotary evaporation gave morpholine intermediate as an orange solid. The crude material was purified by flash chromatography (eluent 50% hexane, 50% ethyl acetate on silica gel) to give pure iodo-morpholine intermediate (1.2 g, 2.0 mmol) in 38% yield.
[1278] Part C. A 100 mL flask containing a stir bar was charged with iodo-morpholine intermediate (1.2 g, 2.0 mmol) and 10 mL of methylene chloride, followed by dropwise addition of 1 mL TFA with a syringe. The system was flushed with N ₂ while the reaction was stirred at rt overnight. The solution was diluted with methylene chloride and saturated sodium bicarbonate and then transferred to an addition funnel. The aqueous phase was separated and extracted three times with methylene chloride. The organics were combined and washed with brine and then dried over magnesium sulfate. The solution was filtered and the solvent removed by rotary evaporation to afford 3-bromopyrazole as an orange solid. The crude reaction product was purified by flash chromatography to give pure 3-bromopyrazole (560 mg, 1.1 mmol) in 53% yield.
[1279] Part D. Oven-dried 100 mL flasks and stir bars were prepared with 3-bromopyrazole (860 mg, 1.6 mmol), γ-valerolactam (230 mg, 2.5 mmol), potassium carbonate (270 mg, 2.0 mmol) and Charged with 10 mL degassed DMF. Copper iodide (62 mg, 0.33 mmol) was added and a reflux condenser was attached. The system was flushed with N ₂ while the reaction was heated to 120 ° C. overnight. The reaction was cooled to rt and diluted with ethyl acetate and water. The solution was transferred to an addition funnel and the aqueous phase was extracted three times with ethyl acetate. The organics were combined, washed three times with water and once with brine and dried over sodium sulfate. The product solution was filtered and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography to give bromo-lactam (150 mg, 0.3 mmol) in 19% yield.
[1280] Part E. An oven-dried 100 mL flask containing a stir bar was charged with bromo-lactam (90 mg, 0.18 mmol), 2-formylbenzeneboronic acid and sodium carbonate (60 mg, 0.54 mmol). The solid was dissolved in 3 mL of a 2: 1 mixture of degassed THF and water. After addition of tetrakis (triphenylphosphine) palladium (10 mg, 0.01 mmol), the flask was equipped with a reflux condenser and the system was flushed with N ₂ . The reaction was heated to 110 ° C. with stirring overnight. The reaction was cooled to rt and diluted with water and ethyl acetate. The solution was transferred to a separatory funnel and the aqueous phase was extracted with ethyl acetate. The organics were combined, washed with brine and dried over sodium sulfate. Removal of solvent by rotary evaporation gave the desired 3-aryl pyrazole (70 mg, 0.13 mmol) in 74% crude yield.
[1281] Part F. An oven-dried 100 mL flask containing a stir bar was charged with 3-aryl pyrazole (70 mg, 0.13 mmol) and 30 mL of a 1: 1 methyl alcohol / THF solution. After flushing the system with N ₂ , 60 μl of pyrrolidine was added by syringe. The reaction was stirred at rt for 15 min. To the reaction solution was added 2M zinc chloride solution in THF (130 μl, 0.06 mmol) followed by sodium cyanoborohydride (10 mg, 0.16 mmol). The reaction was stirred at rt with stirring overnight. The reaction was diluted with ethyl acetate and water. The aqueous phase was separated, washed with brine and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford the crude product. Purification by HPLC followed by freeze-drying afforded the desired amine as a TFA salt. ESI MS m / z 576 (M + H).
[1282] Example 80
[1283] 5-chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) benzamide
[1284] Part A: KHMDS (4.0 mL, 0.5 M solution in toluene) was added to a solution of 2-amino-4-chloropyridine (129 mg, 1.0 mmol) in dry THF at −78 ° C. The mixture was stirred at this temperature under N ₂ for 30 minutes and a solution of 5-chloro-isotoic anhydride (198.0 mg, 1.0 mmol) in THF was added to the mixture. The resulting mixture was gradually warmed to room temperature and stirred for 10 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution, most of the solvent was evaporated and the residue diluted with ethyl acetate, washed with brine and dried over MgSO ₄ . Removal of solvent and chromatography on silica gel (20% ethyl acetate in hexanes) afforded the desired product 2-amino-5-chloro-N- (5-chloro-pyridin-2-yl) -benzamide as a light brown solid. It was. MS measured: (M + 1) &lt; + &gt; = 282.2.
[1285] Part B: Add Oxylyl Chloride (2.0 mmol) to a suspension of 4-[(2-oxo-piperidin) -1-yl] benzoic acid (219 mg, 1.0 mmol) in DMF (0.1 mL) and CH ₂ Cl ₂ . It was. The mixture was stirred for 2 h under N ₂ . The solvent was removed and the residue was dried in vacuo to afford acyl chloride. CH ₂ Cl ₂ to a solution of part A (124 mg, 0.44 mmol) , TEA (0.25 mL) and DAMP (11.0 mg) of the acyl chloride in CH ₂ Cl ₂ mixture was added at 0 ℃. The mixture was warmed to rt and stirred overnight under N ₂ . The mixture was washed with water and purified by reverse phase HPLC (20% CH ₃ CN / H ₂ O, 40 mL / min) to afford the desired product as a light brown solid. ESI MS m / z: (M + l) &lt; + &gt; = 483.0.
[1286] Example 81
[1287] 5-chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) benzamide
[1288] 5-Chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} according to a method analogous to that described in Example 80 Amino) benzamide was obtained as a light yellow solid. ESI MS m / z: (M + l) &lt; + &gt; = 479.0.
[1289] Example 82
[1290] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) -5-methoxybenzamide
[1291] According to a method analogous to that described in Example 80, the title compound was obtained as a light brown solid. ESI MS m / z: (M + l) &lt; + &gt; = 479.1.
[1292] Example 83
[1293] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5-methoxybenzamide
[1294] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5, according to a method analogous to that described in Example 80 -Methoxybenzamide was obtained as a white solid. ESI MS m / z: (M + l) &lt; + &gt; = 475.2.
[1295] Example 84
[1296] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) -5-methylbenzamide
[1297] According to a method analogous to that described in Example 80, the title compound was obtained as a white solid. ESI MS m / z: (M + l) &lt; + &gt; = 463.2.
[1298] Example 85
[1299] N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5-methylbenzamide
[1300] According to a method analogous to that described in Example 80, the title compound was obtained as a white solid. ESI MS m / z: (M + l) &lt; + &gt; = 459.2.
[1301] Example 86
[1302] 1- (3-Chloro-phenyl) -3-methanesulfonyl-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra Solo [3,4-c] pyridin-7-one
[1303] Part A. 3-chloroaniline (5.00 g, 39.2 mmol) was added dropwise to ice-cold 1N hydrochloric acid solution, followed by 4 mL of 12M hydrochloric acid. To the solution was slowly added sodium nitrite (3.00 g, 43.1 mmol) ice cold solution in 4 mL of water while maintaining the internal temperature below 5 ° C. The solution was stirred at 0 ° C. for 45 minutes, during which time a precipitate formed. Glacial acetic acid (1 mL) was added and the precipitate dissolved. The solution was adjusted to pH 4 by addition of solid sodium acetate (about 2 g), followed by the addition of 10 mL of ice-cold acetone, followed by 1-chloro-1-methanesulfonyl-propane-2 in 10 mL acetone. An ice-cold solution of -one was added. The reaction was allowed to warm to room temperature and stirred for 14 hours. The nitrogen stream was passed through the solution to slightly reduce the solvent volume. The solid precipitate was collected by filtration, washed twice with water and dried at 40 ° C. in vacuo to afford 8.47 g (81%) of N- (3-chlorophenyl) -1- (methylsulfonyl) -methanehydrazonoyl chloride in light orange color. Obtained as a solid.
[1304] Methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1- (4-iodo-phenyl) -3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g , 31.7 mmol) were combined in anhydrous toluene. The solution was heated to 70 ° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After complete addition the reaction was warmed to 90 ° C. and stirred at this temperature for 14 hours. Analysis by LC / MS concluded that 1- (4-iodo-phenyl) -3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remained less than 5% 1- (3-Chloro-phenyl) -6- (4-iodo-phenyl) -3-methanesulfonyl-7a-morpholin-4-yl-1,3a, 4,5,6,7a-hexa Formation of hydro-pyrazolo [3,4-c] pyridin-7-one is shown. The solvent was removed in vacuo. To the viscous oil dichloromethane (50 mL) was added, followed by trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue was purified by flash column chromatography, eluting with a gradient of hexane to 40% ethyl acetate / hexanes to give 1- (3-chloro-phenyl) -6- (4-iodo-phenyl) -3- 10.65 g (64%) of methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one were obtained.
[1305] Part B. 1- (3-Chloro-phenyl) -6- (4-iodo-phenyl) -3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo [3, in a round bottom flask 4-c] pyridin-7-one (1.00 g, 1.89 mmol), δ-valerolactam (0.36 g, 3.79 mmol), anhydrous powdered potassium carbonate (1.05 g, 7.58 mmol), cuprous iodide (0.072 g , 0.38 mmol) and 1,10-phenanthroline (0.068 g, 0.38 mmol) were combined. The flask was purged with argon and degassed methylsulfoxide (10 mL) was added and then heated to 120 ° C. After completion of the reaction as judged by TLC or LC / MS, the reaction was cooled to room temperature and 50 mL each of 3M ammonium hydroxide and dichloromethane were added. The phases were separated and the aqueous phase was extracted with additional 30 mL of dichloromethane. The combined dichloromethane extracts were washed successfully four times with water and once with brine. The solution was dried over sodium sulfate, filtered and evaporated to afford an oil which was purified by flash column chromatography, eluting with ethyl acetate, to give 1- (3-chloro-phenyl) -3-methanesulfonyl-6- [4- Colorless 0.424 g (45%) of (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one Obtained as a solid. The material could be recrystallized from acetonitrile.
[1306]
[1307] Example 87
[1308] 3- (5-Chloro-pyridin-2-yl) -6-methoxy-2- [4- (2-oxo-piperidin-1-yl) -phenyl] -3 H-quinazolin-4-one
[1309] A mixture of the product from Example 82 (20 mg, 0.04 mmol) in 4N HCl in dioxane (5 mL) was stirred at reflux for 3.5 h. The reaction mixture was cooled to rt and purified by HPLC (15% CH ₃ CN / H ₂ O, 20 mL / min) to afford the desired product as a white solid. ESI MS m / z: (M + l) &lt; + &gt; = 461.1.
[1310] Example 88
[1311] 3- (5-chloro-pyridin-2-yl) -6-methoxy-2- [4- (2-oxo-pyridin-1-yl) -phenyl] -3 H-quinazolin-4-one
[1312] According to a method analogous to that described in Example 87, the title compound was obtained as a white solid. ESI MS m / z: (M + l) &lt; + &gt; = 457.1.
[1313] Example 89
[1314] Ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1- (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxylate
[1315] The title compound was prepared in Part E of Example 18. High resolution mass spectrometry (M + H) + for C ₂₇ H ₂₅ N ₄ 0 ₅ + 485.1827.
[1316] Example 90
[1317] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid
[1318] Ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyra Solo [3,4-c] pyridine-3-carboxylate (0.5 g, 1.03 mmol) was added to lithium hydroxide (0. 13 g, 3 mmol) and methyl alcohol (5 mL), THF (25 mL) and water ( 25 mL) for 24 hours. The reaction was acidified with concentrated HCl and the resulting solid was filtered off. The product was suspended in 1: 1 CH ₂ Cl ₂ / hexanes, filtered and dried to give 0.37 g (79%) of a white solid; Mass spectrometry (M + H) + 457.3.
[1319] Example 91
[1320] 1- (4-methoxyphenyl) -N, N-dimethyl-7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetra Hydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide
[1321] To dimethylamine hydrochloride (0.35 g, 4.3 mmol) in CH ₂ Cl ₂ (20 mL) was added 2M trimethylaluminum in hexane (2.2 mL, 4.3 mmol) at 0 ° C. After 0.5 h, ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxylate (0.42 g, 0.86 mmol) was added. The reaction was stirred for 24 hours, then poured into diluted HCl and ice water, extracted with CH ₂ Cl ₂ , washed with brine and dried (MgSO ₄ ). Purification by chromatography on silica gel and recrystallization from CH ₂ Cl ₂ / hexanes gave 340 mg (81%); High resolution mass spectrometry (M + H) + 484.1980 for C ₂₇ H ₂₆ N ₅ 0 ₄ .
[1322] Example 92
[1323] N-({1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro- 1H-pyrazolo [3,4-c] pyridin-3-yl} carbonyl) methanesulfonamide
[1324] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6, in CH ₂ Cl ₂ (10 mL) 7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid (0.2 g, 0.43 mmol) to 1- [3- (dimethylamino) propyl] -3-ethyl carbodiimide hydro Chloride (0.1 g, 0.5 mmol) and TEA (0.18 mL, 1.3 mmol) were added and the reaction stirred for 15 minutes. 1-hydroxybenzotriazole (71 mg, 0.5 mmol) was added and the reaction stirred for 15 minutes. Methane sulfonamide (0.125 g, 1.3 mmol) and DMF (1 mL) were added and the reaction stirred for 72 h. The solvent was removed, purified by HPLC and freeze-dried to give 75 mg (33%) of a white solid; High resolution mass spectrometry (M + H) + 534.1468 for C ₂₆ H ₂₄ N ₅ 0 ₆ S.
[1325] Example 93
[1326] 1- (4-hydroxy-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H-pyra Solo [3,4-c] pyridine-3-carboxylic acid amide
[1327] Ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6 in CH ₂ Cl ₂ (30 mL) To, 7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylate (0.2 g, 0.4 mmol) is added BBr ₃ (0.05 mL, 0.5 mmol) at 0 ° C. and the mixture is Stir for 3 hours. The solvent was removed and MeOH (20 mL) and concentrated HCl (0.1 mL) were added and re-esterified by heating to reflux for 24 h. The solvent was removed and the crude ester was placed in 4 mL of ethylene glycol containing 10% NH ₃ and heated in a sealed vessel at 85 ° C. for 1.5 hours. The reaction was cooled, poured into water and extracted with EtOAc. Purification by HPLC and freeze-drying gave 11 mg (6%) of a white solid; High resolution mass spectrometry (M + H) + 446.1840 for C ₂₄ H ₂₄ N ₅ 0 ₄ .
[1328] Example 94
[1329] 1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (1H-tetrazol-5-yl) -1,4,5, 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[1330] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetra in DMF (2 mL) To hydro-1H-pyrazolo [3,4-c] pyridine-3-carbonitrile (0.1 g, 0.23 mmol) add NaN ₃ (19 mg, 0.29 mmol) and NH ₄ Cl (21 mg, 0.38 mmol) The reaction was heated to 105 ° C for 24 h. The reaction was cooled, water (1 mL) was added and the resulting solid was filtered off and dried. The solid was placed in DMF (1 mL), trityl chloride (60 mg, 0.2 mmol) and pyridine (0.2 mL) were added and stirred for 24 hours. The reaction was quenched with water, extracted with EtOAc and dried (Na ₂ SO ₄ ). Purification on silica gel was not successful. The trityl group was removed with TFA (0.5 mL) in CH ₂ Cl ₂ for 2 hours. The solvent was removed and the compound was purified by HPLC and freeze-dried to give 10 mg (9%) of a white solid; High resolution mass spectrometry (M + H) + 481.1749 for C ₂₅ H ₂₁ N ₈ O ₃ .
[1331] Example 95
[1332] 3- {4-[(dimethylamino) methyl] -1,3-oxazol-2-yl} -1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H)- Pyridinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[1333] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo To [3,4-c] pyridine-3-carboxamide (0.161 g, 0.35 mmol) was added excess 1,3-dichloroacetone (0.5 g). The reaction was heated to 130 ° C. for 24 hours. The reaction was cooled and excess 40% NMe ₂ in water was added and the mixture was stirred for 48 hours. The solvent was removed and the residue was chromatographed with 5% MeOH / CH ₂ Cl ₂ containing 1% NH ₃ to give a tan solid (36 mg) which appeared to be a chloro-intermediate. The solid was taken up in ethylene glycol (1 mL) and 40% Me ₂ N / water (1.5 mL) and heated at 80 ° C. for 3 hours. The reaction was cooled and extracted with EtOAc. Purification by HPLC and freeze-drying gave 35 mg (19%) of a white solid; High resolution mass spectrometry (M + H) + 537.2268 for C ₃₀ H ₂₈ N ₆ 0 ₄ .
[1334] Example 96
[1335] 3- {4-[(dimethylamino) methyl] -1,3-oxazol-2-yl} -1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl ) Phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one
[1336] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 To the, 4-c] pyridine-3-carboxamide (0.142 g, 0.31 mmol) was added excess 1,3-dichloroacetone (0.2 g). The reaction was heated to 130 ° C. for 24 hours. The reaction was cooled and excess 40% NMe ₂ in water was added and the resulting mixture was stirred for 48 hours. Repeated purification by HPLC and freeze-dried gave 2 mg (1.2%) of a white solid; High resolution mass spectrometry (M + H) + 541.2582 for C ₃₀ H ₃₃ N ₆ 0 ₄ .
[1337] Example 97
[1338] 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperazinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carboxamide
[1339] Part A. Ethyl-6- (4-iodophenyl) -1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo (3,4-c DMSO (pyridine-3-carboxamide (0.52 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.32 g, 1.4 mmol) and K ₂ CO ₂ (0.22 g, 1.6 mmol) 5 mL) was added. The mixture was degassed with N ₂ . CuI (38 mg, 0.2 mmol) was added and the reaction was heated to 130 ° C. for 18 h. The reaction was diluted with EtOAc and water, extracted with EtOAc and dried (MgSO ₄ ). Purification by chromatography on silica gel using 5% MeOH / CH ₂ Cl ₂ gave 0.2 g (33%) of foam; Mass spectrometry (M + H) + 624.6.
[1340] Part B. The product of Part A (0.2 g, 0.32 mmol) was hydrogenated at 40 psi for 24 hours in the presence of palladium on 10% carbon. The reaction was filtered and then heated in a sealed vial at 80 ° C. with 5% NH ₃ in ethylene glycol for 1.5 h. The reaction was diluted with water and extracted with EtOAc. Purification and freeze-drying with HPLC gave 30 mg (16%) of a white solid; High resolution mass spectrometry (M + H) + 461.1938 for C ₂₄ H ₂₅ N ₆ O ₄ .
[1341] Example 98
[1342] 1- (4-methoxyphenyl) -3- (methylsulfonyl) -6- [4- (2-oxo-1-piperazinyl) phenyl] -1,4,5,6-tetrahydro-7H- Pyrazolo [3,4-c] pyridin-7-one
[1343] 6- (4-iodophenyl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1,4,5,6-tetrahydro-7H-pyrazolo (3,4-c) DMSO (5 mL) in pyridin-7-one (0.55 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.35 g, 1.4 mmol) and K ₂ CO ₃ (0.23 g, 1.6 mmol) Was added. The mixture was degassed with N ₂ . CuI (39 mg, 0.21 mmol) was added and the reaction was heated to 130 ° C. for 18 h. The reaction was diluted with EtOAc and water, extracted with EtOAc and dried (MgSO ₄ ). The intermediate was purified by chromatography on silica gel using 5% MeOH / CH ₂ Cl ₂ and then deprotected during TFA reflux. Purification and freeze-drying by HPLC gave 175 mg (27%) of a white solid; High resolution mass spectrometry (M + H) + 496.1650 for C ₂₄ H ₂₆ N ₆ 0 ₅ S.
[1344] Example 99
[1345] 1- (4-methoxy-phenyl) -3- (4-methyl-oxazol-2-yl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1, 4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1346] Part A. 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyra To the solo [3,4-c] pyridine-3-carboxamide (1 g, 2 mmol) was added excess 1,3-dichloroacetone (2 g). The reaction was heated to 130 ° C. for 24 hours. The reaction was cooled and purified by chromatography using 0-3% MeOH in CH ₂ Cl ₂ to give 0.53 g (42%) of a white solid;
[1347]
[1348] Part B. To the product of Part A (73 mg, 0.13 mmol) was added 10% palladium on carbon (15 mg) and EtOH (35 mL). The mixture was hydrogenated at 40 psi for 1.5 h and then filtered through Celite®. The solvent was evaporated and the residue was purified by HPLC and freeze-dried to give 40 mg (59%) of a white solid; High resolution mass spectrometry (M + H) + 498.2126 for C ₂₈ H ₂₈ N ₅ O ₄ .
[1349] Example 100
[1350] 1- (4-methoxy-phenyl) -3- (4-methyl-oxazol-2-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1, 4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1351] Part A. 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H To the pyrazolo [3,4-c] pyridine-3-carboxamide (0.1 g, 0.20 mmol) was added an excess of 1,3-dichloroacetone (0.5 g). The reaction was heated to 130 ° C. for 24 hours. The reaction was cooled and purified by chromatography using 0-3% MeOH in CH ₂ Cl ₂ to give 0.08 g (69%) of a tan solid.
[1352] Part B. To the product of Part A (80 mg, 0.15 mmol) was added 10% palladium on carbon (20 mg) and EtOH (35 mL). The mixture was hydrogenated at 40 psi for 0.3 hours and then filtered through Celite®. The solvent was evaporated and the residue was purified by HPLC and freeze-dried to give 10 mg (13%) of a white solid; High resolution mass spectrometry (M + H) + 494.1829 for C ₂₈ H ₂₄ N ₅ O ₃ .
[1353] Example 101
[1354] 3-acetyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) phenyl] -1,4,5,6-tetrahydro-pyrazolo [ 3,4-c] pyridin-7-one
[1355] 3-bromo-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra To zolo [3,4-c] pyridin-7-one (0.11 g, 0.22 mmol) in THF (25 mL), 1- (ethoxyvinyl) tributyltin (0.078 mL, 0.23 mmol) and LiCl (27 mg, 0.65 mmol) was added and the mixture was degassed with N ₂ for 15 minutes. Tetrakistriphenylphosphine palladium (0) (12 mg, 0.01 mmol) was added and the reaction heated to reflux for 24 h. The reaction was cooled to rt and treated with 1N HCl for 24 h. After extraction with EtOAc and drying (MgSO ₄ ), the product was purified by silica gel (mixed with KF) chromatography and HPLC using 0-3% MeOH in CH ₂ Cl ₂ to give 6 mg (6%); High resolution mass spectrometry (M + H) + 455.1713 for C ₂₆ H ₂₃ N ₄ O ₄ .
[1356] Example 102
[1357] 3- (4,5-dihydro-1H-imidazol-2-yl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl)- Phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1358] To ethylene diamine (0.4 mL, 6 mmol) in toluene (25 mL) was added 2M trimethylaluminum (1 mL, 2 mmol) in heptane at 0 ° C. and stirred for 20 minutes, then 1- (4-methoxy- Phenyl) -7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c ] Pyridine-3-carboxylic acid ethyl ester (0.1 g, 0.2 mmol) was added and the reaction was heated to 60 ° C. for 24 h. The reaction was quenched with water and MeOH, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was suspended in EtOAc and filtered. Purification and freeze-drying by HPLC gave 15 mg (12%) of a white solid; High resolution mass spectrometry (M + H) + 481.2003 for C ₂₇ H ₂₅ N ₆ 0 ₃ .
[1359] Example 103
[1360] 1- (4-methoxy-phenyl) -3- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -6- [4- (2-oxo-piperidine-1 -Yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1361] To N-methylethylene diamine (0.47 mL, 5 mmol) in toluene (25 mL) was added 2M trimethylaluminum (2.7 mL, 5 mmol) in heptane at 0 ° C. and stirred for 20 minutes, then 1- (4- Methoxy-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxylic acid ethyl ester (0.88 g, 1.8 mmol) was added and the reaction was heated to 100 ° C for 24 h. The reaction was quenched with water and MeOH, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was suspended in EtOAc and filtered. Purification and freeze-drying with HPLC gave 120 mg (11%) of a white solid; Mass spectrometry (M + H) + 499.3.
[1362] Successively washed with saturated aqueous KF, brine and dried (MgSO ₄ ). Silica gel chromatography using 0-5% MeOH / CH ₂ Cl ₂ (1% NH ₃ ) as eluent, then purified by HPLC and freeze-dried to give 0.20 mg (12%) of the title compound: C ₂₉ H HRMS (M + H) &lt; + &gt; for ₂₄ N ₅ O ₃ was 490.1880;
[1363]
[1364] Example 104
[1365] 1- (4-methoxy-phenyl) -3- (1-methyl-1H-imidazol-2-yl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl]- 1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1366] To Example 103 (0.085 g, 0.14 mmol) in dioxane (15 mL) was added KMNO ₄ (48 mg, 0.3 mmol) and the reaction was heated to 100 ° C. After 2 hours excess KMnO ₄ was added to accelerate the reaction and heated for 24 hours. Filtered, purified by HPLC and freeze-dried to give 10 mg (11.7%) of a white solid; Mass spectrometry (M + H) + 497.3.
[1367] Example 105
[1368] 1- (4-methoxy-phenyl) -3-methyl-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1369] 1- (4-methoxy-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7 in THF (25 mL) To tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl ester (0.59 g, 1.2 mmol) was added 2M LiBH ₄ (0.96 mL, 1.9 mmol) in THF and the reaction was Heated to reflux for 2.5 hours. To the crude alcohol was added CH ₂ Cl ₂ (25 mL) and PBr ₃ (0.14 mL) and the reaction was stirred for 24 hours. Extraction with CHCl ₃ , washing with water and drying (Na ₂ SO ₄ ) afforded the crude bromo-compound. The bromo-compound was heated in AcOH (15 mL) and activated Zn (0.39 g, 6 mmol) at 120 ° C. for 24 h. Purification by HPLC and freeze-drying gave 30 mg (58%) of a white solid; High resolution mass spectrometry (M + H) + 431.2092 for C ₂₅ H ₂₇ N ₄ 0 ₃ .
[1370] Example 106
[1371] 3-hydroxymethyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro- Pyrazolo [3,4-c] pyridin-7-one
[1372] 1- (4-methoxy-phenyl) -7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -4,5,6,7 in THF (25 mL) To tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl ester (0.2 g, 0.4 mmol) was added 2M LiBH ₄ (0.31 mL, 0.66 mmol) in THF and the reaction was Heated to reflux for 3 hours. Extracted with EtOAc and washed with water and brine, then left to crystallize the product; High resolution mass spectrometry (M + H) + 443.1730 for C ₂₅ H ₂₃ N ₄ 0 ₄ .
[1373] Example 107
[1374] 3- (1-hydroxy-1-methyl-ethyl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one
[1375] 1- (4-methoxy-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7 in THF (15 mL) To tetrahydro-1H-pyrazolo [3,4-c] pyridine-3carboxylic acid ethyl ester (0.1, 0.2 mmol), add MeMgBr (0.21 mL, 0.6 mmol) at 0 ° C. and react the reaction at room temperature 24. Stir for hours. The reaction was quenched with water and purified by HPLC to give 47 mg (48%) of a white solid; Mass spectrometry (M + H) + 475.
[1376] Example 108
[1377] 3- (1-hydroxy-1-methyl-ethyl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one
[1378] The title compound was prepared according to the method used in example 107. ESI MS m / z 471 (M + H).
[1379] Example 109
[1380] 2-dimethylamino-N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7- Tetrahydro-1H-pyrazolo [3,4-c] pyridin-3-ylmethyl} -N-methylacetamide hydrochloride
[1381] Part A. 6- (4- Iodophenyl) -1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine 3-carboxylic acid ethyl ester (5 g, 9.7 mmol), K ₂ CO ₃ (1.5 g, 110 mmol), piperidin-2-one (1.2 g, 11.6 mmol), CuI (228 mg, 1.2 mmol ) And DMSO (10 mL) were heated at 140 ° C. for 24 h. The solution was cooled to rt, diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the corresponding aryl lactam (1.3 g, 28%): ESI MS m / z 489 (M + H) &lt; + &gt;.
[1382] Part B. LiOH (52 mg, 1.2 mmol) was added to a solution of the ester (500 mg, 1.02 mmol) in THF (5 mL), MeOH (3 mL) and H ₂ O (2 mL) at room temperature. The reaction mixture was stirred for 1 hour, acidified with Dow's-50W-hydrogen ion-exchange resin, filtered and evaporated to afford the corresponding acid as a white solid (471 mg, 99%) used without further purification: ESI MS m / z 461 (M + H) &lt; + &gt;.
[1383] Part C. Et ₃ N (0.17 mL, 1.2 mmol) is added to a cooled (0 ° C.) solution of the acid (500 mg, 1.09 mmol) in THF (10 mL) and isobutyl chloroformate (0.16 mL, 1.2 mmol) was added. The reaction mixture was stirred for 1 h, then NaBH ₄ (82 mg, 2.2 mmol) was added. After 30 minutes, a small piece of ice was added and the reaction mixture was further stirred for 2 hours. The mixture was diluted with EtOAc, washed with 0.1 N HCl and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified on silica gel to give the corresponding alcohol as a white solid (317 mg, 71%): ESI MS m / z 447 (M + H) &lt; + &gt;.
[1384] Part D. A solution of the above prepared alcohol (317 mg, 0.71 mmol) in CH ₂ Cl ₂ (7 mL) was cooled to 0 ° C., then 1M PBr ₃ (0.78 mL, 0.78 mmol) in CH ₂ Cl ₂ was added. It was. The cold bath was removed and the reaction mixture was stirred for 3 hours and then diluted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford the corresponding bromomethyl compound (369 mg,> 99%) used without further purification: ESI MS m / z 509, 511 (M + H) +.
[1385] Part E. A solution of the bromomethyl compound (489 mg, 0.96 mmol) and NaN ₃ (67 mg, 1.1 mmol) prepared above in DMF (10 mL) was heated at 60 ° C. overnight. The reaction mixture was cooled to rt, diluted with EtOAc, washed with 1% aqueous LiCl, dried over Na ₂ SO ₄ , filtered and concentrated to give the corresponding azide (450 mg, 99%) as a white foam: ESI MS m / z 472 (M + H) &lt; + &gt;.
[1386] Part F. The azide (213 mg, 0.45 mmol) prepared above was dissolved in MeOH (5 mL), then 10% Pd / C (30 mg, 10 mol%) was added and the reaction mixture was heated to H ₂ atmosphere ( Balloon). After 3 hours, the reaction mixture was filtered through Celite® and concentrated. The residue was purified on silica gel to give the corresponding aminomethyl compound (151 mg, 75%): ESI MS m / z 446 (M + H) &lt; + &gt;.
[1387] Part G. Aminomethyl (367 mg, 0.82 mmol) prepared above was added N, N-dimethylglycine (127 mg, 1.2 mmol), Huenig's base (0.36 mL, 2.1 mmol), EDCI (237 mg, 1.2 mmol), HOAt (catalyst amount) and CH ₂ Cl ₂ (1.6 mL) were added to the solution. The reaction mixture was stirred at rt overnight then diluted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, then treated with 2N HCl and lyophilized to afford the title compound: ESI MS m / z 531 (M + H) &lt; + &gt;.
[1388] Example 110
[1389] 2-dimethylamino-N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-3-ylmethyl} acetamide hydrochloride
[1390] The title compound was prepared according to the method described for Example 109: ESI MS m / z 527 (M + H) &lt; + &gt;.
[1391] Example 111
[1392] N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridin-3-ylmethyl} -2-pyridin-2-yl-acetamide hydrochloride
[1393] The title compound was prepared according to the method described for Example 109: ESI MS m / z 565 (M + H) &lt; + &gt;.
[1394] Example 112
[1395] N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridin-3-ylmethyl} -2- (1-oxypyridin-2-yl) acetamide
[1396] The title compound was prepared according to the method described for Example 109: APCI MS m / z 581 (M + H) &lt; + &gt;.
[1397] Example 113
[1398] 5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-2- [4- (2-oxopiperidin-1-yl) -benzoylamino] benzamide
[1399] Part A. Methyl 4-iodobenzoate (10.0 g, 0.038 mol), δ-valerolactam (4.53 g, 0.046 mol), PNT (0.76 g, 4.20 mmol) and K ₂ CO _{3 in} DMSO (20 mL) CuI (0.87 g, 4.58 mmol) was added to a mixture of (5.80 g, 0.042 mol) and the reaction mixture was heated at 110 ° C. for 24 h. The solution was cooled to rt and diluted with CH ₂ Cl ₂ , washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography (eluted with 98: 2 CH ₂ Cl ₂ / MeOH) to give the corresponding lactam (3.4 g, 38%):
[1400]
[1401] Part B. LiOH (198 mg, 4.72 mmol) was added at 0 ° C. to a solution of the ester (1.0 g, 4.29 mmol) prepared above in THF (16 mL) and H ₂ O (4 mL). The reaction mixture was stirred at rt for 14 h and partitioned between EtOAc and 2M HCl solution. The organics were washed with brine, dried over MgSO ₄ , filtered and evaporated to afford the corresponding acid as a white solid (525 mg, 56%):
[1402]
[1403] Part C. To a suspension of the acid (0.21 g, 0.96 mmol) prepared above in CH ₂ Cl ₂ (5 mL) was added SOCl ₂ (0.21 mL, 2.89 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated to give crude acid chloride as white solid. Crude acid chloride was used directly in the next step.
[1404] Part D. ₂ -amino-5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-benzamide (150 mg, 0.48 mmol) in CH ₂ Cl ₂ (5 mL), DMAP ( To a solution of 24 mg, 0.19 mmol) and pyridine (95 mg, 1.21 mmol) was added a solution of the crude acid chloride prepared above in CH ₂ Cl ₂ (5 mL) and the reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with water, 0.25 M NaOH solution and brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography to give the title compound as a white solid (99 mg, 40%):
[1405]
[1406] Example 114
[1407] 5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-2- [4- (2-oxo-2H-pyridin-1-yl) -benzoylamino] benzamide
[1408] The title compound was prepared according to the method described for Example 113:
[1409]
[1410] Example 115
[1411] 6- [4- (1,1-Dioxo-116-isothiazolidin-2-yl) -phenyl] -1- (4-methoxy-phenyl) -7-oxo-4,5,6,7 -Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide
[1412] Part A. 6- (4-amino-phenyl) -1- (4-methoxy-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [in THF (20 mL) [ Triethylamine (0.144 mL, 1 mmol) is added to 3,4-c] pyridine-3-carboxylic acid ethyl ester (0.35 g, 0.86 mmol) and 3-chloropropanesulfonyl chloride (0.125 mL, 1 mmol) And the reaction was stirred for 24 hours. Potassium tert-butoxide (0.31 g, 2.5 mmol) was added and the reaction stirred for 24 hours. The ester was purified by chromatography using 1-5% MeOH in CH ₂ Cl ₂ .
[1413] Part B. The ester obtained from Part A was placed in a sealed tube containing 10% NH ₃ in ethylene glycol and heated to 80 ° C. for 3 hours. The reaction was cooled, quenched with water and extracted with EtOAc. Purification by HPLC and lyophilization gave 19 mg (4.6%) of a white solid; High resolution mass spectrometry (M + H) + 482.1493 for C ₂₃ H ₂₄ N ₅ 0 ₅ S.
[1414] Example 116
[1415] N-hydroxy-3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetra Hydro-pyrazolo [3,4-c] pyridin-1-yl} -benzamidine
[1416] Part A. 3- [6- (4-iodo-phenyl) -7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [3,4-c] pyridine- To a solution of 1-yl] -benzonitrile (0.403 g, 0.793 mmol) was added 2-hydroxypyridine (0.226 g, 2.38 mmol), potassium carbonate (0.328 g, 2.38 mmol) and 3 mg CuI. The reaction mixture was refluxed for 18 hours, cooled and quenched with HCl (1N). The organics were extracted with ethyl acetate (2 x 100 mL), dried (MgSO ₄ ) and concentrated to afford the desired crude product. ESI mass spectrum 476 (M + H).
[1417] Part B. The crude product (0.18 g, 0.37 mmol) obtained from part A in anhydrous methyl alcohol (10 mL) was treated with hydroxylamine hydrochloride (0.04 g, 0.57 mmol) and excess triethylamine (0.5 mL). . The reaction mixture was stirred at rt for 48 h, concentrated and purified by reverse phase HPLC to give 78 mg (40%) of the title compound. ESI mass spectrum 509 (M + H).
[1418] Example 117
[1419] N-methoxy-3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetra Hydro-pyrazolo [3,4-c] pyridin-1-yl} -benzamidine
[1420] In Example 116 the product obtained from Part A (0.2 g) was dissolved in methyl alcohol (10 mL). HCl gas was bubbled and capped for 5 minutes. The reaction mixture was stirred at rt for 24 h, concentrated and evaporated to a semisolid mass. The crude material was redissolved in methyl alcohol (10 mL) and 0.5 g of O-methoxyhydroxylamine hydrochloride and 1 mL of triethylamine were added to the mixture. The reaction mixture was stirred at rt for 24 h, concentrated and purified via HPLC. Colorless crystals of the title compound were obtained. ESI mass spectrum 523 (M + H).
[1421] Example 118
[1422] 1- (3-cyano-4-fluorophenyl-7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide
[1423] Condensation of 3-chloro-4-fluoro-phenylhydrazine with 1- (4-iodo-phenyl) -3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one 1 -(3-Chloro-4-fluoro-phenyl) -6- (4-iodo-phenyl) -3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo [3,4- c] pyridin-7-one was obtained. This was then treated with 2-hydroxypyridine under Ullman conditions to give 1- (3-chloro-4-fluoro-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] 3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one was obtained. ESI mass spectrum 482 (M + H). The conversion of chlorine to cyano groups was achieved through a palladium catalyzed cyanation method using zinc cyanide. MS (AP +): 473.2 (M + H).
[1424] Example 119
[1425] 1- (3-Aminomethyl-4-fluoro-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7- Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide
[1426] The cyano group of Example 118 was reduced to benzylamine via hydrogenation (Par shaker, MeOH, Pd / C 10%, AcOH) and purified via HPLC. ESI mass spectrum 477 (M + H).
[1427] Example 120
[1428] 2- {7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzenesulfonamide
[1429] The title compound was synthesized in a similar manner to Example 6, except that 2-sulfonamidophenyl-hydrazine was used instead of 4-methoxyhydrazine hydrochloride. MS (AP +): 534.1 (M + H).
[1430] Example 121
[1431] 2- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzenesulfonamide
[1432] The title compound was synthesized in a similar manner to Example 6, except that 2-sulfonamidophenyl-hydrazine was used instead of 4-methoxyhydrazine hydrochloride. MS (AP +): 530.1 (M + H).
[1433] Example 122
[1434] N-acetyl-2- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro -Pyrazolo [3,4-c] pyridin-1-yl} -benzenesulfonamide
[1435] The sulfonamide of Example 121 was acetylated with acetic anhydride to afford the title compound. MS (ES &lt; + &gt;): 572.1 (M + H).
[1436] Example 123
[1437] 1- (3-Chloro-phenyl) -3-methanesulfonyl-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra Solo [3,4-c] pyridin-7-one
[1438] In the same manner as described in Example 86, parts A and B, the title compound was synthesized by substituting δ-valerolactam with 2-pyridone.
[1439]
[1440] Example 124
[1441] 1- (4-methoxy-phenyl) -3-methyl-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1442] 3-hydroxymethyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1 in CH ₂ Cl ₂ (10 mL), To 4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one (65 mg, 0.15 mmol) was added triethylsilane (0.1 mL) and TFA (0.05 mL). After 2 h additional triethylsilane (0.2 mL) and TFA (0.1 mL) were added and the reaction stirred for 72 h. Without proceeding the reaction, the solvent was stripped and replaced with acetic acid (10 mL), triethylsilane (0.5 mL) and TFA (0.1 mL). The reaction was heated at 80 ° C. for 24 h. Mass spectrum showed that only acetyl product was formed. Solvent was removed. The acetyl group was removed by stirring with LiOH (0.1 g) in THF / H ₂ O for 3 hours. The reaction was quenched with 1N HCl, extracted with EtOAc and dried (MgSO ₄ ) alcohol. PBr ₃ was added to the alcohol in CHCl ₃ and the reaction was stirred for 24 hours. The reaction was quenched with ice water, extracted with CHCl ₃ and dried (Na ₂ SO ₄ ). Activated Zn (80 mg) and acetic acid (10 mL) were added to the crude bromide and heated to 120 ° C. for 24 h. The product was purified by silica gel chromatography using 0-3% MeOH in CH ₂ Cl ₂ and recrystallized from CH ₃ CN / H ₂ O to give 22 mg (35%); Mass spectrometry (M + H) + 427.3.
[1443] Example 125
[1444] 3- (4-methoxy-phenyl) -5- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3,5,6,7-tetrahydro- [1,2,3 ] Triazolo [4,5-c] pyridin-4-one
[1445] Part A. Para-anisidine (7 g) was dissolved in TFA (10 mL) and the solution was cooled to 0 ° C. To the ice-cooled solution was added dropwise an aqueous solution containing sodium nitrite (4.8 g). After 30 minutes an aqueous solution containing sodium azide (4.43 g) was added. The reaction became exothermic, which was further stirred for 2 hours, quenched with water (1 L) and the organics extracted with methylene chloride (2 x 100 mL) and dried (magnesium sulfate). Concentration gave the desired azide and immediately redissolved in toluene (100 mL). To the solution was added 1- (4-iodo-phenyl) -3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (21.85 g) and the solution was added for 48 hours. It was gently refluxed. Toluene was concentrated, the crude was poured directly onto a silica gel column and eluted with hexanes: ethyl acetate 7: 3 to give 5- (4-iodo-phenyl) -3- (4-methoxy-phenyl) -3,5, Approximately 1.2 g of 6,7-tetrahydro- [1,2,3] triazolo [4,5-c] pyridin-4-one were obtained. ESI mass spectrum m / z 447 (M + H).
[1446] Part B. The compound obtained from Part A (0.41 g) as described above was treated with 2-hydroxypyridine under Ullman conditions to give the title compound (50 mg). ESI mass spectrum m / z 414 (M + H).
[1447] Example 126
[1448] 3- (4-methoxy-phenyl) -5- [4- (2-oxo-piperidin-1-yl) -phenyl] -3,5,6,7-tetrahydro- [1,2,3 ] Triazolo [4,5-c] pyridin-4-one
[1449] The title compound was obtained after purification via silica chromatography by the Ulman coupling method using δ-valerolactam described above. ESI mass spectrum m / z 418 (M + H).
[1450] Example 127
[1451] 3- (3-chloro-phenyl) -5- [4- (2-oxo-piperidin-1-yl) -phenyl] -3,5,6,7-tetrahydro- [1,2,3] Triazolo [4,5-c] pyridin-4-one
[1452] The m-chlorophenyl title compound was prepared in the same manner as described for analogs with para-methoxytriazole. ESI mass spectrum m / z 422 (M + H).
[1453] Example 128
[1454] 3- (3-Chloro-phenyl) -5- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3,5,6,7-tetrahydro- [1,2,3] Triazolo [4,5-c] pyridin-4-one
[1455] The m-chlorophenyl title compound was prepared in the same manner as described for analogs with para-methoxytriazole. ESI mass spectrum m / z 418 (M + H).
[1456] Example 129
[1457] 1- (3-chloro-phenyl) -3- (1-hydroxy-1-methyl-ethyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4 , 5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one
[1458] 1- (3-Chloro-phenyl) -7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -4,5,6,7-tetrahydro-1H-pyra Jolo [3,4-c] pyridine-3-carboxylic acid ethyl ester (0.098 g, 0.216 mmol) was dissolved in THF (10 mL). Methylmagnesium bromide (0.179 mL, 0.539 mmol) was added dropwise to the reaction. The reaction was stirred at rt overnight. The reaction was quenched with 1N HCl (100 mL) and extracted with ethyl acetate (4 × 50 mL), washed with brine (1 × 50 mL) and dried (MgSO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as eluent followed by a 0% -100% methanol / ethyl acetate gradient yielded 54.6 mg (53%) of the title product:
[1459]
[1460] Example 130
[1461] 1- (3-Chloro-phenyl) -3- (1-hydroxy-1-methyl-ethyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4 , 5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one
[1462] Meta-chloro-lactam-ethyl ester (0.036 g, 0.078 mmol) was dissolved in THF (6 mL). Methylmagnesium bromide (0.07 mL, 0.196 mmol) was added dropwise to the reaction. The reaction was stirred at rt overnight. The reaction was quenched with 1N HCl (50 mL) and extracted with ethyl acetate (4 × 25 mL), washed with brine (1 × 25 mL) and dried (MgSO ₄ ). Purification by silica gel chromatography using a 0% -100% ethyl acetate / hexanes gradient as the eluent followed by a 0% -100% methanol / ethyl acetate gradient yielded 15.7 mg (42%):
[1463]
[1464] Example 131
[1465] 3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzamide
[1466] Example 116, product (0.05 g) from Part A was dissolved in dichloromethane (10 mL). To this was added sodium hydroxide (1N, 5 mL), hydrogen peroxide (3 mL) and tetrabutylammonium hydroxide (0.01 g). The reaction mixture was stirred at rt for 24 h and concentrated. Quench with water (50 mL), extract the organics with ethyl acetate (2 x 50 mL), dry (MgSO ₄ ) and concentrate. The crude was purified to a colorless solid via preparative HPLC. ESI mass spectra 494 (M + H) and 492 (MH).
[1467] Example 132
[1468] 3-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide
[1469] Step A. 4- (2-oxo-2H-pyridin-1-yl) benzoyl chloride (0.44 g, 2.05 mmol) was stirred in CH ₂ Cl ₂ (10 mL) at room temperature under N ₂ . Cis-1,2-diaminocyclohexane (0.5 mL, 4.17 mmol) was added quickly at once to the stirred solution. The mixture was stirred at rt for 10 min. It was quenched with aqueous dilute HCl and then extracted with EtOAc (twice). The water layer was basified with 1N NaOH and extracted with EtOAc (twice). The organic layer was washed with H ₂ O, brine, dried over MgSO ₄ and concentrated to dryness. Pure N-cis-1,2- (2-amino-cyclohexyl) -4- (2-oxo-2H-pyridin-1-yl) benzamide with FCC (silica gel, CH ₂ Cl ₂ , then EtOAc) (0.54 g, yield: 84%) was obtained.
[1470] Step B. To a solution of the product obtained from step A (50 mg, 0.16 mmol) in DMF (0.5 mL) was added 3-chloro-1H-indole-6-carboxylic acid (47 mg, 0.24 mmol), followed by HATU (80 mg, 0.21 mmol) and DIEA (0.08 mL, 0. 46 mmol) were added. The mixture was stirred at rt overnight. The residue was diluted with MeOH and purified by LC / MS to give the desired 3-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino } Cyclohexyl) -1H-indole-6-carboxamide (14 mg, yield: 18%) was obtained. LC / MS-ESI, 489.4 (M + H).
[1471] Example 133
[1472] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide
[1473] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 489.6.
[1474] Example 134
[1475] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide
[1476] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 456.6.
[1477] Example 135
[1478] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide
[1479] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 457.4.
[1480] Example 136
[1481] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide
[1482] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 490.4.
[1483] Example 137
[1484] 3-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide
[1485] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 490.4.
[1486] Example 138
[1487] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide
[1488] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 457.4.
[1489] Example 139
[1490] 5-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide
[1491] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 493.4.
[1492] Example 140
[1493] 3-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide
[1494] According to a method analogous to that described in Example 132, the title compound was obtained. LC / MS ESI (M + H) &lt; + &gt; 493.4.
[1495] The following table includes representative examples of the present invention. Each heading in each table is paired with each formula at the beginning of the table. For example, in Table 1, Example 1-1 is paired with each of the formulas shown. The following names represent group A in the table below.
[1496]
[1497]
[1498]
[1499]
[1500]
[1501]
[1502]
[1503]
[1504]
[1505]
[1506]
[1507]
[1508]
[1509]
[1510] Examples 3-1 to 3-6090 use the structures from Table 2 and use the corresponding A and G groups from Examples 1-203 of Table 2: Examples 3-1 to 3-203, R ^1a is CH ₂ CH ₃ ; Examples 3-204 to 3-406, R ^1a is CF ₃ ; Examples 3-407 to 3-609, R ^1a is SCH ₃ ; Examples 3-610 to 3-812, R ^1a is SOCH ₃ ; Examples 3-813 to 3-1015, R ^1a is SO ₂ CH ₃ ; Examples 3-1016 to 3-1218, R ^1a is Cl; Examples 3-1219 to 3-1421, R ^1a is F; Examples 3-1422 to 3-1624, R ^1a is CO ₂ CH ₃ ; Examples 3-1625 to 3-1827, R ^1a is CH ₂ OCH ₃ ; Examples 3-1828 to 3-2030, R ^1a is CONH ₂ ; Examples 3-2031 to 3-2233, R ^1a is -CN; Examples 3-2234 to 3-2436, and R ^1a is CH ₂ NHCH ₃ ; Examples 3-2437 to 3-2639, R ^1a is CH ₂ NHSO ₂ CH ₃ ; Examples 3-2640 to 3-2842, R ^1a is 1-imidazolyl-CH ₂ ; Examples 3-2843 to 3- 3045, R ^1a is Br; Examples 3-3046 to 3-3248, R ^1a is 5-tetrazolyl; Examples 3-3249 to 3-3451, R ^1a is N (CH ₃ ) ₂ ; Examples 3-3452 3-3654, R ^1a is NHCH ₃ ; Examples 3-3655 to 3-3857, R ^1a is SO ₂ NH ₂ ; Examples 3-3858 to 3-4060, and R ^1a is 2 -Pyridine; Examples 3-4061 to 3-4263, R ^1a is 3-pyridine; Examples 3-4264 to 3-4466, R ^1a is 4-pyridine; Examples 3-4467 to 3-4872, R ^1a is 2-pyridine-N-oxide; Examples 3-4873 to 3-5075, R ^1a is 3-pyridine-N-oxide; Examples 3-5076 to 3-5287, R ^1a is 4-pyridine-N- Oxide; Examples 3-5288 to 3-5481, R ^1a is OCH ₃ ; Examples 3-5482 to 3-5684, R ^1a is CH ₂ OC (O) NHCH ₃ ; Examples 3-5685 to 3-5887 , R ^1a is CH ₂ NHCO ₂ CH ₃ ; Examples 3-5888 to 3-6090, R ^1a is CH ₂ NHC (O) NHCH ₃ ; And, Examples 3-6091 to 3-6293, R ^1a is H.
[1511]
[1512] Example numberG 4-14-methoxyphenyl 4-22-aminomethylphenyl 4-33-aminomethylphenyl 4-42-amidophenyl 4-52-amido-4-methoxy-phenyl 4-63-amidophenyl 4-73-chlorophenyl 4-83-amino-4-chloro-phenyl 4-92-aminosulfonyl-phenyl 4-102-aminosulfonyl-4-methoxyphenyl 4-113- (1 ', 2', 4'-triazolin-5'-one-3'-yl) phenyl 4-121-aminoisoquinolin-6-yl 4-131-aminoisoquinolin-7-yl 4-144-aminoquinazol-6-yl 4-154-aminoquinazol-7-yl 4-163-aminobenzisoxazol-5-yl 4-173-aminobenzisoxazol-6-yl 4-183-aminoindazol-5-yl 4-193-aminoindazol-6-yl 4-20Indolin-5-day 4-21Indolin-6-day 4-222-naphthyl 4-233-amido-naphth-2-yl 4-243-methylsulfonyl-naphth-2-yl 4-253-aminomethyl-naphth-2-yl 4-263-fluoro-naphth-2-yl 4-273-chloro-naphth-2-yl 4-283-aminosulfonyl-naphth-2-yl 4-296-chloro-naphth-2-yl
[1513]
[1514]
[1515] In Examples 5-33 to 5-64, G is 2-aminomethylphenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1516] In Examples 5-65 to 5-96, G is 3-aminomethylphenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1517] In Examples 5-97 to 5-128, G is 2-amidophenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1518] In Examples 5-129 to 5-160, G is 2-amido-4-methoxyphenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1519] In Examples 5-161 to 5-192, G is 3-amidophenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1520] In Examples 5-193 to 5-224, G is 3-chlorophenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1521] In Examples 5-225 to 5-256, G is 3-amino-4-chlorophenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1522] In Examples 5-257 to 5-288, G is 2-aminosulfonylphenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1523] In Examples 5-289 to 5-320, G is 2-aminosulfonyl-4-methoxyphenyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1524] In Examples 5-321 to 5-352, G is 3- (1 ', 2', 4'-triazolin-5'-one-3'-yl) phenyl, and R ^1a is Examples 5-1 to 5 As shown in -32.
[1525] In Examples 5-353 to 5-384, G is 1-aminoisoquinolin-6-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1526] In Examples 5-385 to 5-416, G is 1-aminoisoquinolin-7-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1527] In Examples 5-417 to 5-448, G is 4-aminoquinazol-6-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1528] In Examples 5-449 to 5-480, G is 4-aminoquinazol-7-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1529] In Examples 5-481 to 5-512, G is 3-aminobenzisoxazol-5-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1530] In Examples 5-513 to 5-544, G is 3-aminobenzisoxazol-6-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1531] In Examples 5-545 to 5-576, G is 3-aminoindazol-5-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1532] In Examples 5-577 to 5-608, G is 3-aminoindazol-6-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1533] In Examples 5-609 to 5-640, G is indolin-5-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1534] In Examples 5-641 to 5-672, G is indolin-6-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1535] In Examples 5-673 to 5-704, G is 2-naphthyl and R ^1a is as shown in Examples 5-1 to 5-32.
[1536] In Examples 5-705 to 5-736, G is 3-amido-naphth-2-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1537] In Examples 5-737 to 5-768, G is 3-methylsulfonyl-naphth-2-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1538] In Examples 5-769 to 5-800, G is 3-aminomethyl-naphth-2-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1539] In Examples 5-801 to 5-832, G is 3-fluoro-naphth-2-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1540] In Examples 5-833 to 5-864, G is 3-chloro-naphth-2-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1541] In Examples 5-865 to 5-896, G is 3-aminosulfonyl-naphth-2-yl and R ^1a is as shown in 5-1 to 5-32.
[1542] In Examples 5-897 to 5-928, G is 6-chloro-naphth-2-yl and R ^1a is as shown in Examples 5-1 to 5-32.
[1543] Many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

权利要求:
Claims (20)
[1" claim-type="Currently amended] A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
<Formula I>

In the above formula,
M is a 4-10 membered heterocycle consisting of 3 to 10 membered carbocycles or carbon atoms and 1 to 3 heteroatoms selected from 0, S (O) _p , N and NZ ² ;
Ring M is substituted with 0-3 R ^1a and 0-2 carbonyl groups, and there are 0-3 ring double bonds present;
P is a 5, 6 or 7 membered heterocycle fused on ring M and consists of 5, 6 or 7 membered carbocycles or carbon atoms and 1 to 3 heteroatoms selected from 0, S (O) _p and N ;
Ring P is substituted with 0-3 R ^1a and 0-2 carbonyl groups, and 0-3 ring double bonds are present;
Alternatively, ring P is absent and P ₄ is directly attached to ring M, provided that if ring P is absent, P ₄ and M ₄ are 1,2, 1,3 or 1,4 positions of ring M Attached to;
One of P ₄ and M ₄ is -ZAB, and the other is -G ₁ -G;
G is a group of formula IIa or IIb;
<Formula IIa>

<Formula IIb>

here,
Ring D is a 5-6 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O and S (O) _p , including the two atoms of ring E to which it is attached;
Ring D is substituted with 0-2 R, and 0-3 ring double bonds are present;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl and is substituted with 1 to 2 R;
Alternatively, ring D is absent and ring E is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl and Thiazolyl, ring E is substituted with 1 to 2 R;
Alternatively, ring D is absent and ring E is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl and Selected from thiazolyl, wherein ring E is substituted with a 5-6 membered heterocycle consisting of 1 R and a carbon atom and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p , wherein A 5-6 membered heterocycle is substituted with 0-1 carbonyl and 1-2 R, and 0-3 ring double bonds are present;
R is H, C _1-4 alkyl, F, Cl, Br, I, OH, OCH ₃ , OCH ₂ CH ₃ , OCH (CH ₃ ) ₂ , OCH ₂ CH ₂ CH ₃ , CN, C (= NR ⁸ ) NR ⁷ R ⁹ , NHC (= NR ⁸ ) NR ⁷ R ⁹ , ONHC (= NR ⁸ ) NR ⁷ R ⁹ , NR ⁸ CH (= NR ⁷ ), NH ₂ , NH (C _1-3 alkyl), N ( C _1-3 alkyl) ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NH (C _1-3 alkyl), CH ₂ N (C _1-3 alkyl) ₂ , CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ NH (C _1-3 alkyl), CH ₂ CH ₂ N (C _1-3 alkyl) ₂ , (CR ⁸ R ⁹ ) _t C (O) H, (CR ⁸ R ⁹ ) _t C ( O) R ^2c , (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ , (CR ⁸ R ⁹ ) _t C (O) NR ⁷ R ⁸ , (CR ⁸ R ⁹ ) _t NR ⁷ C (O) R ⁷ , ( CR ⁸ R ⁹ ) _t OR ³ , (CR ⁸ R ⁹ ) _t S (0) _p NR ⁷ R ⁸ , (CR ⁸ R ⁹ ) _t NR ⁷ S (0) _p R ⁷ , (CR ⁸ R ⁹ ) _t SR ³ , (CR ⁸ R ⁹ ) _t S (0) R ³ , (CR ⁸ R ⁹ ) _t S (0) ₂ R ³ and OCF ₃ ;
Alternatively, when two R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is
C _3-10 carbocycle substituted with 0 to 2 R ⁴ , and
Is selected from a carbon atom and a 5-12 membered heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ⁴ ;
Provided that A is other than dihydro-benzopyran;
B is or; Provided that Z and B are attached to different atoms on A, and the AXN moiety forms something other than an NNN group;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C═O and SO ₂ ;
Ring Q is a 4-8 membered monocyclic or bicyclic group consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the NQ ₁ group shown above Ring, where
0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 4-8 membered monocyclic or bicyclic ring to which another ring is fused, wherein
The 4 to 7 membered ring consists of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 2 double bonds. Present in this ring;
The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of carbon atoms and 1 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ ;
The ring Q comprising the 4 to 7 membered ring and the fused ring is substituted with 0 to 3 R ^4a ;
Alternatively, two nonadjacent atoms in one of the rings of ring Q are bridged with 1 to 2 atoms selected from carbon atoms, NR ^4C , O, S, S (O) and S (O) ₂ , with 0 being There are bonds other than -0, S (O) _p -O, S (O) _p -S (O) _p , NO and NS (O) _p ;
X is not present or _{^{- (CR 2 R 2a) 1-4}} -, -CR 2 (CR 2 R 2b) (CH 2) t -, -C (O) -, -C (= NR 1c) -, - ^{CR 2 (NR 1c R 2)} -, -CR 2 (OR 2) -, -CR 2 (SR 2) -, -C (O) CR 2 R 2a -, -CR 2 R 2a C (O), - S (O) -, -S ( O) 2 -, -SCR 2 R 2a -, -S (O) CR 2 R 2a -, -S (O) 2 CR 2 R 2a -, -CR 2 R 2a S (O)-, -CR ² R ^2a S (O) _2- , -S (O) ₂ NR ² CR ² R ^2a -,-NR ² S (O) _2- , -CR ² R ^2a NR ² S ( ^{_{O) 2 -, -NR 2 S}} (O) 2 CR 2 R 2a -, -NR 2 C (O) -, -C (O) NR 2 CR 2 R 2a -, -NR 2 C (O) CR 2 R ^2a - is selected ^{from, -CR 2 R 2a NR 2 C} (O) -, -NR 2 CR 2 R 2a - - , and -OCR ² R ^2a;
G ₁ is absent or (CR ³ R ^3a ) _1-5 , (CR ³ R ^3a ) _0-2 CR ³ = CR ³ (CR ³ R ^3a ) _0-2 , (CR ³ R ^3a ) _0-2 C (C (CR ³ R ^3a ) _0-2 , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u OC (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u OC (O) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (O) O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (O ) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b C (S) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b S (O) ₂ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u N ^3b S (O) ₂ N ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3e (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O ) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) NR ^3b C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) NR ^3b S (O) ₂ ( CR ³ R ^3a ) _w and (CR ³ R ^3a ) _u S (O) ₂ NR ^3b C (O) NR ^3b (CR ³ R ^3a ) _w , wherein the sum of u + w is 0, 1, 2, 3 or 4, provided that G ₁ does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
Z is a bond,-(CR ³ R ^3e ) _1-4- , (CR ³ R ^3e ) _q O (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b (CR ³ R ^3e ) _q1 , ( CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) 0 (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q OC (O) ( CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) (CR ³ R ^3e ) _q1 , ( CR ³ R ^3e ) _q OC (O) O (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q OC (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) O (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b C (O) (CR ³ R ^3e ) _q C (O) NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (O) ₂ (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q SO ₂ NR ^3b (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q NR ^3b SO ₂ (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q S (O) NR ^3b C (O) (CR ³ R ^3e ) _q1 , (CR ³ R ^3e ) _q C (O) NR ^3b S (O) ₂ (CR ³ R ^3e ) _q1 and (CR ³ R ^3e ) _q NR ^3b SO ₂ NR ^3b (CR ³ R ^3e ) _q1 wherein q + q1 sum is 0, 1, 2, 3 or 4, provided Z is NS, NCH and other groups to which it is attached Does not form ₂ N, NCH ₂ 0 or NCH ₂ S bonds;
Provided that BAZ forms other than pyridone-phenyl-CH ₂ , pyridone-pyridyl-CH ₂ or pyridone-pyrimidyl-CH ₂ , wherein the pyridone, phenyl, pyridyl and pyrimidyl groups are substituted or substituted Without;
Z ² is H, S (O) ₂ NHR ^3b , C (O) R ^3b , C (O) NHR ^3b , C (O) OR ^3f , S (O) R ^3f , S (O) ₂ R ^3f , 0 or two R ^{1a-substituted} C _1-6 alkyl, 0-2 R ^1a a C _2-6 alkenyl substituted with 0 to 2 R ^1a substituted C _2-6 alkynyl, a 0 to a 3 substituted by R ^1a - (C _O-4 alkyl) -C _3-10 carbonyl which is substituted by cycle and 0-3 R ^1a carbon atoms, and N, O, and S (O) selected from the group consisting of _p Is selected _from- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms;
R ^1a is, in each case, H,-(CR ³ R ^3a ) _r -R ^1b ,-(CR ³ R ^3a ) _r -CR ³ R ^1b R ^1b ,-(CR ³ R ^3a ) _r -O- ( CR ³ R ^3a ) _r -R ^1b , -C _2-6 alkenylene-R ^1b , -C _2-6 alkynylene-R ^1b ,-(CR ³ R ^3a ) _r -C (= NR ^1b ) NR ³ R ^1b , NR ³ CR ³ R ^3a R ^1c , OCR ³ R ^3a R ^1c , SCR ³ R ^3a R ^1c , NR ³ (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , C (O) NR ² (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , CO ₂ (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , O (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , S (CR ³ R ^3a ) ₂ (CR ³ R ^3a ) _t R ^1b , S (O) _p (CR ³ R ^3a ) _r R ^1d , O (CR ³ R ^3a ) _r R ^1d , NR ³ (CR ³ R ^3a ) _r R ^1d , OC (O) NR ³ (CR ³ R ^3a ) _r R ^1d , NR ³ C (O) NR ³ (CR ³ R ^3a ) _r R ^1d , NR ³ C (O) 0 (CR ³ R ^3a ) _r R ^1d and NR ³ C (O) (CR ³ R ^3a ) _r R ^1d , provided that R ^1a is other than N-halo, NS, 0-0 or N-CN bond To form one;
Alternatively, when two R ^1a groups are attached to an adjacent atom, the groups together with the atoms to which they are attached are selected from the group consisting of carbon atoms, and from 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p ; Forms a seven membered ring, wherein the ring is substituted with 0-2 R ^4b and 0-3 ring double bonds are present;
R ^1b is H, C _1-3 alkyl, F, Cl, Br, I, -CN, -NO ₂ , -CHO, (CF ₂ ) _r CF ₃ , (CR ³ R ^3a ) _r OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC (O) R ² , (CF ₂ ) _r CO ₂ R ^2a , S (O) _p R ^2b , NR ² (CH ₂ ) _r OR ² , C (= NR ^2c ) NR ² R ^2a , NR ² C (O) R ^2b , NR ² C (O) NHR ² , NR ² C (O) ₂ R ^2a , OC (O) NR ² R ^2a , C (O ) NR ² R ^2a , C (O) NR ² (CH ₂ ) _r OR ² , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , C (O) NR ² SO ₂ R ² , 0 to 2 R C _3-6 carbocycle substituted with ^4b , and carbon atoms, and 5 to 5 substituted with 0 to 2 R ^4b and consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p Selected from a 10 membered heterocycle, provided that R ^1b forms other than 0-0, N-halo, NS or N-CN bond;
R ^1c is H, CH (CH ₂ OR ² ) ₂ , C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ² , S (O) ₂ R ² and SO ₂ NR ² R ^Is selected from ^2a ;
R ^1d is C _3-6 carbocycle substituted with 0 to 2 R ^4b and a carbon atom and 1 to 4 heteroatoms selected from the group consisting of N, O, and S (O) _p and 0 to Selected from 5 to 10 membered heterocycles substituted with two R ^4b , provided that R ^1d forms other than NS bonds;
R ² is, at each occurrence, H, CF ₃ , C _1-6 alkyl, benzyl, — (CH ₂ ) _r —C _3-10 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p is selected ^from- (CH ₂ ) _r -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0-2 R ^4b substituted;
R ^2a is, at each occurrence, H, CF ₃ , C _1-6 alkyl, benzyl, — (CH ₂ ) _r —C _{3-10 carbocycle} substituted with 0 to 2 R ^4b , and a carbon atom, and Is selected ^from- (CH ₂ ) _r -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and consist of 0 to 1 additional heteroatoms selected from the group consisting of N, O, and S (O) _p or 5 or To form a six-membered saturated, partially saturated or unsaturated ring;
R ^2b is, the in each case, optionally substituted with CF _3, 0-2 R ^4b a C _1-4 alkoxy, 0-2 R ^4b a C _1-6 alkyl, substituted with 0-2 R ^4b substituted with — (CH ₂ ) _r —C _3-10 carbocycle, and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O, and S (O) _p and substituted with 0 to 2 R ^4b -(CH ₂ ) _r -5 to 10 membered heterocycle;
R ^2c is, in each case, CF ₃ , OH, C _1-4 alkoxy, C _1-6 alkyl, — (CH ₂ ) _r —C _3-10 carbocycle substituted with 0 to 2 R ^4b , and Is selected ^from- (CH ₂ ) _r -5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ^4b ;
R ³ is in each case H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl and phenyl;
R ^3a in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl and phenyl;
Alternatively, R ³ and R ^3a may be combined with the nitrogen atom to which they are attached to 0 to 1 selected from the group consisting of carbon atoms, nitrogen atoms to which R ³ and R ^3a are attached, and N, O, and S (O) _p . To form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring of two additional heteroatoms;
The R ^3b is substituted in each case, in H, 0 to 2 R ^1a a C _1-6 alkyl, 0-2 R a C _2-6 alkenyl, substituted with 0-2 R ^{1a 1a} substituted with C _2-6 alkynyl, 0-3 R ^1a is substituted with - (C _0-4 alkyl) -5 to 10-carbonyl which is substituted by-cycle, and 0-3 R ^1a carbon atoms, and N, O _And- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of S (O) _p ;
R ^3c in each case is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ( CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl and phenyl;
R ^3d is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C _1-4 alkyl-phenyl and C ( ^═O ) R ^3c ;
R ^3e is, in each case, H, SO ₂ NHR ³ , S0 ₂ NR ³ R ³ , C (O) R ³ , C (O) NHR ³ , C (O) OR ^3f , S (O) R ^3f , S (O) ₂ R ^3f, 0-2 R ^1a is substituted with a C _1-6 C alkyl, 0-2 C _2-6 alkenyl substituted with R ^1a, the 0-2 R ^1a is substituted by _{2 -6} alkynyl, 0-3 R ^1a is substituted by - (C _O-4 alkyl) -5 to 10-carbonyl which is substituted by-cycle, and 0-3 R ^1a carbon atoms, and N, O and S (O) _p is selected _from- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of _p ;
R ^3f is, in each case, a C ₂ substituted with 0-2 R ^1a a C _1-6 alkyl, 0-2 R ^1a Roach unsubstituted C _2-6 alkenyl, substituted with 0-2 R ^1a _-6 alkynyl, 0 to 3 of R ^1a is substituted by - (C _0-4 alkyl) -5 to 10-carbonyl which is substituted by-cycle, and 0-3 R ^1a carbon atoms, and N, O and S (O) _p is selected _from- (C _0-4 alkyl) -5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of _p ;
R ⁴ is in each case H, = 0, (CR ³ R ^3a ) _r OR ² , F, Cl, Br, I, C _1-4 alkyl, (CR ³ R ^3a ) _r CN, (CR ³ R ^3a ) _r NO ₂ , (CR ³ R ^3a ) _r NR ² R ^2a , (CR ³ R ^3a ) _r C (O) R ^2c , (CR ³ R ^3a ) _r NR ² C (O) R ^2b , (CR ³ R ^3a ) _r C (O) NR ² R ^2a , (CR ³ R ^3a ) _r NR ² C (O) NR ² R ^2a , (CR ³ R ^3a ) _r C (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r C (= NS (O) ₂ R ⁵ ) NR ² R ^2a , (CR ³ R ^3a ) _r NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r C ( O) NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r S0 ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r NR ² SO ₂ R ⁵ , (CR ³ R ^3a ) _r S (O) _p R ^5a , (CR ³ R ^3a ) _r (CF ₂ ) _r CF ₃ , NHCH ₂ R ^1c , OCH ₂ R ^1c , SCH ₂ R ^1c , NH (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , O (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , S ( CH ₂ ) ₂ (CH ₂ ) _t R ^1b , (CR ³ R ^3a ) _r -5 to 6-membered carbocycle substituted with 0 to 1 R ⁵ , and a carbon atom, and N, O and S (O) consisting of 1 to 4 heteroatoms selected from the group consisting of _p and 0 to 1 R ⁵ Substituted (CR ³ R ^3a ) _r -5 to 6 membered heterocycle;
R ^4a is, in each case, H, = 0, (CR ³ R ^3a ) _r OR ² , (CR ³ R ^3a ) _r F, (CR ³ R ^3a ) _r Br, (CR ³ R ^3a ) _r Cl, C _1-4 alkyl, (CR ³ R ^3a ) _r CN, (CR ³ R ^3a ) _r NO ₂ , (CR ³ R ^3a ) _r NR ² R ^2a , (CR ³ R ^3a ) _r C (O) R ^2c , (CR ³ R ^3a ) _r NR ² C (O) R ^2b , (CR ³ R ^3a ) _r C (O) NR ² R ^2a , (CR ³ R ^3a ) _r N = CHOR ³ , (CR ³ R ^3a ) _r C (O) NH (CH ₂ ) ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² C (O) NR ² R ^2a , (CR ³ R ^3a ) _r C (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r NR ² SO ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r C (O) NHS0 ₂ -C _1-4 alkyl, (CR ³ R ^3a ) NR ² SO ₂ R ⁵ , (CR ³ R ^3a ) _r S (O) _p R ^5a , (CR ³ R ^3a ) _r (CF ₂ ) _r CF ₃ , (CR ³ R ^3a ) _r -5 substituted with 0 to 1 R ⁵ (CR ³ R ^3a ) _r consisting of from 6 to 6 membered carbocycles and carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ -5 to 6 membered heterocycle Is selected from;
R ^4b is in each case H, = 0, (CH ₂ ) _r OR ³ , (CH ₂ ) _r F, (CH ₂ ) _r Cl, (CH ₂ ) _r Br, (CH ₂ ) _r I, C _1-4 alkyl, (CH ₂ ) _r CN, (CH ₂ ) _r NO ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , (CH ₂ ) _r C (O ) OR ^3c , (CH ₂ ) _r NR ³ C (O) R ^3a , (CH ₂ ) _r -C (O) NR ³ R ^3a , (CH ₂ ) _r NR ³ C (O) NR ³ R ^3a , ( CH ₂ ) _r -C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r NR ^3C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r S0 ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ SO ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ SO ₂ -C _1-4 alkyl, (CH ₂ ) _r NR ³ SO ₂ CF ₃ , (CH ₂ ) _r NR ³ SO ₂ -phenyl, ( CH ₂ ) _r S (O) _p CF ₃ , (CH ₂ ) _r S (O) _p -C _1-4 alkyl, (CH ₂ ) _r S (O) _p -phenyl and (CH ₂ ) _r (CF ₂ ) _r CF ₃ ;
R ^4c is, in each case, H, C _1-4 alkyl, (CR ³ R ^3a ) _r1 OR ² , (CR ³ R ^3a ) _r1 F, (CR ³ R ^3a ) _r1 Br, (CR ³ R ^3a ) _r1 Cl, (CR ³ R ^3a ) _r1 CN, (CR ³ R ^3a ) _r1 NO ₂ , (CR ³ R ^3a ) _r1 NR ² R ^2a , (CR ³ R ^3a ) _r C (O) R ^2c , (CR ³ R ^3a ) _r1 NR ² C (O) R ^2b , (CR ³ R ^3a ) _r C (O) NR ² R ^2a , (CR ³ R ^3a ) _r1 N = CHOR ³ , (CR ³ R ^3a ) _r C (O) NH (CH ₂ ) ₂ NR ² R ^2a , (CR ³ R ^3a ) _r1 NR ² C (O) NR ² R ^2a , (CR ³ R ^3a ) _r1 C (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r1 NHC (= NR ² ) NR ² R ^2a , (CR ³ R ^3a ) _r SO ₂ NR ² R ^2a , (CR ³ R ^3a ) _r1 NR ² S0 ₂ NR ² R ^2a , (CR ³ R ^3a ) _r1 NR ² S0 ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r C (O) NHSO ₂ -C _1-4 alkyl, (CR ³ R ^3a ) _r1 NR ² SO ₂ R ⁵ , (CR ³ R ^3a ) _r S (O) _p R ^5a , (CR ³ R ^3a ) _r (CF ₂ ) _r CF ₃ , (CR ³ R ^3a ) _r -5 to 6 substituted with 0 to 1 R ⁵ (CR ³ R ^3a ) _r -5 composed of 1 to 4 heteroatoms selected from the group of carbocycles, and carbon atoms, and N, O and S (O) _p and substituted with 0 to 1 R ⁵ To 6 yuan he It is selected from Rosa cycle;
R ⁵ is in each case H, C _1-6 alkyl, = 0, (CH ₂ ) _r OR ³ , F, Cl, Br, I, -CN, N0 ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , (CH ₂ ) _r C (O) OR ^3c , (CH ₂ ) _r NR ³ C (O) R ^3a , (CH ₂ ) _r C (O) NR ³ R ^3a , (CH ₂ ) _r NR ³ C (O) NR ³ R ^3a , (CH ₂ ) _r CH (= NOR ^3d ), (CH ₂ ) _r C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r NR ³ C (= NR ³ ) NR ³ R ^3a , (CH ₂ ) _r SO ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ SO ₂ NR ³ R ^3a , (CH ₂ ) _r NR ³ S0 ₂ -C _1-4 alkyl, (CH ₂ ) _r NR ³ SO ₂ CF ₃ , (CH ₂ ) _r NR ³ SO ₂ -phenyl, (CH ₂ ) _r S (O) _p CF ₃ , (CH ₂ ) _r S (O) _p -C _{1-4 alkyl, (CH 2) r S (} O) p - , phenyl-, (CF _{2) r} CF _3, 0 to 2 r ⁶ is phenyl substituted with 0 to 2 r ⁶ Substituted naphthyl and benzyl substituted with 0 to 2 R ⁶ ;
R ^5a is, in each case, C _1-6 alkyl, (CH ₂ ) _r OR ³ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , (CH ₂ ) _r C (O) OR ^3c , (CH ₂ ) _r NR ³ C (O) R ^3a , (CH ₂ ) _r C (O) NR ³ R ^3a , (CF ₂ ) _r CF ₃ , substituted with 0 to 2 R ⁶ phenyl, 0 to 2 are selected from benzyl substituted by two R ⁶ and naphthyl substituted with 0-2 R ^6, with the proviso that, R ^5a is not SN forms a bond or _{S (O) p -C (O} ) Without;
R ⁶ in each case is H, OH, (CH ₂ ) _r OR ² , halo, C _1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C ( O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , C (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² S0 ₂ C _1-4 alkyl;
R ⁷ is in each case H, OH, C _1-6 alkyl, C _1-6 alkyl-C (O)-, C _1-6 alkyl-O-, (CH ₂ ) _n -phenyl, C _{1- 4} alkyl-OC (O)-, C _6-10 aryl-0-, C _6-10 aryl-OC (O)-, C _6-10 aryl-CH ₂ -C (O)-, C _1-4 alkyl -C (O) OC _1-4 alkyl-OC (O)-, C _6-10 aryl-C (O) OC _1-4 alkyl-OC (O)-, C _1-6 alkyl-NH ₂ -C ( O)-, phenyl-NH ₂ -C (O)-and phenyl-C _1-4 alkyl-C (O)-;
R ⁸ is in each case selected from H, C _1-6 alkyl and (CH ₂ ) _n -phenyl;
Alternatively, a 5-10 membered heterocyclic ring consisting of 0 to 2 additional heteroatoms selected from the group consisting of carbon atoms and N, O and S (O) _p , when R ⁷ and R ⁸ are attached to the same nitrogen, To form;
R ⁹ is in each case selected from H, C _1-6 alkyl and (CH ₂ ) _n -phenyl;
n is in each case selected from 0, 1, 2 and 3;
p is in each case selected from 0, 1 and 2;
r is in each case selected from 0, 1, 2, 3, 4, 5 and 6;
r1 is, in each case, selected from 1, 2, 3, 4, 5 and 6;
t is in each case selected from 0, 1, 2 and 3;
only,
(a) when ring M is phenyl and is substituted 1,2 by M ₄ and P ₄ and G ₁ are present, ZA is NHC (O) -thienyl, NHCH ₂ -thienyl, NHC (O) -benzo Other than thienyl and NHCH ₂ -benzothienyl;
(b) when B is 2-oxo-1-pyrrolidinyl and the ring PM is 1,7-dihydro-2-methyl-6H-purin-6-one, GG ₁ is other than unsubstituted phenyl.
[2" claim-type="Currently amended] A compound according to claim 1 which is a compound of formula II or a stereoisomer or a pharmaceutically acceptable salt thereof.
<Formula II>

In the above formula,
Ring M comprising P ₁ , P ₂ , M ₁ and M ₂ is a 5, 6 or 7 membered carbocycle or carbon atom and 1 to 3 heteros selected from 0, S (O) _p , N and NZ ² A 5, 6 or 7 membered heterocycle consisting of atoms;
Ring M is substituted with 0-2 R ^1a and 0-2 carbonyl groups and 0-3 ring double bonds are present;
Ring P comprising P ₁ , P ₂ and P ₃ is a 5 or 6 membered aromatic heterocycle consisting of carbon atoms and 1 to 3 heteroatoms selected from O, S (O) _p , and N;
Alternatively, ring P comprising P ₁ , P ₂ and P ₃ is a 5 or 6 membered dihydro-aromatic heterocycle consisting of carbon atoms and 1 to 3 heteroatoms selected from O, S (O) _p and N;
Ring P is substituted with 0-2 R ^1a ;
One of P ₄ and M ₄ is -ZAB, and the other is -G ₁ -G;
G is a group of formula IIa or IIb;
<Formula IIa>

<Formula IIb>

here,
Ring D comprises two atoms of ring E to which it is attached and is a 5-6 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O and S (O) _p ;
Ring D is substituted with 0-2 R, and 0-3 ring double bonds are present;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl and substituted with 1 to 2 R;
Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl, pyrimidyl and thienyl, wherein Ring E is substituted with 1 to 2 R;
Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl and thienyl, wherein Ring E is substituted with one R and is selected from the group consisting of carbon atoms and N, O and S (O) _p Substituted with a 5 membered heterocycle consisting of 1 to 4 heteroatoms selected, wherein the 5 membered heterocycle is substituted with 0 to 1 carbonyl and 1 to 2 R, and 0 to 3 ring double bonds are present;
R is H, C _1-4 alkyl, F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CN, C (= NH) NH ₂ , C (= NH) NHOH, C ( = NH) NHOCH ₃ , NH ₂ , NH (C _1-3 alkyl), N (C _1-3 alkyl) ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NH (C _1-3 alkyl ), CH ₂ N (C _1-3 alkyl) ₂ , (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , CH ₂ C (O) NR ⁷ R ⁸ , S (O) _p NR ⁷ R ⁸ , CH ₂ S (O) _p NR ⁷ R ⁸ , SO ₂ R ³ and OCF ₃ ;
Alternatively, when two R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
A is
C _5-10 carbocycle substituted with 0 to 2 R ⁴ , and
A carbon atom, and is selected from a 5 to 10 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 2 R ⁴ ;
Provided that A is other than dihydro-benzopyran;
B is or; Provided that Z and B are attached to different atoms on A, and that the AXN moiety forms something other than an NNN group;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C═O and SO ₂ ;
Ring Q is a 4-7 membered monocyclic or tricyclic ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown Where
0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 4-7 membered ring to which another ring is fused, wherein
The 4 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , O, and S;
The ring Q comprising the 4 to 7 membered ring and the fused ring is substituted with 0 to 3 R ^4a ;
X is not present or _{^{- (CR 2 R 2a) 1-4}} -, -C (O) -, -C (O) CR 2 R 2a -, -CR 2 R 2a C (O), -S (O) _{2 -, -S (O) 2} CR 2 R 2a -, -CR 2 R 2a S (O) 2 -, -NR 2 S (O) 2 -, -NR 2 CR 2 R 2a - , and -OCR ² R ^2a- ;
Z is a bond, CH ₂ , CH ₂ CH ₂ , CH ₂ 0, OCH ₂ , C (O), NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O ) NH, NHC (O), NHC (O) CH ₂ C (O) NH, S (O) ₂ , CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHS0 ₂ Provided that Z does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
Z ² is selected from H, C _1-4 alkyl, phenyl, benzyl, C (O) R ^3b , S (O) R ^3f and S (O) ₂ R ^3f ;
R ^1a is H,-(CH ₂ ) _r -R ^1b ,-(CH (CH ₃ )) _r -R ^1b ,-(C (CH ₃ ) ₂ ) _r -R ^1b , NHCH ₂ R ^1c , OCH ₂ R ^1c , SCH ₂ R ^1c , NH (CH ₂ ) ₂ (CH ₂ ) _t R ^1b and O (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , provided that R ^1a is N-halo, NS or N To form other than -CN bonds;
Alternatively, when two R ^1a groups are attached to an adjacent atom, the groups together with the atoms to which they are attached are selected from the group consisting of carbon atoms, and from 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p ; Forms a seven membered ring, wherein the ring is substituted with 0-2 R ^4b and 0-3 ring double bonds are present;
R ^1b is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , F, Cl, Br, I, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC (O) R ² , CO ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , NR ² C (O) NHR ² , NR ² C (O) ₂ R ^2a , OC (O) NR ² R ^2a , C (O) NR ² R ^2a , C (O) NR ² (CH ₂ ) _r OR ² , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 2 R ^4b , provided that R ^1b is other than OO, N-halo, NS or N-CN bond Will;
R ^1c is H, CH (CH ₂ 0R ² ) ₂ , C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ² , S (O) ₂ R ² and SO ₂ NR ² R ^Is selected from ^2a ;
R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH _{3 ) 2, CH (CH 3)} CH 2 CH 3, C (CH 3) 3, a C ₅ optionally substituted with benzyl, 0-2 R ^4b a C _5-6 carbocycle, 0-2 R ^4b substituted with _-6 carbocyclic -CH ₂ - group, and carbon atoms, and N, O and S (O) comprises one to four heteroatoms selected from the group consisting of a 5 to 6 _p substituted with 0-2 R ^4b Selected from circular heterocycles;
R ^2a is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S ( O) a 5-6 membered heterocycle consisting of 1-4 heteroatoms selected from the group consisting of _p and substituted with 0-2 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
R ^2b is, in each case, CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O, and S (O) _p is selected from the 5-6 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 2 R ^4b ;
R ^2c is, in each case, CF ₃ , OH, C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and N, O and Is selected from a 5-6 membered heterocycle containing 1-4 heteroatoms selected from the group consisting of S (O) _p and substituted with 0-2 R ^4b ;
R ³ is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
R ^3a is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
Alternatively, R ³ and R ^3a join together with the nitrogen atom to which they are attached to form a five or six membered saturated, partially unsaturated or unsaturated ring consisting of a carbon atom and a nitrogen atom to which R ³ and R ^3a are attached;
R ^3c is in each case selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
R ^3d in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ -phenyl, CH ₂ CH ₃ -phenyl and C (═O) R Selected from ^3c ;
R ⁴ is in each case H, = 0, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Cl, Br, I, C _1-4 alkyl, -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , S (O) _p R ^5a , CF ₃ , CF ₂ CF ₃ , 5-6 membered carbocycle substituted with 0-1 R ⁵ , and carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 1 R ⁵ ;
R ^4a is in each case H, = 0, CH ₂ 0R ² , OR ² , CH ₂ F, F, CH ₂ Br, Br, CH ₂ Cl, Cl, C _1-4 alkyl, CH ₂ -CN, -CN, CH ₂ NO ₂ , NO ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , CH ₂ -C (O) R ^2c , C (O) R ^2c , NR ² C (O) R ^2b , ( CH ₂ ) _r C (O) NR ² R ^2a , NRC (O) NR ² R ^2a , (CH ₂ ) _r SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a , NR ² SO ₂ -C ₁ CH ₂ -5 to 6-membered carbo substituted with _-4 alkyl, NR ² SO ₂ R ⁵ , (CH ₂ ) _r S (O) _p R ^5a , CH ₂ CF ₃ , CF ₃ , 0 to 1 R ⁵ A cycle, a 5-6 membered carbocycle substituted with 0-1 R ⁵ , and a carbon atom, and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0-1 CH ₂ -5 to 6 membered heterocycle substituted with R ⁵ , and a carbon atom and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ Selected from 5-6 membered heterocycle;
R ^4b in each case is H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a , CH ₂ NR ³ C (O) NR ³ R ^3a , C (= NR ³ ) NR ³ R ^3a , CH ₂ C (= NR ³ ) NR ³ R ^3a , NR ³ C (= NR ³ ) NR ³ R ^3a , CH ₂ NR ³ C (= NR ³ ) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ NR ³ R ^3a , CH ₂ NR ³ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , CH ₂ NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -Phenyl, CF ₃ and CH ₂ -CF ₃ ;
R ^4c is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN, CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , CH ₂ NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ -C _1-4 alkyl, C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ NR ² SO ₂ R ⁵ , S (O) _p R ^5a , CH ₂ S (O ) _p R ^5a, CF _3, CH ₂ CF _3, 0-1 R ⁵ of the 5 to 6 membered carbocycle, 0-1 of R ⁵ the CH ₂ -5 to 6-membered carbocycle substituted with substituted with, 5 to 6 membered heterocycle consisting of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ⁵ , and carbon atoms, and N, O and from 1 to 4, selected from the group consisting of S (O) _p The hetero atom is made is selected from a CH ₂ -5 to 6 membered heterocycle substituted with 0-1 of R ^5;
R⁵In each case, H, = 0, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH (CH₃)₂, CH (CH₃) CH₂CH₃, C (CH₃)₃, OR³, CH₂OR³, F, Cl, -CN, N0₂, NR³R^3a, CH₂NR³R^3a, C (O) R³, CH₂C (O) R³, C (O) OR^3c, CH₂C (O) OR^3c, NR³C (O) R^3a, C (O) NR³R^3a, NR³C (O) NR³R^3a, CH (= NOR^3d), C (= NR³) NR³R^3a, NR³C (= NR³) NR³R^3a, SO₂NR³R^3a, NR³SO₂NR³R^3a, NR³SO₂-C_1-4Alkyl, NR³SO₂CF₃, NR³SO₂-Phenyl, S (O)_pCF₃, S (O)_p-C_1-4Alkyl, S (O)_p-Phenyl, CF₃, 0 to 2 R⁶Phenyl substituted by 0 to 2 R⁶Naphthyl and 0 to 2 R substituted by⁶Benzyl substituted;
R ⁶ in each case is H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CN, NO ₂ , NR ² R ^2a , CH ² NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , C (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl.
[3" claim-type="Currently amended] The method of claim 2,
Ring M is substituted with 0-2 R ^1a and is selected from the group below;





Ring P comprising P ₁ , P ₂ , P ₃ and P ₄ is selected from the following group;



One of P ₄ and M ₄ is -ZAB and the other is -G ₁ -G;
G is selected from the following group;





G ₁ is absent or (CR ³ R ^3a ) _1-3 , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C ( O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ (CR ³ R ^3a ) _w , ( CR ³ R ^3a ) _u S (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b S (O) ₂ (CR ³ R ^3a ) _w and (CR ³ R ^3a ) _u S (O) ₂ NR ^3b (CR ³ R ^3a ) _w wherein u + w total is 0, 1 or 2, provided that G ₁ is NS, NCH ₂ N, NCH ₂ 0 or Does not form an NCH ₂ S bond;
A is phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxa substituted with 0-2 R ⁴ Zolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl, indolyl, benzimida Is selected from one of a carbocyclic group and a heterocyclic group of zolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl;
B is or; Provided that Z and B are attached to different atoms on A;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C═O and SO ₂ ;
Ring Q is a 5-7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
0 to 2 double bonds are present in the ring and the ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
The 5 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , O and S;
Ring Q comprising said 5-7 membered ring and said fused ring is substituted with 0-3 R ^4a ;
R ^1a is selected from H, R ^1b , CH (CH ₃ ) R ^1b , C (CH ₃ ) ₂ R ^1b , CH ₂ R ^1b and CH ₂ CH ₂ R ^1b , provided that R ^1a is N-halo, NS Or to form other than N-CN bonds;
Alternatively, when two R ^1a groups are attached to adjacent carbons, together with the atoms to which they are attached, the groups are 5 to 5 carbon atoms and 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p Forms a six membered ring, wherein the ring is substituted with 0-2 R ^4b and 0-3 ring double bonds are present;
R ^1b is H, CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC ( O) R ² , C0 ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , phenyl substituted with 0 to 2 R ^4b , and 1 to 4 heteroatoms selected from the group consisting of carbon atoms, and N, O and S (O) _p and 0 to Selected from 5-6 membered aromatic heterocycles substituted with two R ^4b , provided that R ^1b forms other than 0-0, N halo, NS, or N-CN bond;
R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , phenyl substituted with 0 to 2 R ^4b , 0 to 2 5-6 membered aromatic heterocycle consisting of benzyl substituted with R ^4b and carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b Is selected from;
R ^2a in each case is H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and carbon An atom and a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 or 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
R ^2b in each case is substituted with CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, 0-2 R ^4b Phenyl, and a carbon atom, and is selected from a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
R ^2c is, in each case, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and 0 to 2 R ^4b containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p It is selected from a 5-6 membered aromatic heterocycle substituted with;
R ⁴ is, in each case, H, CH ₂ 0R ² , (CH ₂ ) ₂ OR ² , OR ² , F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
R ^4a is in each case H, = 0, CH ₂ 0R ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and -CF ₃ Become;
R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , —CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ -C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ -C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -phenyl and CF ₃ ;
R ^4c is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN, CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , S (O) _p R ^5a , CH ₂ S (O) _p R ^5a , CF ₃ , phenyl substituted with 0 to 1 R ⁵ and 0 to 1 R Benzyl substituted by ⁵ ;
R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, S (O _{) p CF 3, S (O} ) p -C 1-4 alkyl, S (O) _p -, phenyl, CF _3, 0-2 substituted with one R ⁶ is phenyl, substituted with 0-2 R ⁶ -naphthyl And benzyl substituted with 0 to 2 R ⁶ ;
R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl Compound selected from.
[4" claim-type="Currently amended] The method of claim 3,
Ring M is substituted with 0-2 R ^1a and is selected from the group below;



Ring P comprising P ₁ , P ₂ , P ₃ and P ₄ is selected from the following group;

One of P ₄ and M ₄ is -AB and the other is -G;
G is selected from the following group;



G ₁ is absent or CH ₂ , CH ₂ CH ₂ , CH ₂ O, OCH ₂ , NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O) NH, NHC (O), CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), S0 ₂ NH and NHS0 ₂ , provided that G ₁ is NS, NCH ₂ N, NCH and the other groups to which it is attached Does not form a ₂ 0 or NCH ₂ S bond;
A is selected from phenyl, pyridyl and pyrimidyl and is substituted with 0 to 2 R ⁴ ;
B is or; Provided that Z and B are attached to different atoms on A;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C═O and SO ₂ ;
Ring Q is a 6-7 membered ring consisting of carbon atoms and 0-1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
The 5 to 7 membered ring is composed of carbon atoms and 0 to 1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
The fused ring is phenyl;
Ring Q comprising said 5-7 membered ring and said fused ring is substituted with 0-2 R ^4a ;
R ^1a is selected from H, R ^1b , C (CH ₃ ) ₂ R ^1b and CH ₂ R ^1b , provided that R ^1a forms other than N-halo, NS or N-CN bonds;
R ^1b is CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , CO ₂ R ^2a , S ( O) _p R ² , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , and 1 to 1 selected from the group consisting of carbon atoms, and N, O and S (O) _p . Selected from a 5-6 membered aromatic heterocycle consisting of 4 heteroatoms and substituted with 0-2 R ^4b , provided that R ^1b forms other than OO, N-halo, NS or N-CN bonds;
R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a 5-6 membered aromatic heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of carbon atoms, N, O and S (O) _p and substituted with 0 to 1 R ^4b ;
R ^2a in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and a carbon atom, and N, O and S (O) _p is selected from a 5-6 membered aromatic heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 1 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
R ^2b is, in each case, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ^4b Selected from 5 to 6 membered aromatic heterocycles;
R ^2c is, in each case, OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ^4b 5 to 6 membered aromatic heterocycle;
R ⁴ is, in each case, OH, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Br, Cl, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
R ^4a in each case is H, ═O, CH ₂ 0R ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and CF ₃ ;
R ^4b is in each case H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , NR ³ S0 ₂ -C _1-4 alkyl, NR ³ S0 ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl and CF ₃ ;
R ^4c are, at each occurrence, H, CH _3, CH ₂ CH _3, 0 and is selected from benzyl substituted by one R ⁵ is phenyl and R ⁵ is substituted by from 0 to 1;
R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CF ₃ , 0 to 2 R selected from benzyl substituted by phenyl, ^6, 0-2 R ^6, naphthyl, and substituted with 0-2 R ⁶ is substituted by;
R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a .
[5" claim-type="Currently amended] The method of claim 4, wherein
Ring M is substituted with 0 to 1 R ^1a and is selected from the group below;


Ring P, including P ₁ , P ₂ , P ₃ and P ₄ , is selected from the following group;

One of P ₄ and M ₄ is -AB and the other is -G;
G is selected from the following group;


A is phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-amino Phenyl and 2-methoxyphenyl;
B is attached to an atom different from M on A and is selected from the group below;



R ^1a is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ F, CH ₂ Cl, Br, CH ₂ Br, -CN, CH ₂ CN, CF ₃ , CH ₂ CF ₃ , OCH ₃ , CH ₂ OH, C (CH ₃ ) ₂ OH, CH ₂ OCH ₃ , NH ₂ , CH ₂ NH ₂ , NHCH ₃ , CH ₂ NHCH ₃ , N (CH ₃ ) ₂ , CH ₂ N (CH ₃ ) ₂ , CO ₂ H, COCH ₃ , CO ₂ CH ₃ , CH ₂ CO ₂ CH ₃ , SCH ₃ , CH ₂ SCH ₃ , S (O) CH ₃ , CH ₂ S (O) CH ₃ , S (O) ₂ CH ₃ , CH ₂ S (O) ₂ CH ₃ , C (O) NH ₂ , CH ₂ C (O) NH ₂ , SO ₂ NH ₂ , CH ₂ SO ₂ NH ₂ , NHSO ₂ CH ₃ , CH ₂ NHSO ₂ CH ₃ , pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N- Oxide, imidazol-1-yl, CH ₂ -imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N, N-dimethylaminomethyl-oxazol-2-yl, 1, 2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH ₂ -1,2,3,4-tetrazol-1-yl and CH ₂ -1 , 2,3,4-tetrazol-5-yl, provided that R ^1a forms other than N-halo, NS or N-CN bonds;
R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a carbon atom, and selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of N, O, and S (O) _p and substituted with 0 to 1 R ^4b and a 5-membered aromatic heterocycle;
R ^2a is in each case selected from H, CH ₃ and CH ₂ CH ₃ ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p Selected from saturated, partially saturated or unsaturated rings of the circle;
R ^2b is in each case selected from OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
R ^2c is in each case selected from OH, OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
R ^4a in each case is H, ═O, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ and C (CH ₃ ) ₃ ;
R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -phenyl, S (O) ₂ CH ₃ , S (O) ₂ -phenyl and CF ₃ ;
R ⁵ is in each case H, ═O, CH ₃ , CH ₂ CH ₃ , OR ³ , CH ₂ 0R ³ , F, Cl, NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO _{2- phenyl, S (O) 2 -CH 3} , S (O) 2 - , phenyl, CF _3, 0-2 R ⁶ substituted by phenyl, 0-2 R ⁶ substituted naphthyl, and 0-2 R Benzyl substituted by ⁶ ;
R ⁶ is in each case H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C ( O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a .
[6" claim-type="Currently amended] The method of claim 5,
P ₄ is -G;
M ₄ is -AB;
G is selected from;

A-B is selected from


Compounds selected from the following.



[7" claim-type="Currently amended] The method of claim 6,
P ₄ is -G;
M ₄ is -AB;
A-B is selected from

Compounds selected from the following.

[8" claim-type="Currently amended] The compound of claim 1 wherein the compound is
3-methoxy-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7-H-pyra Zolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -3-[(methylamino) methyl] -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one;
1- (3-chloro-4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6- Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- [3- (aminomethyl) -4-fluorophenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5 , 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (3-amino-1, 2-benzisoxazol-5-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1, 4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxohexahydro-1H-azin-1-yl) phenyl] -3- (trifluoromethyl) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperazinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-imidazolidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
6- [4- (3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) phenyl] -1- (4-methoxyphenyl) -3- (trifluoro Methyl) -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carbonitrile;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (1H-tetrazol-5-yl) -1,4,5,6- Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl-4,5,6,7-tetrahydro-1H-pyrazole- [3 , 4-c] pyridine-3-carboxamide;
3-bromo-1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [ 3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (4-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (4-pyridinyl-N-oxide) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (3-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (3-pyridinyl-N-oxide) -1,4,5,6 Tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (2-pyridinyl) -1,4,5,6-tetrahydro-7H -Pyrazolo [3,4-c] -7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c ] Pyridin-7-one;
1- (4-methoxyphenyl) -7-oxo-6- [5- (2-oxo-1-piperidinyl) -2-pyridinyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -3- (methylsulfonyl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -1,4,5,6-tetrahydro-7H- Pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- (4- (2-oxo-1 (2H) -pyridinyl) phenyl-3- (2-pyridinyl) -1,4,5,6-tetrahydro- 7H-pyrazolo [3,4-c] pyridin-7-one;
1- [3- (aminomethyl) phenyl] -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydro -7H-pyrazolo [3,4-c] pyridin-7-one;
3- [7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-1-yl] benzamide;
1- (3-chlorophenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide;
1- (3-chlorophenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [ 3,4-c] pyridine-3-carboxamide;
1- (3-chlorophenyl) -N, N-dimethyl-7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H -Pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carbonitrile;
1- (3-amino-1 H-indazol-5-yl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (3-amino-1, 2-benzisoxazol-5-yl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7 -Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (trifluoromethyl) -1 , 4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (2,3-dihydro-1H-indol-6-yl) -6- [4- (2-oxo-1-piperidinyl) phenyl] -3- (trifluoromethyl) -1,4 , 5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (2,3-dihydro-1H-isoindol-5-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) phenyl] -3-trifluoromethyl-1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -3- (2-pyrrolidin-1-ylmethyl-phenyl) -1 , 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
Ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyra Solo [3,4-c] pyridine-3-carboxylate;
1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid;
1- (4-methoxyphenyl) -N, N-dimethyl-7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl-4,5,6,7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxamide;
N-({1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -4,5,6,7-tetrahydro- 1H-pyrazolo [3,4-c] pyridin-3-yl} carbonyl) methanesulfonamide;
1- (4-hydroxy-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxylic acid amide;
1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- (1H-tetrazol-5-yl) -1,4,5, 6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
3- {4-[(dimethylamino) methyl] -1,3-oxazol-2-yl} -1- (4-methoxyphenyl) -6- [4- (2-oxo-1 (2H)- Pyridinyl) phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
3- {4-[(dimethylamino) methyl] -1,3-oxazol-2-yl} -1- (4-methoxyphenyl) -6- [4- (2-oxo-1-piperidinyl ) Phenyl] -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperazinyl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine-3-carboxamide;
1- (4-methoxyphenyl) -3- (methylsulfonyl) -6- [4- (2-oxo-1-piperazinyl) phenyl] -1,4,5,6-tetrahydro-7H- Pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxy-phenyl) -3- (4-methyl-oxazol-2-yl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxy-phenyl) -3- (4-methyl-oxazol-2-yl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
3-acetyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one;
3- (4,5-dihydro-1H-imidazol-2-yl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl)- Phenyl] -1,4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxy-phenyl) -3- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -6- [4- (2-oxo-piperidine-1 -Yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxy-phenyl) -3- (1-methyl-1H-imidazol-2-yl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl]- 1,4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
1- (4-methoxy-phenyl) -3-methyl-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one;
3-hydroxymethyl-1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro- Pyrazolo [3,4-c] pyridin-7-one;
3- (1-hydroxy-1-methyl-ethyl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
3- (1-hydroxy-1-methyl-ethyl) -1- (4-methoxy-phenyl) -6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1, 4,5,6-tetrahydropyrazolo [3,4-c] pyridin-7-one;
2-dimethylamino-N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7- Tetrahydro-1H-pyrazolo [3,4-c] pyridin-3-ylmethyl} -N-methylacetamide;
2-dimethylamino-N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c] pyridin-3-ylmethyl} acetamide;
N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl-4,5,6,7-tetrahydro-1H-pyra Zolo [3,4-c] pyridin-3-ylmethyl} -2-pyridin-2-yl-acetamide;
N- {1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridin-3-ylmethyl} -2- (1-oxypyridin-2-yl) -acetamide;
6- [4- (1,1-Dioxo-116-isothiazolidin-2-yl) -phenyl] -1- (4-methoxy-phenyl) -7-oxo-4,5,6,7 -Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide;
N-hydroxy-3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetra Hydro-pyrazolo [3,4-c] pyridin-1-yl} -benzamidine;
N-methoxy-3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetra Hydro-pyrazolo [3,4-c] pyridin-1-yl} -benzamidine;
1- (3-cyano-4-fluorophenyl-7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl] -4,5,6,7-tetrahydro-1H- Pyrazolo [3,4-c] pyridine-3-carboxamide;
1- (3-Aminomethyl-4-fluoro-phenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5,6,7- Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide;
2- {7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzenesulfonamide;
2- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzenesulfonamide;
N-acetyl-2- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro -Pyrazolo [3,4-c] pyridin-1-yl} -benzenesulfonamide;
1- (3-Chloro-phenyl) -3-methanesulfonyl-6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra Zolo [3,4-c] pyridin-7-one;
1- (3-Chloro-phenyl) -3-methanesulfonyl-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -1,4,5,6-tetrahydro-pyra Zolo [3,4-c] pyridin-7-one;
1- (3-Chloro-phenyl) -3- (1-hydroxy-1-methyl-ethyl) -6- [4- (2-oxo-piperidin-1-yl) -phenyl] -1,4 , 5,6-tetrahydro-pyrazolo [3,4-c] pyridin-7-one; And
3- {7-oxo-6- [4- (2-oxo-2H-pyridin-1-yl) -phenyl] -3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo [ 3,4-c] pyridin-1-yl} -benzamide or a pharmaceutically acceptable salt thereof.
[9" claim-type="Currently amended] The compound of claim 1, wherein the compound is a compound of Formula IIIa, IIIb or IIIc or a stereoisomer or a pharmaceutically acceptable salt thereof.
<Formula IIIa>

<Formula IIIb>

<Formula IIIc>

In the above formula,
Ring M comprising M ₁ , M ₂ and M ₃ , if present, is phenyl or a 1 to 4 heteroatom selected from 3 to 10 membered carbocyclic or carbon atoms and O, S (O) _p , N and NZ ² 4 to 10 membered heterocyclic ring;
Ring M is substituted with 0-3 R ^1a and 0-2 carbonyl groups, and there are 0-3 ring double bonds present;
One of P ₄ and M ₄ is -ZAB, and the other is -G ₁ -G;
G is a group of formula IIa or IIb;
<Formula IIa>

<Formula IIb>

here,
Ring D is a 5-6 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O and S (O) _p , including the two atoms of ring E to which it is attached;
Ring D is substituted with 0-2 R, and 0-3 ring double bonds are present;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl and substituted with 1 to 2 R;
Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl, pyrimidyl and thienyl, wherein Ring E is substituted with 1 to 2 R;
Alternatively, Ring D is absent and Ring E is selected from phenyl, pyridyl and thienyl, wherein Ring E is substituted with one R and is selected from the group consisting of carbon atoms and N, O and S (O) _p Substituted with a 5 membered heterocycle consisting of 1 to 4 heteroatoms selected, wherein the 5 membered heterocycle is substituted with 0 to 1 carbonyl and 1 to 2 R, and 0 to 3 ring double bonds are present;
R is H, C _1-4 alkyl, F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CN, C (= NH) NH ₂ , C (= NH) NHOH, C ( = NH) NHOCH ₃ , NH ₂ , NH (C _1-3 alkyl), N (C _1-3 alkyl) ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NH (C _1-3 alkyl ), CH ₂ N (C _1-3 alkyl) ₂ , (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , CH ₂ C (O) NR ⁷ R ⁸ , S (O) _p NR ⁷ R ⁸ , CH ₂ S (O) _p NR ⁷ R ⁸ , SO ₂ R ³ and OCF ₃ ;
Alternatively, when two R groups are attached to adjacent carbons, they combine to form methylenedioxy or ethylenedioxy;
A is
C _5-10 carbocycle substituted with 0 to 2 R ⁴ , and
A carbon atom and a 5-10 membered heterocycle consisting of 1-4 heteroatoms selected from N, O and S (O) _p and substituted with 0-2 R ⁴ ;
Provided that A is other than dihydro-benzopyran;
B is or; Provided that Z and B are attached to different atoms on A, and that the AXN moiety forms something other than an NNN group;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C = 0 and SO ₂ ;
Ring Q is a 4-7 membered monocyclic or tricyclic ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , 0, S, S (O) and S (O) ₂ , in addition to the NQ ₁ group shown Where,
0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 4-7 membered ring to which another ring is fused, wherein
The 4 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , 0 and S;
The ring Q comprising the 4 to 7 membered ring and the fused ring is substituted with 0 to 3 R ^4a ;
X is not present or _{^{- (CR 2 R 2a) 1-4}} -, -C (O) -, -C (O) CR 2 R 2a -, -CR 2 R 2a C (O), -S (O) _{2 -, -S (O) 2} CR 2 R 2a -, -CR 2 R 2a S (O) 2 -, -NR 2 S (O) 2 -, -NR 2 CR 2 R 2a - , and -OCR ² R ^2a- ;
Z is a bond, CH ₂ , CH ₂ CH ₂ , CH ₂ 0, OCH ₂ , C (O), NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O ) NH, NHC (O), NHC (O) NH, NHC (O) CH ₂ C (O) NH, C (O) NHS (O) ₂ , S (O) ₂ , CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHSO ₂ , provided that Z does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
Z ² is selected from H, C _1-4 alkyl, phenyl, benzyl, C (O) R ^3b , S (O) R ^3f and S (O) ₂ R ^3f ;
R ^1a is H,-(CH ₂ ) _r -R ^1b ,-(CH (CH ₃ )) _r -R ^1b ,-(C (CH ₃ ) ₂ ) _r -R ^1b , NHCH ₂ R ^1c , OCH ₂ R ^1c , SCH ₂ R ^1c , NH (CH ₂ ) ₂ (CH ₂ ) _t R ^1b and O (CH ₂ ) ₂ (CH ₂ ) _t R ^1b , provided that R ^1a is N-halo, NS or N To form other than -CN bonds;
Alternatively, when two R ^1a groups are attached to adjacent carbons, together with the atoms to which they are attached, the groups are 5 to 5 carbon atoms and from 0 to 2 heteroatoms selected from the group consisting of N, O and S (O) _p Forms a seven membered ring, which is substituted with 0-2 R ^4b , and there are 0-3 ring double bonds present;
R ^1b is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , F, Cl, Br, I, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC (O) R ² , CO ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , NR ² C (O) NHR ² , NR ² C (O) ₂ R ^2a , OC (O) NR ² R ^2a , C (O) NR ² R ^2a , C (O) NR ² (CH ₂ ) _r OR ² , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 2 R ^4b , provided that R ^1b is other than OO, N-halo, NS or N-CN bond To form one;
R ^1c is H, CH (CH ₂ 0R ² ) ₂ , C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ² , S (O) ₂ R ² and SO ₂ NR ² R ^Is selected from ^2a ;
R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH _{3 ) 2, CH (CH 3)} CH 2 CH 3, C (CH 3) 3, a C ₅ optionally substituted with benzyl, 0-2 R ^4b a C _5-6 carbocycle, 0-2 R ^4b substituted with _-6 carbocyclic -CH ₂ - group, and carbon atoms, and N, O and S (O) comprises one to four heteroatoms selected from the group consisting of a 5 to 6 _p substituted with 0-2 R ^4b Selected from circular heterocycles;
R ^2a is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S ( O) a 5-6 membered heterocycle consisting of 1-4 heteroatoms selected from the group consisting of _p and substituted with 0-2 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a circular saturated, partially saturated or unsaturated ring;
R ^2b is, in each case, CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and a carbon atom, and N, O and S (O) _p is selected from the 5-6 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 2 R ^4b ;
R ^2c is, in each case, CF ₃ , OH, C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , benzyl, C _5-6 carbocycle substituted with 0 to 2 R ^4b , and N, O and Is selected from a 5-6 membered heterocycle containing 1-4 heteroatoms selected from the group consisting of S (O) _p and substituted with 0-2 R ^2b ;
R ³ is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
R ^3a is in each case selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
Alternatively, R ³ and R ^3a join together with the nitrogen atom to which they are attached to form a five or six membered saturated, partially unsaturated or unsaturated ring consisting of a carbon atom and a nitrogen atom to which R ³ and R ^3a are attached;
R ^3c is in each case selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl and phenyl;
R ^3d in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ -phenyl, CH ₂ CH ₂ -phenyl and C (═O) R Selected from ^3c ;
R ⁴ is in each case H, = 0, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Cl, Br, I, C _1-4 alkyl, -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , S (O) _p R ^5a , CF ₃ , CF ₂ CF ₃ , 5-6 membered carbocycle substituted with 0-1 R ⁵ , and carbon atom, and N, O and S (O) _p Selected from the group consisting of 1 to 4 heteroatoms selected from the group consisting of 5 to 6 membered heterocycles substituted with 0 to 1 R ⁵ ;
R ^4a in each case is H, = 0, CH ₂ OR ² , OR ² , CH ₂ F, F, CH ₂ Br, Br, CH ₂ Cl, Cl, C _1-4 alkyl, CH ₂ -CN, -CN, CH ₂ NO ₂ , NO ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , CH ₂ -C (O) R ^2c , C (O) R ^2c , NR ² C (O) R ^2b , ( CH ₂ ) _r C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , (CH ₂ ) _r SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a , NR ² SO _2- C _{1-4 ^{alkyl, NR 2 SO 2 R 5,}} (CH 2) r S (O) p R 5a, CH 2 CF 3, CF 3, 0 to CH substituted with 1 to 6 R ⁵ ₂ -5 Carbocycle, 5-6 membered carbocycle substituted with 0-1 R ⁵ , and carbon atoms, and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0- CH ₂ -5 to 6 membered heterocycle substituted with 1 R ⁵ , and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0 to 1 R ⁵ Is selected from a 5-6 membered heterocycle substituted with;
R ^4b in each case is H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a , CH ₂ NR ³ C (O) NR ³ R ^3a , C (= NR ³ ) NR ³ R ^3a , CH ₂ C (= NR ³ ) NR ³ R ^3a , NR ³ C (= NR ³ ) NR ³ R ^3a , CH ₂ NR ³ C (= NR ³ ) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ NR ³ R ^3a , CH ₂ NR ³ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , CH ₂ NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -Phenyl, CF ₃ and CH ₂ -CF ₃ ;
R ^4c in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , CH ₂ NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ NR ² R ^2a , CH ₂ NR ² SO ₂ -C _1-4 alkyl, C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ C (O) NHSO ₂ -C _1-4 alkyl, CH ₂ NR ² SO ₂ R ⁵ , S (O) _p R ^5a , CH ₂ S (O) ^{_{p R 5a, CF 3, CH}} 2 CF 3, 0 to 1 of the R ⁵ substituted with a 5 to 6 membered carbocycle, substituted with 0-1 of R ⁵ CH ₂ -5 to 6 membered carbocycle, carbon 5-6 membered heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of atoms, and N, O and S (O) _p and substituted with 0 to 1 R ⁵ , and a carbon atom, and N, O and 1 to 4, selected from the group consisting of S (O) _p The hetero atom is made is selected from a CH ₂ -5 to 6 membered heterocycle substituted with 0-1 of R ^5;
R ⁵ is in each case H, ═O, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, N0 ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a , CH (= NOR ^3d ), C (= NR ³ ) NR ³ R ^3a , NR ³ C (= NR ³ ) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , S (O) _p -C _{1- 4} alkyl, S (O) _p -, phenyl, CF _3, 0 and is selected from benzyl substituted by two R ⁶ is phenyl, 0-2 R ⁶ naphthyl and 0-2 R ⁶ substituted with substituted with ;
R ⁶ in each case is H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , C (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl.
[10" claim-type="Currently amended] The method of claim 9,
Ring M comprising M ₁ , M ₂ and M ₃ , if present, is phenyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3- Triazole, 1,2,4-triazole, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole , 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-tetazole, 1,2,3,5- Tetrazole, pyran, thiopyran, thiopyran = 1,1-dioxide, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2, 3,4-tetrazine, dihydro-pyrrole, dihydro-furan, dihydro-thiophene, dihydro-pyrazole, dihydro-imidazole, dihydro-isoxazole, dihydro-oxazole, dihydro- Isothiazole, dihydro-thiazole, dihydro-1,2,3-triazole, dihydro-1,2,4-triazole, dihydro-1,3,4-triazole, dihydro-1 , 2,3-oxadiazole, dihydro-1,2,4-oxadiazole, dihydro-1,3,4-jade Diazole, dihydro-1,2,3-thiadiazole, dihydro-1,2,4-thiadiazole, dihydro-1,3,4-thiadiazole, dihydro-1,2,3 , 4-tetrazole, dihydro-1,2,3,5-tetrazole, dihydro-pyran, dihydro-thiopyran, dihydro-thiopyran = 1,1-dioxide, dihydro-pyridine, di Hydro-pyrimidine, dihydro-pyridazine, dihydro-pyrazine, dihydro-1,2,3-triazine, dihydro-1,2,4-triazine, dihydro-1,2,3,4 -Tetrazine, cyclopentene, cyclopentane, cyclohexene, cyclohexane, tetrahydro-pyrrole, tetrahydro-furan, tetrahydro-thiophene, tetrahydro-thiophene-1,1-dioxide, tetrahydro-pyrazole , Tetrahydro-imidazole, tetrahydro-isoxazole, tetrahydro-oxazole, tetrahydro-isothiazole, tetrahydro-thiazole, tetrahydro-1,2,3-triazole, tetrahydro-1,2 , 4-triazole, tetrahydro-1,3,4-triazole, tetra Hydro-1,2,3-oxadiazole, tetrahydro-1,2,4-oxadiazole, tetrahydro-1,3,4-oxadiazole, tetrahydro-1,2,3-thiadiazole , Tetrahydro-1,2,4-thiadiazole, tetrahydro-1,3,4-thiadiazole, tetrahydro-1,2,3,4-tetazole, tetrahydro-1,2,3, 5-tetrazole, tetrahydro-pyran, tetrahydro-thiopyran, tetrahydro-thiopyran-1,1-dioxide, tetrahydro-pyridine, tetrahydro-pyrimidine, tetrahydro-pyridazine, tetrahydro-pyrazine , Tetrahydro-1,2,3-triazine, tetrahydro-1,2,4-triazine and tetrahydro-1,2,3,4-tetraazine;
Ring M is substituted with 0-3 R ^1a and 0-1 carbonyl group;
G is selected from the group below;






G ₁ is absent or (CR ³ R ^3a ) _1-3 , (CR ³ R ^3a ) _u C (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u O (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C ( O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b C (O) (CR ³ R ^3a ) _u C (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ (CR ³ R ^3a ) _w , ( CR ³ R ^3a ) _u S (O) NR ^3b (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u NR ^3b S (O) ₂ (CR ³ R ^3a ) _w , (CR ³ R ^3a ) _u S (O) ₂ NR ^3b (CR ³ R ^3a ) _w and (CR ³ R ^3a ) _u C (O) NR ^3b S (O) ₂ (CR ³ R ^3a ) _w , wherein the sum of u + w is 0 , 1 or 2, provided that G ₁ does not form an NS, NCH ₂ N, NCH or NCH ₂ S bond with another group to which it is attached;
A is phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxa substituted with 0-2 R ⁴ Zolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl, indolyl, benzimida Is selected from one of carbocyclic and heterocyclic groups of zolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl;
B is or; Provided that Z and B are attached to different atoms on A;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C═O and SO ₂ ;
Ring Q is a 5-7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
The 5 to 7 membered ring is composed of carbon atoms and 0 to 2 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
The fused ring is phenyl or a 5-6 membered heteroaromatic consisting of a carbon atom and 1 to 2 heteroatoms selected from NR ^4c , 0 and S;
Ring Q comprising said 5-7 membered ring and said fused ring is substituted with 0-3 R ^4a ;
R ^1a is selected from H, R ^1b , CH (CH ₃ ) _r R ^1b , C (CH ₃ ) ₂ R ^1b , CH ₂ R ^1b and CH ₂ CH ₂ R ^1b , provided that R ^1a is N-halo, Other than NS or N-CN bonds;
Alternatively, when two R ^1a groups are attached to an adjacent atom, the groups together with the atoms to which they are attached are selected from the group consisting of 5 to 5 heteroatoms selected from the group consisting of carbon atoms and N, O and S (O) _p Forms a 6-membered ring, which ring is substituted with 0-2 R ^4b , and 0-3 ring double bonds are present;
R ^1b is H, CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, -CHO, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , OC ( O) R ² , C0 ₂ R ^2a , S (O) _p R ² , NR ² (CH ₂ ) _r OR ² , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , phenyl substituted with 0 to 2 R ^4b , and 1 to 4 heteroatoms selected from the group consisting of carbon atoms, and N, O and S (O) _p and 0 to Selected from 5-6 membered aromatic heterocycles substituted with two R ^4b , provided that R ^1b forms other than OO, N-halo, NS or N-CN bonds;
R ² is, in each case, H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , phenyl substituted with 0 to 2 R ^4b , 0 to 2 5-6 membered aromatic heterocycle consisting of benzyl substituted with R ^4b and carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b Is selected from;
R ^2a in each case is H, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and carbon An atom and a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 2 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p Selected from circle saturated, partially saturated or unsaturated rings;
R ^2b in each case is substituted with CF ₃ , C _1-4 alkoxy, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, 0-2 R ^4b Phenyl, and a carbon atom, and is selected from a 5-6 membered aromatic heterocycle consisting of 1-4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0-2 R ^4b ;
R ^2c is, in each case, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 2 R ^4b , and 0 to 2 R ^4b containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p It is selected from a 5-6 membered aromatic heterocycle substituted with;
R ⁴ is in each case H, CH ₂ OR ² , (CH ₂ ) ₂ 0R ² , OR ² , F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, NO ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
R ^4a is in each case H, = 0, CH ₂ 0R ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , -CN, N0 ₂ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and -CF ₃ Become;
R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , —CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ -C (O) R ³ , C (O) OR ^3c , CH ₂ -C (O) OR ^3c , NR ³ C (O) R ^3a , CH ₂ NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , CH ₂ -C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , CH ₂ SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, CH ₂ NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, CH ₂ NR ³ SO ₂ -phenyl, S (O) _p CF ₃ , CH ₂ S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, CH ₂ S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CH ₂ S (O) _p -phenyl and CF ₃ ;
R ^4c is, in each case, H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ 0R ² , CH ₂ F, CH ₂ Br, CH ₂ Cl, CH ₂ CN, CH ₂ NO ₂ , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , CH ₂ NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH ₂ C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , CH ₂ SO ₂ NR ² R ^2a , S (O) _p R ^5a , CH ₂ S (O) _p R ^5a , CF ₃ , phenyl substituted with 0 to 1 R ⁵ and 0 to 1 R Benzyl substituted by ⁵ ;
R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , CH ₂ C (O) OR ^3c , NR ³ C (O) _r R ^3a , C (O) NR ³ R ^3a , S0 ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ₂ -phenyl, S ( _{O) p CF 3, S (} O) p -C 1-4 alkyl, S (O) _p -, phenyl, CF _3, 0-2 substituted with one R ⁶ is phenyl, substituted with 0-2 R ⁶ naphthyridin Butyl and benzyl substituted with 0-2 R ⁶ ;
R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, N0 ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b , SO ₂ NR ² R ^2a and NR ² SO ₂ C _1-4 alkyl Compound selected from.
[11" claim-type="Currently amended] The method of claim 10,
J is selected from 0, S, NH and NR ^1a ;
G is selected from the group below;



G ₁ is absent or CH ₂ , CH ₂ CH ₂ , CH ₂ 0, OCH ₂ , NH, CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O) NH, NHC (O), NHC (O) NH, C (O) NHS (O) ₂ , CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), S0 ₂ NH and NHS0 ₂ , but , G ₁ does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached;
A is selected from indolinyl, phenyl, pyridyl and pyrimidyl and is substituted with 0 to 2 R ⁴ ;
B is or; Provided that Z and B are attached to different atoms on A;
Provided that B is other than triazolone, quinolone or isoquinolone, wherein the triazolone, quinolone and isoquinolone groups are substituted or unsubstituted;
Q ₁ is selected from C═O and SO ₂ ;
Ring Q is a 6-7 membered ring consisting of carbon atoms and 0-1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) _{2 in} addition to the NQ ₁ group shown, wherein
0 to 2 double bonds are present in the ring, which ring is substituted with 0 to 2 R ^4a ;
Alternatively, ring Q is a 5-7 membered ring to which another ring is fused, wherein
The 5 to 7 membered ring is composed of carbon atoms and 0 to 1 heteroatoms selected from NR ^4c , O, S, S (O) and S (O) ₂ , in addition to the amide group shown, and 0 to 1 double bond. Present in this ring;
The fused ring is phenyl;
Ring Q comprising said 5-7 membered ring and said fused ring is substituted with 0-2 R ^4a ;
R ^1a is selected from H, R ^1b , C (CH ₃ ) ₂ R ^1b and CH ₂ R ^1b , provided that R ^1a forms other than N-halo, NS or N-CN bonds;
R ^1b is CH ₃ , CH ₂ CH ₃ , F, Cl, Br, -CN, CF ₃ , OR ² , NR ² R ^2a , C (O) R ^2b , CO ₂ R ^2b , C0 ₂ R ^2a , S ( O) _p R ² , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , NR ² SO ₂ R ² , and 1 to 1 selected from the group consisting of carbon atoms, and N, O and S (O) _p . Selected from a 5-6 membered aromatic heterocycle consisting of 4 heteroatoms and substituted with 0-2 R ^4b , provided that R ^1b forms other than OO, N-halo, NS or N-CN bonds;
R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a carbon atom, and from 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and selected from 5 to 6 membered aromatic heterocycles substituted with 0 to 1 R ^4b and ;
R ^2a in each case is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and a carbon atom, and N, O and S (O) _p is selected from a 5-6 membered aromatic heterocycle consisting of 1 to 4 heteroatoms selected from the group consisting of 0 to 1 R ^4b ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a circular saturated, partially saturated or unsaturated ring;
R ^2b is, in each case, OH, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and 0 to 1 R ^4b It is selected from a 5-6 membered aromatic heterocycle substituted with;
R ^2c is, in each case, OH, OCH ₃ , OCH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ , CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , benzyl, phenyl substituted with 0 to 1 R ^4b , and containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and substituted with 0 to 1 R ^4b 5 to 6 membered aromatic heterocycle;
R ⁴ is, in each case, OH, OR ² , CH ₂ OR ² , (CH ₂ ) ₂ OR ² , F, Br, Cl, I, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₃ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , (CH ₂ ) ₂ NR ² R ^2a , CF ₃ and CF ₂ CF ₃ ;
R ^4a in each case is H, = 0, CH ₂ OR ² , OR ² , F, Br, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , C (CH ₃ ) ₃ , CH ₂ NR ² R ^2a , NR ² R ^2a , C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , SO ₂ NR ² R ^2a and CF ₃ ;
R ^4b is in each case H, = 0, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl and CF ₃ ;
R ^4c are, at each occurrence, H, CH _3, CH ₂ CH _3, 0 and is selected from benzyl substituted by one R ⁵ is phenyl and R ⁵ is substituted by from 0 to 1;
R ⁵ , in each case, is H, = 0, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OR ³ , CH ₂ 0R ³ , F, Cl, -CN, NO ₂ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO ₂ -phenyl, S (O) _p -C _1-4 alkyl, S (O) _p -phenyl, CF ₃ , 0 to 2 R selected from benzyl substituted by phenyl, ^6, 0-2 R ^6, naphthyl, and substituted with 0-2 R ⁶ is substituted by;
R ⁶ is, in each case, H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , -CN, NO ₂ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C (O) R ^2b , NR ² C (O) R ^2b and S0 ₂ NR ² R ^2a ,
Compounds selected from the following.




[12" claim-type="Currently amended] The method of claim 11,
J is selected from O, S, NH and NR ^1a ;
P ₄ is G ₁ -G;
M ₄ is -ZAB;
G is selected from;


G ₁ is absent or CH ₂ NH, NHCH ₂ , CH ₂ C (O), C (O) CH ₂ , C (O) NH, NHC (O), NHC (O) NH, CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHS0 ₂ , provided that G ₁ does not form an NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bond with another group to which it is attached ;
A is indolinyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, It is selected from the group of 2-aminophenyl and 2-methoxyphenyl;
B is attached to an atom different from M on A and is selected from the group below;



R ^1a is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ F, CH ₂ Cl, Br, CH ₂ Br, -CN, CH ₂ CN, CF ₃ , CH ₂ CF ₃ , OCH ₃ , CH ₂ OH, C (CH ₃ ) ₂ 0H, CH ₂ OCH ₃ , NH ₂ , CH ₂ NH ₂ , NHCH ₃ , CH ₂ NHCH ₃ , N (CH ₃ ) ₂ , CH ₂ N (CH ₃ ) ₂ , CO ₂ H, COCH ₃ , C0 ₂ CH ₃ , CH ₂ CO ₂ CH ₃ , SCH ₃ , CH ₂ SCH ₃ , S (O) CH ₃ , CH ₂ S (O) CH ₃ , S (O) ₂ CH ₃ , CH ₂ S (O) ₂ CH ₃ , C (O) NH ₂ , CH ₂ C (O) NH ₂ , S0 ₂ NH ₂ , CH ₂ SO ₂ NH ₂ , NHSO ₂ CH ₃ , CH ₂ NHSO ₂ CH ₃ , pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N- Oxide, imidazol-1-yl, CH ₂ -imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N, N-dimethylaminomethyl-oxazol-2-yl, 1, 2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH ₂ -1,2,3,4-tetrazol-1-yl and CH ₂ -1 , 2,3,4-tetrazol-5-yl, provided that R ^1a forms other than N-halo, NS or N-CN bonds;
R ² at each occurrence, with _{H, CH 3, CH 2 CH} 3, CH 2 CH 2 CH 3, CH (CH 3) 2, 0 to 1 R ^4b is phenyl, 0 to 1 R ^4b substituted with Substituted benzyl and a carbon atom, and from 1 to 4 heteroatoms selected from the group consisting of N, O and S (O) _p and selected from 5 membered aromatic heterocycles substituted with 0 to 1 R;
R ^2a is in each case selected from H, CH ₃ and CH ₂ CH ₃ ;
Alternatively, R ² and R ^2a , together with the atoms to which they are attached, are substituted with 0 to 1 R ^4b and 5 or 6 consisting of 0 to 1 additional heteroatoms selected from the group consisting of N, O and S (O) _p To form a saturated, partially saturated or unsaturated ring of the circle;
R ^2b is in each case selected from OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
R ^2c is in each case selected from OH, OCH ₃ , OCH ₂ CH ₃ , CH ₃ and CH ₂ CH ₃ ;
R ^4a in each case is H, ═O, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ and C (CH ₃ ) ₃ ;
R ^4b is in each case H, ═O, OR ³ , CH ₂ 0R ³ , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -phenyl, S (O) ₂ CH ₃ , S (O) ₂ -phenyl and CF ₃ ;
R ⁵ is in each case H, = 0, CH ₃ , CH ₂ CH ₃ , OR ³ , CH ₂ 0R ³ , F, Cl, NR ³ R ^3a , CH ₂ NR ³ R ^3a , C (O) R ³ , C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , SO ₂ NR ³ R ^3a , NR ³ SO ₂ -C _1-4 alkyl, NR ³ SO _{2- phenyl, S (O) 2 -CH 3} , S (O) 2 - , phenyl, CF _3, 0-2 R ⁶ substituted by phenyl, 0-2 R ⁶ substituted naphthyl, and 0-2 R Benzyl substituted by ⁶ ;
R ⁶ is in each case H, OH, OR ² , F, Cl, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , CH ₂ C ( O) R ^2b , NR ² C (O) R ^2b and SO ₂ NR ² R ^2a ,
Compounds selected from the following.


[13" claim-type="Currently amended] The method of claim 12,
G is selected from;


A-B is selected from the following;


Compounds selected from the following.

[14" claim-type="Currently amended] The method of claim 13,
P ₄ is -G;
A-B is selected from the following;

Compounds selected from the following.

[15" claim-type="Currently amended] The compound of claim 1 wherein said compound is
1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1-piperidinyl) -2,3-dihydro-1 H-indole-1 -Yl] carbonyl} -1 H-pyrazole-3-carboxamide;
1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[6- (2-oxo-1-piperidinyl-2,3-dihydro-1H-indole-1- Il] carbonyl} -1H pyrazole-3-carboxamide;
1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxohexahydro-1 H-azin-1-yl) -2,3-dihydro- 1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide;
1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[6- (2-oxohexahydro-1 H-azin-1-yl) -2,3-dihydro- 1H-indol-1-yl] carbonyl} -1H-pyrazole-3-carboxamide;
2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] benzamide;
2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] benzamide;
2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] benzamide;
5-chloro-N- [2-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide;
5-chloro-N- [2-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide;
5-chloro-N- [2-({[4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide;
4-chloro-2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] benzamide;
4-chloro-2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] benzamide;
4-chloro-2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] benzamide;
2-[(4-chlorobenzoyl) amino] -4-[(methylsulfonyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] benzamide;
2-[(4-chlorobenzoyl) amino] -4-[(methylsulfonyl) amino] -N- [4- (2-oxo-1 (2H) -pyridinyl) phenyl] benzamide;
2-[(4-chlorobenzoyl) amino] -4-[(methylsulfonyl) amino] -N- [4- (2-oxotetrahydro-1 (2H) -pyrimidinyl) phenyl] benzamide;
5-chloro-N- [5-[(methylsulfonyl) amino] -2-({4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarbox amides;
2-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] nicotinamide;
3-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] isonicotinamide;
4-[(4-chlorobenzoyl) amino] -N- [4- (2-oxo-1-piperidinyl) phenyl] nicotinamide;
5-chloro-N- [3-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) -4-pyridinyl] -2-pyridinecarboxamide;
5-chloro-N- [3-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) -4-pyridinyl] -2-pyridinecarboxamide;
5-chloro-N- [5-chloro-3-methoxy-2-({[4- (2-oxo-1 (2H) -pyridinyl) phenyl] amino} carbonyl) phenyl] -2-pyridincar Boxamide;
5-chloro-N- [5-chloro-3-methoxy-2-({[4- (2-oxo-1-piperidinyl) phenyl] amino} carbonyl) phenyl] -2-pyridinecarboxamide ;
Methyl 2- [2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] -3- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H -Pyrazol-5-yl] -3-oxopropanoate;
1- (3-fluoro-4- {2- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2-oxoethyl} phenyl) -2 (1H) -pyridinone;
1- (4- {2- [1- (3-amino-1, 2-benzisoxazol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -2- Oxoethyl} -3-fluorophenyl) -2 (1H) -pyridinone;
5-{[2-fluoro-4- (2-oxo-1 (2H) -pyridinyl) phenyl] acetyl} -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxamide;
1- (3-amino-1, 2-benzisoxazol-5-yl) -5-{[5- (2-oxo-1 (2H) -pyridinyl) -2,3-dihydro-1H-indole -1-yl] carbonyl} -1 H-pyrazole-3-carboxamide;
5-chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) benzamide;
5-chloro-N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) benzamide;
N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl} amino) -5-methoxybenzamide;
N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5-methoxybenzamide;
N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-piperidin) -1-yl] benzoyl) amino) -5-methylbenzamide;
N- (5-chloropyridin-2-yl) -2-({4-[(2-oxo-pyridin) -1-yl] benzoyl} amino) -5-methylbenzamide;
2- (5-chloro-pyridin-2-yl) -7-methoxy-3- [4- (2-oxo-piperidin-1-yl) -phenyl] -2H-isoquinolin-1-one;
2- (5-chloro-pyridin-2-yl) -7-methoxy-3- [4- (2-oxo-pyridin-1-yl) -phenyl] -2H-isoquinolin-1-one;
5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-2- [4- (2-oxopiperidin-1-yl) -benzoylamino] benzamide;
5-chloro-N- (5-chloropyridin-2-yl) -3-methoxy-2- [4- (2-oxo-2H-pyridin-1-yl) -benzoylamino] benzamide;
3-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (1,2-cis-2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
3-chloro-N- (1,2-cis-2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
5-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
3-chloro-N- (1,2-cis-2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -1H-indole-6-carboxamide;
3-chloro-N- (3-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} tetrahydro-2H-pyran-4-yl) -1H-indole-6-carboxamide ;
3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} tetrahydro-2H-pyran-3-yl) -1H-indole-6-carboxamide ;
3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} piperidin-3-yl) -1H-indole-6-carboxamide;
3-chloro-N- (3-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} piperidin-4-yl) -1H-indole-6-carboxamide;
3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} pyrrolidin-3-yl) -1H-indole-6-carboxamide;
3-chloro-N- (4-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} tetrahydrofuran-3-yl) -1H-indole-6-carboxamide;
3-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -1H-indole-6-carboxamide;
3-chloro-N- (1,1-dioxido-4-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} tetrahydro-3-thienyl) -1H-indole -6-carboxamide;
3-chloro-N- (1,1-dioxido-4-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} tetrahydro-2H-thiopyran-3-yl) -1H-indole-6-carboxamide;
3-chloro-N- (1,1-dioxido-3-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} tetrahydro-2H-thiopyran-4-yl) -1H-indole-6-carboxamide;
N- (2-{[(3-chloro-1H-indol-6-yl) sulfonyl] methyl} cyclohexyl) -4- (2-oxopiperidin-1-yl) benzamide;
N- (2-{[(6-chloro-2-naphthyl) sulfonyl] methyl} cyclohexyl) -4- (2-oxopiperidin-1-yl) benzamide;
5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophen-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thiophene-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopyrazin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -1H-indole-2-carboxamide;
5-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) -1H-indole-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
6-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
6-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
6-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -2-naphtamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) -2-naphtamide;
6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -2-naphtamide;
2-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
2-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
2-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
2-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
2-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) quinoline-6-carboxamide;
2-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} pentyl) quinoline-6-carboxamide;
2-chloro-N- (2-{[4- (2-oxopyridin-1-yl) benzoyl] amino} cyclopentyl) quinoline-6-carboxamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) -1-benzothiophene-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-car Boxamide;
6-chloro-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
6-chloro-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) thieno [2,3-b] pyridine-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thieno [2,3-b] pyridine-2-carboxamide;
6-chloro-N- (2-{[4- (2-oxopiperidin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thieno [2,3-b] pyridine-2-carbox amides;
5-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-methoxy-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-methoxy-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-methoxy-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
5-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) thiophene-2-carboxamide;
5-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) thiophene-2-carboxamide;
4-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclohexyl) benzamide;
4-methoxy-N- (2-{[4- (2-oxopiperazin-1-yl) benzoyl] amino} cyclohexyl) benzamide;
4-methoxy-N- (2-{[4- (2-oxo-1,3-oxazinan-3-yl) benzoyl] amino} cyclohexyl) benzamide;
4-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclohexyl) benzamide;
4-methoxy-N- (2-{[4- (3-oxomorpholin-4-yl) benzoyl] amino} cyclohexyl) benzamide;
4-methoxy-N- (2-{[4- (2-oxopyridin-1 (2H) -yl) benzoyl] amino} cyclopentyl) benzamide;
4-methoxy-N- (2-{[4- (2-oxopiperidin-1-yl) benzoyl] amino} cyclopentyl) benzamide or a pharmaceutically acceptable salt thereof compound.
[16" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof.
[17" claim-type="Currently amended] Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of thromboembolic disorders.
[18" claim-type="Currently amended] The use of a compound according to claim 17 wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders and thromboembolic disorders in the atrioventricular chamber.
[19" claim-type="Currently amended] 18. The method of claim 17 wherein the thromboembolic disorder is unstable angina, acute coronary syndrome, primary myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral obstructive artery disease, venous thrombosis, deep vein thrombosis Thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and (a) artificial valves or other implants, (b) indwelling catheter, (c) stent, (d) cardiopulmonary Use of a compound selected from bypass, (e) hemodialysis or (f) thrombosis arising from other treatments in which the blood is exposed to an artificial surface that promotes thrombosis.
[20" claim-type="Currently amended] A compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt form thereof for therapeutic use.