Pyrazole derivatives

专利摘要:
The present invention relates to certain pyrazole derivatives of formula I, p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, methods of use thereof, and methods of preparing these compounds: Formula I
公开号:KR20020030124A
申请号:KR1020027003730
申请日:2000-09-14
公开日:2002-04-22
发明作者:골드슈타인데이비드마이클；라바디샤라다쉔비；로트슈타인데이비드마크；스죠그렌에릭브라이언；탈라마스프란시스코크사비어
申请人:프리돌린 클라우스너, 롤란드 비. 보레르；에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Pyrazole derivatives {PYRAZOLE DERIVATIVES}
[2] TNF and IL-1 have been shown to play a central role in the pathological process of numerous chronic inflammatory and autoimmune diseases. IL-1 has been described as rheumatoid arthritis (see Arend, WP, Arthritis & Rheumatism 38 (2): 151-160, (1995)), osteoarthritis, bone resorption disease, toxic shock syndrome, tuberculosis, atherosclerosis , Diabetes, Hodgkin's disease (see Benharroch D et al . ( Euro. Cytokine Network 7 (1): 51-57)) and Alzheimer's disease. Excessive or unregulated TNF production is rheumatoid arthritis (Mai Needle (Maini, RN) et al., [APMIS 105 (4):. 257-263, (1997)]; Feldman (Feldmann, M.) the literature [J such as of the Royal College of Physicians of London 30 (6): 560-570, (1996); Lorenz, HM et al., J. of Immunology 156 (4): 1646-1653, (1996). Osteoarthritis, spondylitis, sepsis, septic shock (see Abraham, E. et al., JAMA. 277 (19): 1531-1538, (1997)), adult respiratory distress syndrome, asthma Shah, A. et al. Clin. & Exp. Allergy 1038-1044, (1995) and Lassalle, P. et al. Clin. & Exp. Immunol. 94 (1) : 105-110, (1993)), bone resorption diseases, fever (see Cooper, AL et al ., Am. J. of Physiology 267 (6 Pt. 2): 1431-1436), encephalomyelitis , demyelination (clean to Stuttgart (Klindert, WE) et al. [J. of Neuroimmunol 72 (2) :. 163-168, (1997)] , see) and that would mediate diseases such as periodontal disease or worsen It is related.
[3] Clinical trials of IL-1 and TNF receptor antagonists have shown to significantly improve inflammatory diseases in humans by blocking these cytokines' ability to signal through these receptors. Thus, the regulation of these inflammatory cytokines is considered to be one of the most effective strategies to block chronic inflammation and yield positive therapeutic results. In addition, p38 MAP kinase plays an important role in the regulation of TNF and IL-1 transduction and has been shown to be involved in the biochemical signaling of these molecules (Lee, JC et al., Nature. 6508): 739-46, (1994). Compounds that bind p38 MAP are effective at inhibiting bone resorption, inflammation, and other immune and infectious pathologies. Due to the nature of p38 MAP kinases and their central role in the biosynthesis of TNF and IL-1, these kinases have become of interest for the treatment of diseases mediated by these cytokines.
[4] Thus, it would be desirable to provide a p38 MAP kinase inhibitor, thereby providing a means to treat diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. The present invention fulfills this and related requirements.
[5] Summary of the Invention
[6] In a first aspect, the present invention provides compounds selected from the group of compounds represented by Formula I, their precursors, individual isomers, mixtures of isomers, or pharmaceutically acceptable salts:
[7]
[8] Where
[9] R ¹ is hydrogen or acyl;
[10] R ² is hydrogen or alkyl;
[11] A is an aryl or heteroaryl ring;
[12] B is an aryl or heteroaryl ring;
[13] R ³ is
[14] (a) amino, alkylamino or dialkylamino;
[15] (b) acylamino;
[16] (c) optionally substituted heterocyclyl;
[17] (d) optionally substituted aryl or heteroaryl;
[18] (e) heteroalkyl;
[19] (f) heteroalkenyl;
[20] (g) heteroalkynyl;
[21] (h) heteroalkoxy;
[22] (i) heteroalkylamino;
[23] (j) optionally substituted heterocyclylalkyl;
[24] (k) optionally substituted heterocyclylalkenyl;
[25] (l) optionally substituted heterocyclylalkynyl;
[26] (m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy or heterocyclyloxy;
[27] (n) optionally substituted heterocyclylalkylamino;
[28] (o) optionally substituted heterocyclylalkylcarbonyl;
[29] (p) heteroalkylcarbonyl;
[30] (q) optionally substituted cycloalkylamino;
[31] (r) -NHSO ₂ R ⁶ , wherein R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
[32] (s) -NHSO ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently of each other hydrogen, alkyl or heteroalkyl;
[33] (t) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O-, -NH- or -S (O) _n- , where n is an integer from 0 to 2, and R ⁹ is cyano, optionally substituted heteroaryl, -COOH, -COR ¹⁰ , -COOR ¹¹ , -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or- NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹⁰ is alkyl or optionally substituted heterocycle, R ¹¹ is alkyl, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ is independently of each other hydrogen, alkyl or heteroalkyl);
[34] (u) —C (═NR ²⁰ ) (NR ²¹ R ²² ), wherein R ²⁰ , R ²¹ and R ²² are independently hydrogen, alkyl or hydroxy, or R ²⁰ and R ²¹ together are — (CH ₂ ) _n -where n is 2 or 3 and R ²² is hydrogen or alkyl;
[35] (v) -NHC (X) NR ²³ R ²⁴ , wherein X is -O- or -S- and R ²³ and R ²⁴ are independently of each other hydrogen, alkyl or heteroalkyl;
[36] (w) -CONR ²⁵ R ²⁶ wherein R ²⁵ and R ²⁶ are independently of each other hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl or heterocyclyl optionally substituted with the nitrogen to which they are attached; To form a ring);
[37] (x) -S (O) _n R ²⁷ where n is an integer from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, or -NR ²⁸ R ²⁹ wherein R ²⁸ and R ²⁹ are, independently from each other, hydrogen, alkyl, or heteroalkyl;
[38] (y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, which are optionally substituted with alkyl, halo, hydroxy or amino;
[39] (z) arylaminoalkylene or heteroarylaminoalkylene;
[40] (aa) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² , wherein Z is -NH-, -N- (alkyl)-or -O-, and R ³⁰ , R ³¹ and R ³² Are independently of each other hydrogen, alkyl or heteroalkyl;
[41] (bb) —OC (O) -alkylene-CO ₂ H or —OC (O) —NR′R ″ wherein R ′ and R ″ are independently hydrogen or alkyl;
[42] (cc) heteroarylalkenylene or heteroarylalkynylene;
[43] (dd) X- (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] where X is -O-, -NH-, -NR- (where , R is alkyl, or -S (O) _p- , where p is an integer from 0 to 2; R ⁴⁰ is acyl, C (O) OR ⁴¹ , wherein R ⁴¹ is hydrogen, alkyl or cyclo Alkyl), C (O) ONR ⁴¹ R ⁴² , wherein R ⁴¹ is as defined above and R ⁴² is hydrogen or alkyl, or C (O) NR ⁴¹ R ⁴² , wherein R ⁴¹ and R ⁴² Are as defined above; R 'and R "are independently hydrogen or alkyl; m and n are independently an integer from 0 to 3, provided that m and n are not simultaneously 0;
[44] (ee) X- (alkylene) -CH (OH) CH ₂ NHR ⁵⁰ , wherein X is -O-, -NH-, -NR- (where R is alkyl) or S (O) _n- ( Wherein n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen or alkyl being);
[45] (ff) X- (alkylene) -CH (NR ⁵⁰ ) -CH ₂ OH, wherein X is -O-, -NH-, -NR- (where R is alkyl) or S (O) _n- Where n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen or Alkyl)
[46] Selected from the crowd consisting of;
[47] R ⁴ is
[48] (a) hydrogen;
[49] (b) halo;
[50] (c) alkyl;
[51] (d) alkoxy; And
[52] (e) hydroxy
[53] Selected from the crowd consisting of;
[54] R ⁵ is
[55] (a) hydrogen;
[56] (b) halo;
[57] (c) alkyl;
[58] (d) haloalkyl;
[59] (e) thioalkyl;
[60] (f) hydroxy;
[61] (g) amino;
[62] (h) alkylamino;
[63] (i) dialkylamino;
[64] (j) heteroalkyl;
[65] (k) optionally substituted heterocycle;
[66] (l) optionally substituted heterocyclylalkyl;
[67] (m) optionally substituted heterocyclylalkoxy;
[68] (n) alkylsulfonyl;
[69] (o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;
[70] (p) heteroalkoxy; And
[71] (q) carboxy
[72] Selected from the crowd consisting of;
[73] R ⁶ is
[74] (a) hydrogen;
[75] (b) halo;
[76] (c) alkyl; And
[77] (d) alkoxy
[78] It is chosen from a crowd consisting of.
[79] In a second aspect, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
[80] In a third aspect, the present invention provides a method of treating a disease in a mammal that is treatable by administering a p38 MAP kinase inhibitor comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[81] In a fourth aspect, the present invention provides a method for preparing a compound of formula (I).
[1] The present invention relates to certain pyrazole derivatives that inhibit p38 MAP kinase, pharmaceutical compositions containing them, methods of use thereof, and methods of preparing these compounds.
[82] Justice
[83] Unless stated otherwise, the following terms used in the specification and claims have the following meanings:
[84] "Alkyl" means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms, for example methyl, ethyl, propyl, 2-propyl, pentyl and the like.
[85] "Alkylene" means a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, for example methylene, ethylene, propylene, 2-methylpropylene, pentylene and the like. .
[86] "Alkenyl" means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms, for example ethenyl, propenyl, and the like, including one or more double bonds.
[87] "Alkenylene" means a linear divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched divalent hydrocarbon radical of 3 to 6 carbon atoms, for example ethenylene, propenylene, and the like, including one or more double bonds.
[88] "Alkynyl" means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched divalent hydrocarbon radical of 3 to 6 carbon atoms, including one or more triple bonds, for example ethynyl, propynyl and the like.
[89] "Alkynylene" means a linear divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms, for example ethynylene, propynylene, or the like, including one or more triple bonds.
[90] "Alkoxy" means an -OR radical where R is alkyl as defined above, such as methoxy, ethoxy, propoxy, 2-propoxy and the like.
[91] "Acyl" means an -C (O) R radical, such as acetyl, trifluoroacetyl, or the like, wherein R is hydrogen, alkyl, cycloalkyl or haloalkyl.
[92] “Acylamino” refers to an —NRC (O) R ′ radical, such as acetylamino, 2-amino-2-, wherein R is hydrogen or alkyl, and R 'is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl. Methyl propionamide, etc. are meant.
[93] "Halo" means fluoro, chloro, bromo or iodo, preferably fluoro and chloro.
[94] "Haloalkyl" means alkyl substituted with one or more identical or different halo atoms, such as -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CCl ₃ , and the like.
[95] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical having 6 to 10 ring atoms, such as phenyl, 1-naphthyl, 2-naphthyl and the like. The aryl ring is optionally conjugated, optionally including one or two heteroatoms independently selected from oxygen, nitrogen or sulfur, the remaining ring atoms being C and one or two carbon atoms optionally substituted with a carbonyl group It may be a 5-, 6- or 7-membered monocyclic saturated ring. Representative aryl radicals having conjugated rings include 2,3-dihydrobenzo [1,4] dioxane, chromman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran , Benzo [1,3] -dioxol, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole, 2,3 -Dihydro-1H-isoindole, benzimidazol-2-one, 3H-benzoxazol-2-one, and the like.
[96] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms containing 1, 2 or 3 heteroatoms selected from N, O or S, and the remaining ring atoms being C . The term also refers to monovalent monocyclic or bicyclic aromatic radicals in which heteroatoms in the ring are oxidized or quaternized, for example to form N-oxides or quaternary salts. Representative examples include thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, Benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinyl, pyridazino Nil, pyrimidinyl, oxazoloyl, and their corresponding N-oxides (eg, pyridyl N-oxides, quinolinyl N-oxides), quaternary salts thereof, and the like, and the like. Do not.
[97] "Cycloalkyl" means a cyclic non-aromatic hydrocarbon radical of 3 to 8 ring atoms in which one or two C atoms are optionally replaced with carbonyl groups. Representative examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
[98] "Heterocycle" or "heterocyclyl" is a heteroatom wherein one, two or three ring atoms are selected from N, O, or S (O) _n , where n is an integer from 0 to 2, and the remaining ring atoms are C By cyclic non-aromatic radicals of 3 to 8 ring atoms wherein one or two C atoms are optionally substituted with a carbonyl group. The term also refers to cyclic nonaromatic radicals in which ring nitrogen atoms are oxidized or quaternized, for example to form N-oxides or quaternary salts. Representative examples include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl, 2, 2-dimethyl-1,3-dioxalanyl, sulfolanil, 2-oxazolidonyl, 2-imidazolidonyl, S, S-dioxo-thiomorpholino, and the like. .
[99] "Heterocycloamino" means a saturated monovalent cyclic group where at least one ring atom is N and optionally further contains one ring atom selected from N or O and the remaining ring atoms are C. The term includes groups such as pyrrolidino, piperidino, morpholino, piperazino and the like.
[100] "Optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl" means an aryl, heteroaryl, cycloalkyl or heterocyclyl ring as defined above, which optionally includes alkyl, phenyl, benzyl, haloalkyl, hetero Alkyl, halo, cyano, cycloalkyl, acyl, -OR (where R is hydrogen or alkyl), -NRR ', wherein R and R' are independently selected from hydrogen, alkyl or acyl, -NHCOR ( Wherein R is alkyl, -NRS (O) _n R 'wherein R is hydrogen or alkyl, n is an integer from 0 to 2, and R' is hydrogen, alkyl or heteroalkyl, -NRS ( O) _n NR'R ", where R is hydrogen or alkyl, n is an integer from 0 to 2, and R 'and R" are independently hydrogen, alkyl or heteroalkyl, -S (O) _n R Where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl, -S (O) _n NRR ', where n is an integer from 0 to 2, and R and R' are poison Is hydrogen, alkyl or heteroalkyl), -OOOR,-(alkylene) COOR, where R is hydrogen or alkyl, -CONR'R "or-(alkylene) CONR'R", where R 'And R' are independently hydrogen or alkyl) and are independently substituted with one or two substituents selected from.
[101] "Heteroalkyl" means -NR^aR^b, -OR^cWhere R^a, R^bAnd R^cAre independently of each other hydrogen, alkyl, cycloalkyl or acyl, or R^aAnd R^bTogether form a heterocycloamino group) It means an alkyl radical as defined above having one, two or three substituents selected from. Representative examples include hydroxymethyl, acetoxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-acetylaminoethyl, 3 -(Pyrrolidin-1-yl) -ethyl and the like.
[102] "Heteroalkenyl" is -NR^aR^b, -OR^cOr -S (O)_nR^dWhere R^a, R^bAnd R^cAre independently of each other hydrogen or alkyl, and R^dIs alkyl or -NRR 'wherein R and R' are independently of each other hydrogen or alkyl An alkenyl radical as defined above having one or two substituents selected from. Representative examples include, but are not limited to, 3-hydroxy-1-propenyl, 3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, and the like.
[103] "Heteroalkynyl" is -NR^aR^b, -OR^c, -S (O)_nR^dOr -S (O)_nNRR 'where R^a, R^bAnd R^cAre independently of each other hydrogen or alkyl, and R^dIs alkyl, n is an integer from 0 to 2, and R and R 'are independently of each other hydrogen or alkyl) It means an alkynyl radical as defined above having one or two substituents selected from. Representative examples include, but are not limited to, 3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl, and the like.
[104] “Heteroalkoxy” means an —OR radical where R is a heteroalkyl group as defined above, for example 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2,3-dihydro Oxy-1-methylpropoxy, 2-aminoethoxy and the like.
[105] "Heteroalkylamino" means an -NR ^a R ^b radical, for example 2-hydroxyethylamino, 3-dimethylaminopropylamino, etc., wherein R ^a is hydrogen or alkyl and R ^b is a heteroalkyl group as defined above. .
[106] “Optionally substituted heterocyclylalkyl” refers to a —R ^a R ^b radical wherein R ^a is an alkylene group and R ^b is an optionally substituted heterocyclyl group as defined above, eg, 2- (morpholin-4- 1) ethyl, 3- (piperidin-1-yl) -2-methylpropyl, and the like.
[107] “Optionally substituted heterocyclylalkenyl” means an —R ^a R ^b radical, for example 3- (morpholine-4, wherein R ^a is an alkenylene group and R ^b is an optionally substituted heterocyclyl group as defined above -Yl) prop-1-enyl, 3- (piperidin-1-yl) prop-1-enyl, 3- (4-methylpiperazin-1-yl) prop-1-enyl and the like do.
[108] “Optionally substituted heterocyclylalkynyl” means an —R ^a R ^b radical, for example 3- (morpholine-4, wherein R ^a is an alkynyl group and R ^b is an optionally substituted heterocyclyl group as defined above. -Yl) prop-1-ynyl, 3- (piperidin-1-yl) prop-1-ynyl and the like.
[109] "Optionally substituted cycloalkoxy" means an -OR radical, such as cyclopentyloxy, cyclohexyloxy, etc., wherein R is optionally substituted cycloalkyl as defined above.
[110] “Optionally substituted heterocyclyloxy” refers to an —OR radical where R is an optionally substituted heterocyclyl group as defined above, such as piperidin-2-yloxy, pyrrolidin-3-yloxy, pipepe Rajin-2-yloxy and the like.
[111] “Optionally substituted heterocyclylalkoxy” means an —OR radical where R is an optionally substituted heterocyclylalkyl group as defined above, for example 2- (morpholin-4-yl) -ethoxy, 3- (pipe) Razin-1-yl) propoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy and the like.
[112] “Optionally substituted cycloalkylamino” means an —NR ^a R ^b radical wherein R ^a is hydrogen or alkyl and R ^b is an optionally substituted cycloalkyl group as defined above, such as cyclopropylamino, cyclohexylamino, 3 , 4-dihydroxycyclopentylamino and the like.
[113] “Optionally substituted heterocyclylalkylamino” means an —NR ^a R ^b radical, for example 2- (pyrroli, wherein R ^a is hydrogen or alkyl and R ^b is an optionally substituted heterocyclylalkyl group as defined above Din-2-yl) ethylamino, 3- (piperidin-1-yl) propylamino and the like.
[114] “Optionally substituted heteroaralkyloxy” refers to an —OR ^a radical where R ^a is a heteroaralkyl radical, eg, 2- (pyridin-3-yl) ethoxy, 2- [3 (2H) -pyridazone- 1-yl] ethoxy and the like.
[115] “Optional” or “optionally” means that an event or situation described subsequently may occur but need not occur, and the description includes examples where the event or situation does or does not occur. For example, “an aryl group optionally monosubstituted or disubstituted with an alkyl group” means that alkyl may be present but does not need to be present, the description being when the aryl group is monosubstituted or disubstituted with an alkyl group and heterocyclo group is an alkyl group. Includes unsubstituted cases.
[116] “Amino protecting groups” are organic groups used to protect nitrogen atoms against unwanted reactions during the synthesis process, such as benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (Boc), trifluoroacetyl Etc.
[117] Compounds of the invention may comprise one or more asymmetric centers. Thus, such compounds can be prepared as (R)-or (S) -stereoisomers or mixtures thereof. Unless stated to the contrary, the specification and claims are intended to include their respective enantiomers, mixtures of enantiomers, racemics and the like when describing or naming specific compounds. Methods for determining stereochemistry and methods for separating stereoisomers are well known in the art (see "Advanced Organic Chemistry" Chapter 4, 4th edition J. March, John Wiley and Sons, New York, 1992).
[118] "Pharmaceutically acceptable excipient" is an excipient useful for preparing pharmaceutical compositions, generally safe and nontoxic, and biologically or otherwise reasonable, and acceptable for veterinary as well as human pharmaceutical use. It includes. “Pharmaceutically acceptable excipient” as used in the specification and claims includes one or more such excipients.
[119] "Pharmaceutically acceptable salt" of a compound means a salt of a compound of the invention that is pharmaceutically acceptable and has the desired pharmacological activity. Such salts include:
[120] (1) formed with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid , Succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] -oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl Acid addition salts formed with sulfuric acid, gluconic acid, glutamic acid, hydroxynaphic acid, salicylic acid, stearic acid, muconic acid, and the like; or
[121] (2) The acid protons present in the compounds of the invention are substituted with metal ions, for example alkali metal ions, alkaline earth metal ions or aluminum ions, or organic bases such as ethanolamine, diethanolamine, triethanolamine, tro Salts formed when coordinated with metamine, N-methylglucamine and the like.
[122] "Pro-drug" means any compound which, when administered to a mammalian subject, releases the active parent drug according to formula (I) in vivo. Precursors of compounds of formula (I) are prepared by modifying functional groups present in compounds of formula (I), and the modifications can be degraded in vivo to release the parent compound. Precursors include compounds of formula (I) in which a hydroxy, amino or sulfhydryl group in formula (I) is bonded to any group that can be degraded in vivo to yield a free hydroxyl, amino or sulfhydryl group, respectively. Examples of precursors include those in which the hydroxy functional groups in the compounds of formula (I) are esters (eg, acetate, formate and benzoate derivatives), carbamate (eg, N, N-dimethylaminocarbonyl), and the like. But not limited to this.
[123] "Treating a disease" or "treating a disease"
[124] (1) preventing a disease, that is, preventing the clinical manifestations of the disease from manifesting in a mammal that may be exposed to or easily affected by the disease but has not yet experienced or exhibited the symptoms of the disease,
[125] (2) inhibiting the disease, ie stopping or reducing the onset of the disease or its clinical symptoms, or
[126] (3) alleviating the disease, ie restoring the disease or its clinical symptoms
[127] It includes.
[128] A "therapeutically effective amount" means an amount of a compound that is sufficient to carry out the treatment of a disease when administered to a mammal to treat the disease. A "therapeutically effective amount" will vary depending on the compound, the disease, the severity of the disease, and the age, weight, etc. of the mammal to be treated.
[129] denomination
[130] Naming and numbering of the compounds of the present invention are shown in Formula Ia
[131]
[132] The nomenclature used in the present invention is generally based on the IUPAC recommendation, for example R ¹ , R ² , R ⁴ , R ⁶ are hydrogen, Is 4- (3-hydroxypropyl) phenyl, Is a 4-fluorophenyl, the compound of formula (Ia) is named 5-amino-1- (4-fluorophenyl) -4- [4- (3-hydroxypropyl) -benzoyl] pyrazole, R ¹ , R ² , R ⁴ , R ⁶ are hydrogen, Is 3- [3- (morpholin-4-yl) prop-1-ynyl] -phenyl, Is a 4-fluorophenyl, wherein the compound of formula (Ia) is 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylprop-1-ynyl) benzoyl] pyra It is named pawns.
[133] Representative Compounds of the Invention
[134] I. R ¹ , R ² and R ⁴ are hydrogen, B is phenyl and other groups of the compounds of formula
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144] The compounds of Compound Nos. 121-145 are described in the tables after Examples 14, 15, 19, and 23.
[145] Preferred Embodiment
[146] Although the broadest definition of the invention has been described in the Summary of the Invention, certain compounds of formula (I) are preferred.
[147] For example, the preferred group of compounds is
[148] R ³ is
[149] (a) optionally substituted heterocyclyl;
[150] (b) halo, alkyl, amino, alkoxy, carboxy, lower alkoxy carbonyl, SO ₂ R 'where R' is alkyl, or SO ₂ NHR'R ", where R 'and R" are independently hydrogen Or alkyl; aryl or heteroaryl optionally substituted with a substituent selected from;
[151] (c) heteroalkyl;
[152] (d) heteroalkenyl;
[153] (e) heteroalkylamino;
[154] (f) heteroalkoxy;
[155] (g) optionally substituted heterocyclylalkyl, heterocyclyloxy; Cycloalkoxy or cycloalkylalkyloxy;
[156] (h) optionally substituted heterocyclylalkenyl;
[157] (i) optionally substituted heterocyclylalkynyl;
[158] (j) optionally substituted heterocyclylalkoxy;
[159] (k) optionally substituted heterocyclylalkylamino or cycloalkylamino;
[160] (l) optionally substituted heterocyclylalkylcarbonyl;
[161] (k) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ^17, or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are mutually Independently hydrogen, alkyl or heteroalkyl);
[162] (l) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, which are optionally substituted with alkyl, halo, hydroxy or amino;
[163] (m) arylaminoalkylene or heteroarylaminoalkylene; or
[164] (n) Z-alkylene-NR ³⁰ R ³¹ , wherein Z is -NH-, -N (alkyl)-or -O-, and R ³⁰ and R ³¹ are independently of each other hydrogen, alkyl or heteroalkyl Among them.
[165] In this preferred crowd, more preferred groups of compounds are those in which A and B are aryl, preferably phenyl.
[166] In the above preferred group and more preferred crowds, the group of even more preferred compounds wherein R ¹ is hydrogen; R ² is hydrogen or alkyl, preferably hydrogen or methyl, more preferably hydrogen; R ⁴ is hydrogen, halo or alkyl, preferably hydrogen, chloro, fluoro or methyl, more preferably hydrogen; R ⁵ is halo or alkyl; And R ⁶ is hydrogen, halo or alkoxy.
[167] In the above preferred group and more preferred crowds, the group of particularly preferred compounds is those wherein R ³ is in the 3-position and optionally substituted heteroaryl, preferably pyridinyl, N-oxidopyridinyl or pyridonyl.
[168] Another group of particularly preferred compounds is R ³ in the 3-position, optionally substituted phenyl, preferably sulfamoylphenyl, alkylsulfamoylphenyl, carboxyphenyl, carboxamidophenyl, alkoxycarbonylphenyl, alkylaminocarbo Or is alkylphenylcarbonylphenyl.
[169] The third particularly preferred group of compounds is
[170] R ³ is in the 3-position,
[171] (a) heteroalkyl;
[172] (b) heteroalkoxy;
[173] (c) heteroalkylamino;
[174] (d) optionally substituted heterocyclylalkyl;
[175] (e) optionally substituted heterocyclylalkoxy, cycloalkoxy or cycloalkylalkyloxy;
[176] (f) optionally substituted heterocyclylalkylamino;
[177] (g) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ^17, or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are mutually Independently hydrogen, alkyl or heteroalkyl); or
[178] (h) Z-alkylene-NR ³⁰ R ³¹ wherein Z is -NH-, -N (alkyl)-or -O-, and R ³⁰ and R ³¹ are independently of each other hydrogen, alkyl or heteroalkyl It is chosen from.
[179] In this preferred group, the preferred group of compounds is one in which R ³ is in the 3-position and heteroalkyl.
[180] Preferred groups for R ³ are 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methylbutyl or 3- Hydroxybutyl.
[181] Groups of other preferred compounds are those wherein R ³ is amino, 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, 3-dimethylamino Selected from the group comprising prop-1-enyl, 3-dimethylaminoprop-1-ynyl and 2-dimethylaminoethylcarbonyl.
[182] Other groups of preferred groups for R ³ include 3- (morpholin-4-yl) propoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4-yl) propyl, 2- (Morpholin-4-yl) ethyl, 4- (morpholin-4-yl) butyl, 3- (morpholin-4-yl) propylamino, 2- (morpholin-4-yl) ethylamino, 3- (Morpholin-4-yl) -prop-1-enyl, 3- (morpholin-4-yl) prop-1-ynyl, 4-methylpiperazin-1-yl, piperazin-1-yl, Pyridin-3-yl, morpholin-4-ylmethylcarbonyl, 3-dimethylaminoprop-1-enyl, 3-dimethylaminoprop-1-ynyl, 2-aminosulfonylethyl, 2-aminosulfonyl It is selected from ethenyl, acetylamino and trifluoroacetylamino, preferably from 2- (morpholin-4-yl) ethoxy and 3- (morpholin-4-yl) -propyl.
[183] A fourth group of particularly preferred compounds is that R ⁵ is halo or alkyl and R ⁶ is hydrogen, halo or alkyl, preferably R ⁵ is 4-F or 2-Me and R ⁶ is hydrogen or R ⁵ is 2-F and R ⁶ are 4-F.
[184] Another group of preferred compounds are those wherein A and B are aryl, preferably phenyl, R ³ is in the 3-position, heteroalkoxy, optionally substituted heterocyclylalkoxy, optionally substituted cycloalkoxy, and optionally substituted Heterocyclylalkylamino.
[185] Preferred groups for R ³ are 2,2- (dihydroxymethyl) ethoxy, 2,3-dihydroxy-propoxy, (2,2-dimethyl-1,3-dioxolane-4 (S)- Yl) methoxy, (2,2-diethyl, 1,3-dioxolan-4 (S) -yl) methylamino, (1,3-dioxolan-2-one-4 (R) -yl) meth Methoxy, (2-thioxo-1,3-dioxolan-4-yl) methoxy, (2,2-diethyl-1,3-dioxolan-4 (S) -yl) methoxy, 2-methyl 2-ethyl-1,3-dioxolan-4 (S) -yl) methoxy, and 3,4- (dihydroxy) cyclopentyloxy.
[186] In this preferred group, another preferred group of compounds is that R ¹ is hydrogen; R ² is hydrogen or alkyl, preferably hydrogen or methyl; R ⁴ is hydrogen or alkyl; R ^{5 is} halo; R ⁶ is hydrogen or alkyl.
[187] Another preferred group of compounds is
[188] R ³ is in the 3-position,
[189] (a) -S (O) _n R ²⁷ where n is an integer from 0 to 2; R ²⁷ is alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, or -NR ²⁸ R ²⁹ , wherein R ²⁸ and R ²⁹ are, independently of each other, hydrogen, alkyl, or heteroalkyl;
[190] (b) X- (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] where X is -O-, -NH-, -NR-, wherein , R is alkyl, or -S (O) _p- , where p is an integer from 0 to 2; R ⁴⁰ is acyl, C (O) OR ⁴¹ , wherein R ⁴¹ is hydrogen, alkyl or cyclo Alkyl), C (O) ONR ⁴¹ R ⁴² , wherein R ⁴¹ is as defined above and R ⁴² is hydrogen or alkyl, or C (O) NR ⁴¹ R ⁴² , wherein R ⁴¹ and R ⁴² Are as defined above; R 'and R "are independently hydrogen or alkyl; m and n are independently an integer from 0 to 3, provided that m and n are not simultaneously 0;
[191] (c) X- (alkylene) -CH (OH) CH ₂ NHR ⁵⁰ , wherein X is -O-, -NH-, -NR-, where R is alkyl, or -S (O) _n -Wherein n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen Or alkyl);
[192] (d) X- (alkylene) -CH (NR ⁵⁰ ) -CH ₂ OH, wherein X is -O-, -NH-, -NR where R is alkyl, or -S (O) _n -Wherein n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen Or alkyl).
[193] Preferred groups for R ³ in the crowd are 2 (S), 3- (diacetoxy) propoxy, 2 (S), 3- (diisobutanyloxy) propoxy, 2 (S), 3- ( Dipivaloyloxy) propoxy, and 2 (S), 3- (dimethoxycarbonyloxy).
[194] Examples of particularly preferred compounds are
[195] 5-amino-1- (4-fluorophenyl) -4- [3- (2-morpholin-4-ylethoxy) benzoyl] pyrazole,
[196] 5-amino-1- (2,4-difluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl] -pyrazole,
[197] 5-amino-4- (3-aminobenzoyl) -1- (4-fluorophenyl) pyrazole,
[198] 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl] pyrazole,
[199] 5-amino-4- [3- (2-aminosulfonylethenyl) benzoyl] -1- (4-fluorophenyl) pyrazole,
[200] 5-amino-4- (3-acetylaminobenzoyl) -1-phenylpyrazole,
[201] 5-amino-4- [3- (2-aminoethyl) benzoyl] -1- (4-fluorophenyl) pyrazole,
[202] 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylpropylamino) benzoyl] pyrazole,
[203] 5-amino-4- [3- (2-aminosulfonylethyl) benzoyl] -1- (4-fluorophenyl) pyrazole,
[204] 5-amino-1- (4-fluorophenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole,
[205] 5-amino-1- (2-methylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole,
[206] 5-amino-1- (2-methylphenyl) -4- [3- (N-oxidopyridin-3-yl) benzoyl] pyrazole,
[207] 5-amino-4- [3- (2,3-dihydroxypropoxy) benzoyl] -1- (4-fluorophenyl) pyrazole,
[208] 5-amino-4- [3- (1,2-dihydroxyethyl) benzoyl] -1- (4-fluorophenyl) pyrazole,
[209] 5-amino-1- (4-fluorophenyl) -4- [3-sulfamoylbenzoyl] pyrazole,
[210] 5-amino-1- (4-fluorophenyl) -4- [3-[(2,2-dimethyl-1,3-dioxolan-4 (S) -yl) -methoxy] benzoyl] pyrazole,
[211] 5-amino-1- (4-fluorophenyl) -4- [3-[(2 (S), 3- (diacetoxy) propoxy] benzoyl] pyrazole,
[212] 5-amino-1- (4-fluorophenyl) -4- [3-[(2 (S), 3- (dimethoxycarbonyloxy) propoxy] benzoyl] pyrazole,
[213] 5-amino-1- (4-fluorophenyl) -4- [3-[(1,3-dioxolan-2-one-4 (R) -yl) methoxy] benzoyl] pyrazole,
[214] 5-amino-1- (4-fluorophenyl) -4- [3-[(2-thioxo-1,3-dioxolan-4-yl) methoxy] benzoyl] pyrazole.
[215] General Synthetic Method
[216] Compounds of the present invention can be prepared by the methods described in the following schemes.
[217] Starting materials and reagents used to prepare these compounds may be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, WI), Bachem (Torrance, CA), EMCA -Available from Emka-Chemie or Sigma (St. Louis, Missouri, USA) or referenced in Fieser and Fieser's Reagents for Organic Synthesis , Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds , Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions , Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry , (John Wiley and Sons, 4th Edition); And Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), by methods known to those skilled in the art. These schemes are merely illustrative of some of the ways in which the compounds of the present invention can be synthesized, and various modifications are possible to these schemes, and various variations will be suggested to those skilled in the art with reference to the disclosure. .
[218] The starting materials and intermediates of the reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc., if desired. Such materials can be characterized using conventional means, including physical constants and spectral data.
[219] Preparation of Compounds of Formula (I)
[220] Schemes A1, A2, B and C describe the preparation of compounds of formula (I).
[221] Compounds of formula (I) in which R ² is hydrogen and other groups are defined in the Summary of the Invention can be prepared as follows.
[222] Method (a)
[223]
[224] Method (b)
[225]
[226] In general, the compounds of formula (I) can be prepared by one of the methods of (a) or (b) described below.
[227] Method (a)
[228] 2-ketoacetonitrile of Formula 1, wherein Z is halo (e.g., bromo or iodo), alkoxy, nitro or acetylamino, is reacted with N, N-diphenylformamidine 2-keto-3-phenylamino-acrylonitrile of 2 is produced. The reaction takes place by heating in a high boiling aromatic hydrocarbon such as toluene, xylene and the like.
[229] In general, the compounds of formula 1 are either commercially available or can be prepared by methods well known in the art. For example, 2-aroylacetonitrile of the general formula (1), for example 4-methoxybenzoylacetonitrile, 3-nitrobenzoylacetonitrile, is commercially available. Other compounds are described in Sjogren, EB et al ., J. Med. Chem , 34, 3295, (1991)], treating acetonitrile with a base such as n-butyllithium and forming the acetonitrile anion with an aroyl / heteroaroyl halide or aryl / heteroaryl ester It can be prepared by reacting.
[230] 2-keto-3-phenylaminoacrylonitrile of Formula 2 is reacted with hydrazine of Formula 3 to produce 5-amino-4-ketopyrazole of Formula 4. The reaction is generally carried out in a polar solvent such as ethanol, isopropanol and the like. Aryl / heteroaryl hydrazines of formula 2, for example 2- or 3-chlorophenylhydrazine, 2-, 3- or 4-fluorophenylhydrazine, phenylhydrazine, 2-hydrazinopyridine, 2-hydrazino -Benzothiazole, 2-hydrazinoquinoline and the like are commercially available.
[231] The compound of formula 4 is then converted to a compound of formula I, which is R ¹ dihydrogen and R ³ is defined in the Summary of the Invention by methods well known in the art. Some of these methods are:
[232] (i) Compounds of formula (I) wherein R ³ is heterocyclylalkoxy can be prepared by the process of (a), (b), (c) or (d):
[233] (a) A compound of formula (I) wherein R ³ is heterocyclylalkoxy can be prepared from the compound of formula 4 wherein Z is alkoxy, as shown in Scheme 1 below:
[234]
[235] A compound of formula (I) wherein R ³ is heterocyclylalkoxy, first dealkylates an alkoxy group from a compound of formula (4), wherein Z is alkoxy, to yield the corresponding compound of formula (5), wherein Z is hydroxy, and heterocyclylalkyl It can be prepared by reacting with a halide (for example, 4- (2-chloroethyl) morpholine, 1- (2-chloroethyl) pyrrolidine and the like). The dealkylation reaction is carried out by treatment with boron tribromide in halogenated organic solvents such as dichloromethane or by heating the compound of formula 4 in pure pyridinium hydrochloride. Alkylation is carried out in the presence of a base (eg potassium carbonate, cesium carbonate, etc.) in a polar organic solvent such as acetonitrile, dimethylformamide, acetone and the like.
[236] (b) alternatively, the compound of formula 5 is reacted with alkyl dihalide and the resulting haloalkoxy intermediate is reacted with a heterocyclyl group (e.g. piperazine, morpholine, pyrrolidine, etc.) The reaction can be carried out to attach a heterocyclylalkyl group. Alkyl dihalides such as 1-bromo-2-chloroethane, 1-chloro-3-iodopropane and the like are commercially available.
[237] (c) another compound of formula (I) wherein R ³ is heterocyclylalkoxy (e.g., the heterocycle in Example 25 is an optionally substituted cyclic ketal) is a bishydroxy alkoxy derivative (For example, the diol of Example 24) and can be prepared by treating ketones or aldehydes under acidic conditions.
[238] (d) Another compound of formula (I) wherein R ³ is heterocyclylalkoxy (e.g., heterocycle is cyclic carbonate in Example 28), a compound of formula 5 is a bishydroxy alkoxy derivative (e.g. , Diol of Example 24), and can be prepared by treatment with a carbonylating agent such as phosgene, diphosgene or triphosgene.
[239] (ii) a compound of Formula I wherein R ³ is -O- (alkylene) -R ⁹ , wherein R ⁹ is -COOH, -COR ¹⁰ , -COOR ^11, or -CONR ¹² R ¹³ From the compound can be prepared as in Scheme 2:
[240]
[241] Compounds of formula (I), wherein R ³ is -O- (alkylene) -COOR ¹¹ , react the compound of formula 5 with an alkylating agent of formula X- (alkylene) -CO ₂ R ¹¹ , wherein X is a halo group It is prepared by making. Hydrolysis of the ester group gives a free acid (R ⁹ is -COOH), and if desired, the acid can be converted to a suitable coupling agent (e.g. carbonyl diimidazole, N, N-dicyclohexylcarbodiimide, etc.). Conversion to a compound of formula I, wherein R ⁹ is -CONR ¹² R ¹³ by treatment in the presence with the general formula NR ¹² R ¹³ , wherein R ¹² and R ¹³ are as defined in the Summary of the Invention You can.
[242] Compounds of formula (I), wherein R ⁹ is -COR ¹⁰ , first convert an acid to Weinreb amide from a compound of formula (I), wherein R ⁹ is -COOH, and Grignard reagent (formula R ¹⁰ MgBr) Or by treating with an organolithium reagent (General Formula R ¹⁰ Li).
[243] (iii) R ³ is X (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] (e.g., in Examples 26 and 27, X is -O R ⁴⁰ is acyl or C (O) OR ⁴¹ where R ⁴¹ is hydrogen, alkyl or cycloalkyl; R ′ and R ″ are hydrogen; m is 0; n is 1 Other compounds of formula I convert compounds of formula 5 to bishydroxy alkoxy derivatives (e.g., diols of Example 24), anhydrides (R ⁴⁰ C (O) OC (O) R ⁴⁰ ), acids It can be prepared by treatment with chloride (R ⁴⁰ C (O) Cl) or chloroformmate ester (ClC (O) OR ⁴¹ ).
[244] R ³ is X (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] where X is -O- and R ⁴⁰ is C (O) NR ⁴¹ R ⁴² (wherein, R ⁴¹ is hydrogen, alkyl or cycloalkyl, R ⁴² is hydrogen or alkyl); R 'and R "is hydrogen; m is 0; n is 1, Im) of other compounds of formula (I) Silver can be prepared by converting the compound of formula 5 to a bishydroxy alkoxy derivative (eg, the diol of Example 24) and treating with alkylcarbamoyl chloride R ⁴¹ R ⁴² NC (O) Cl.
[245] (iv) R ³ is -NH- (alkylene) -R ⁹ , wherein R ⁹ is -COOH, -COR ¹⁰ , -COOR ¹¹ , -CONR ¹² R ¹³ or heterocyclylalkylamino The compound can be prepared by reducing the nitro group to an amino group from the compound of formula 4, wherein Z is a nitro group, and then carrying out the method described above.
[246] (v) Compounds of formula (I) wherein R ³ is heteroalkenyl, heteroalkynyl, heterocyclylalkenyl, heterocyclylalkynyl, heteroalkyl or heterocyclylalkyl can be prepared as shown in Scheme 3 below. .
[247]
[248] Compounds of formula (I) wherein R ³ is heteroalkenyl, heteroalkynyl, heterocyclylalkenyl or heterocyclylalkynyl, include compounds of Formula 4 wherein Z is halo, an organic such as diisopropylamine, or the like. It can be prepared by reacting heteroalkenes, heteroalkynes, heterocyclylalkenes or heterocyclylalkynes in the presence of a palladium (II) catalyst, for example dichlorobis (triphenylphosphine) -palladium (II), in the base, respectively. . Heteroalkenes, heteroalkynes such as allyl alcohol, propazyl alcohol, 3-butyn-1-ol, propazylamine are commercially available. Heterocyclylalkynes can be prepared by reacting alkynyl halides with heterocycles. For example, 2-morpholin-1-ylprop-1-yne can be prepared by reacting propazyl bromide with morpholine. Reduction of double or triple bonds under catalysis hydrogenation reaction conditions provides the corresponding compounds of formula (I) wherein R ³ is a heterocyclylalkyl or heteroalkyl group.
[249] (vi) a compound of Formula I wherein R ³ is -NHSO ₂ R ⁶ , -NHSO ₂ NR ⁷ R ⁸ or NHC (X) R ²³ R ²⁴ , wherein X is -O- or -S-, ^From compounds of formula (I) wherein ³ is amino can be prepared by carrying out the synthesis process described in PCT application WO 97/46524.
[250] The compound of formula (I) wherein R ¹ is an acyl group reacts the corresponding compound of formula (I) wherein R ¹ is hydrogen with an alkylating agent of the general formula R ¹ COL, wherein L is a leaving group under acylation reaction conditions, such as halo It can manufacture by making it. The reaction is carried out in the presence of a base such as sodium hydroxide, cesium carbonate and the like.
[251] Method (b)
[252] Alternatively, the compound of formula (I) may be prepared from the ester of formula 6, wherein Z is as defined above, using the reaction conditions described in method (a) (iv) It can manufacture by converting into a target R <^3> group. The compound of formula 7 is condensed with an acetonitrile anion to produce 2-ketoacetonitrile of formula 8, which is then converted to the compound of formula I using the reaction conditions described in method (a) above.
[253] Compounds of formula I, wherein R ² is thioalkyl or alkyl, can be prepared by carrying out the process described in US Pat. No. 5,712,303.
[254] Selective synthesis of compounds of formula (I), wherein R ² is hydrogen and other groups are defined in the Summary of the Invention, is described in Scheme B below.
[255]
[256] 2-cyano-3-ethoxyacrylate of Formula 9 is condensed with hydrazine of Formula 3 to provide 5-amino-4-ethoxycarbonyl pyrazole of Formula 10. The condensation reaction is carried out in a suitable polar organic solvent such as ethanol, isopropanol and the like. The compound of formula 10 is hydrolyzed in an alcoholic organic solvent (e.g. methanol, ethanol, etc.) with an aqueous base (e.g. sodium hydroxide, lithium hydroxide, etc.) to yield the corresponding 5-amino-4- of formula 11 Obtained carboxy-pyrazole. The compound of formula 11 is treated with dipyridyldisulfide and the resulting thiopyridyl ester derivative 12 is reacted with the organometallic reagent shown above, for example Grignard reagent or organolithium reagent, to obtain a compound of formula I .
[257] Another selective synthesis of a compound of Formula I, wherein R ² is hydrogen and other groups are defined in the Summary of the Invention, is described in Scheme C below.
[258]
[259] 5-amino-4-carboxypyrazole of Formula 11 is thermally decarboxylated to produce the corresponding 5-aminopyrazole of Formula 13. Compound (13) is then converted to the compound of formula (I) as shown in method (a) or (b) above.
[260] In the method (a), the compound of the general formula (13) is prepared by first protecting the amino group of the compound (13) with a suitable amino protecting group (e.g., t-butoxycarbonyl or the like). It is converted to the compound of formula I by producing a protected compound. The compound of formula 14 may be prepared by the formula R ³ COL, wherein L is a leaving group (e.g., alkoxy (preferably methoxy or ethoxy), dialkylamino, or preferably N, under organometallic substitution reaction conditions). And an amino protecting group to remove the compound of formula I. The nucleophilic substitution is equivalent to two equivalents of alkyllithium (e.g., t-butyllithium, etc.). In the presence of an aprotic organic solvent such as tetrahydrofuran The reaction conditions used for the removal of amino protecting groups depend on the nature of the protecting group, for example, when t-butoxycarbonyl is a protecting group It is removed by treatment with an acid such as fluoroacetic acid, hydrochloric acid and the like.
[261] Acid derivatives of the general formula R ³ COL can be prepared by methods well known in the art of organic chemistry. For example, an acid derivative in which L is an N, O-dimethylhydroxyamino group, first converts the acid to an acid chloride with a suitable chlorination reagent such as oxalyl chloride and the presence of an organic base such as triethylamine By treatment with N, O-dimethylhydroxylamine hydrochloride under the corresponding acid.
[262] In method (b), the compound of formula 10 is brominated to yield 5-amino-4-bromo-pyrazole of formula 15. The bromination reaction is carried out in a suitable polar organic solvent, for example dimethylformamide, using a suitable brominating agent, for example N-bromosuccinimide. Compound (15) is then converted to the compound of formula (I) using the reaction conditions described in Method (a), Scheme C above.
[263] Uses, Tests, and Administration
[264] Usage
[265] Since the compounds of formula (I) are p38 MAP kinase inhibitors, the compounds of formula (I) and compositions containing them are useful for diseases such as rheumatoid arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, toxic shock syndrome, endotoxin It is useful for treating sexual shock, tuberculosis, atherosclerosis, diabetes, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, fever, periodontal disease, ulcerative colitis, pyresis, Alzheimer's disease and Parkinson's disease.
[266] exam
[267] The ability of compounds of formula I to inhibit p38 MAP kinase was demonstrated by the in vitro assays described in Example 15. The ability of compounds of formula I to inhibit the release of TNF-α was demonstrated by in vitro and in vivo assays described in detail in Examples 16 and 17, respectively. Anti-inflammatory activity of the compounds of the present invention was determined using adjuvant induced arthritis in the rat assay described in Example 18.
[268] Administration of the pharmaceutical composition
[269] In general, the compounds of the present invention will be administered in a therapeutically effective amount by any mode of administration permitted for reagents that serve similar purposes. The actual amount of a compound of the invention, ie the active ingredient, depends on a number of factors, such as the severity of the disease to be treated, the age and relative health of the subject, the efficacy of the compound used, the route and form of administration, and other factors Will be influenced.
[270] A therapeutically effective amount of a compound of formula (I) may range from about 0.1 to 50 mg / kg of recipient body weight per day, preferably from about 1 to 30 mg / kg body weight of recipient. Thus, if administered to 70 kg of human, the dosage will most preferably be from about 70 mg / 1 day to 2.1 g / 1 day.
[271] In general, the compounds of the present invention may be administered by any one of oral, systemic (eg, by transdermal, intranasal or suppository), or parenteral (eg, intramuscular, intravenous or subcutaneous) administration. And as a pharmaceutical composition. A preferred method of administration is oral administration using a convenient daily dosage regimen that can be adjusted to the extent of pain. Tablets, pills, capsules, semisolids, powders, sustained release combinations, solutions, suspensions, elixirs, aerosols or any other suitable composition.
[272] The choice of combination depends on various factors, such as the mode of drug administration (for example, in the form of tablets, pills or capsules, for oral administration) and the bioavailability of the drug. Recently, pharmaceutical formulations have been developed for drugs which exhibit particularly poor bioavailability based on the principle that the bioavailability can be increased by increasing the surface area, ie reducing the particle size. For example, US Pat. No. 4,107,288 describes pharmaceutical formulations having particles ranging in size from 10 to 1,000 nm, in which the active material is supported on a crosslinked matrix of macromolecules. U. S. Patent No. 5,145, 684 discloses the preparation of pharmaceutical formulations, wherein the drug is ground into nanoparticles (particle size average 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to provide a pharmaceutical formulation exhibiting a significantly high bioavailability. Describe.
[273] The composition generally consists of a compound of formula (I) in combination with one or more pharmaceutically acceptable excipients. Acceptable excipients are nontoxic, assist in administration, and do not adversely affect the therapeutic benefits of the compounds of formula (I). Such excipients may generally be any solid, liquid, semisolid acceptable to those skilled in the art, and may be gaseous excipients for aerosol compositions.
[274] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk powder And the like. Liquid and semisolid excipients can be selected from a variety of oils, including peanut oil, soybean oil, mineral oil, sesame oil, including glycerol, propylene glycol, water, ethanol, and petroleum, animal oils, vegetable oils or synthetic oils. In particular, preferred liquid carriers for injection solutions include water, saline, aqueous dextrose, and glycols.
[275] Compressed gases may be used to disperse the compounds of the present invention in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide and the like.
[276] Other suitable pharmaceutical excipients and combinations thereof are described in Remington's Pharmaceutical Sciences , 18th ed., 1990, edited by EW Martin (Mack Publishing Company).
[277] The amount of compound in the combination can vary within the full range used by those skilled in the art. Typically, the formulation will contain about 0.01 to 99.99% by weight of the compound of formula I, based on the total formulation, with the remainder being suitable pharmaceutical excipients. Preferably, the compound is present in an amount of about 1 to 80 weight percent. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 14.
[278] The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. The following examples should not be understood as limiting the scope of the invention, but should be understood to merely illustrate and represent the invention. The numbers in parentheses refer to the numbers of the compounds in Table 1 below.
[279] Example 1
[280] 5-amino-1- (4-fluorophenyl) -4- [3- [3- (morpholin-4-yl) prop-1-ynyl] benzoyl] pyrazole (3)
[281]
[282] Step 1
[283] n-butyllithium (214 mL, 340 mmol, 1.6 M solution in hexane) was added dropwise to a solution of acetonitrile (23.8 mL, 460 mmol) in anhydrous tetrahydrofuran (1000 mL) at -78 ° C. The reaction mixture was stirred for 20 minutes, then a solution of 4-bromobenzoyl chloride in anhydrous tetrahydrofuran (50 mL) was added dropwise over 20 minutes. After 1 h, saturated aqueous ammonium chloride solution (200 mL) was added and the reaction mixture was allowed to warm to room temperature. The product was extracted with ether and washed with 1N hydrochloric acid (400 mL). The organic solution was removed in vacuo and the residue was redissolved in ethyl acetate. Ammonium hydroxide was added to give a solid, filtered, redissolved in ethyl acetate and washed with 2N hydrochloric acid. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2- (3-bromobenzoyl) -acetonitrile (16.6 g) as a solid.
[284] Step 2
[285] 2- (3-bromobenzoyl) acetonitrile (16.5 g 73.6 mmol) and N, N-diphenylformamidine (14.5 g, 73.6 mmol) in xylene (100 mL) were heated under reflux in a nitrogen atmosphere. After 3 hours, the reaction mixture was cooled to room temperature and diluted with ether to give 2- (3-bromobenzoyl) -3-phenylamino-acrylonitrile (17.9 g) as a solid.
[286] Step 3
[287] A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and 2- (3-bromobenzoyl) -3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) in ethanol (100 mL) was added under nitrogen atmosphere. Heated to reflux. After 4 hours, the reaction mixture was cooled to room temperature and diluted with hexanes to give 5-amino-4- (3-bromobenzoyl) -1- (4-fluorophenyl) pyrazole (9.7 g) as a solid. .
[288] In step 3, 4-fluorophenylhydrazine was replaced with 2,4-difluorophenylhydrazine to thereby 5-amino-4- (3-bromobenzoyl) -1- (2,4-difluorophenyl) pyra A sol was obtained.
[289] Step 4
[290] 5-amino-4- (3-bromobenzoyl) -1- (4-fluorophenyl) pyrazole (1.3 g, 4.16 mmol), 4- (prop-2- in diisopropylamine (60 mL) Inyl) morpholine (2.1g, 16.6mmol) [solution of morpholine in ether (50ml) (14.7ml, 168mmol) dropwise dropwise of propazyl bromide (7.5ml, 84mmol) in ether (50ml) over 30 minutes The reaction mixture was heated to reflux, after 16 h the reaction mixture was cooled to room temperature, filtered through a Buchner funnel, the filtrate was concentrated and flash chromatography (gradient eluent, 20-100% EtOAc). / Hexane) to give 4- (prop-2-ynyl) morpholine (5.0 g)], bis (triphenylphosphine) -palladium chloride (0.29 g, 0.42 mmol) and copper iodide (0.079 g, 0.42 mmol) was heated at 70 ° C. under argon. After 10 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine and dried over sodium sulfate. The organic liquid was removed under vacuum. The crude product was purified by flash chromatography (elution gradient, EtOAc-5% MeOH / EtOAc with 0.2% NH ₄ OH) to 5-amino-1- (4-fluorophenyl) -4- [3- (3 -Morpholin-4-ylprop-1-ynyl) benzoyl] -pyrazole, converted to hydrochloric acid salt and recrystallized from a mixture of methanol / ethylacetate / hexane to give pure product (1.4 g).
[291] In step 4 of Example 1, 4- (prop-2-ynyl) -morpholine was
[292] 1- (prop-2-ynyl) -4-methylpiperazine,
[293] 1- (prop-2-ynyl) piperidine,
[294] 2-propyn-1-ol,
[295] 1-dimethylamino-2-propine, and
[296] As described in Example 1 except that 2-methyl-3-butyn-2-ol was replaced,
[297] 5-amino-1- (4-fluorophenyl) -4- [3- [3- (4-methylpiperazin-1-yl) prop-1-ynyl] benzoyl] pyrazole2HCl (8),
[298] 5-amino-1- (4-fluorophenyl) -4- [3- [3- (piperidin-1-yl) prop-1-ynyl] benzoyl] pyrazole.2HCl (9),
[299] 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxyprop-1-ynyl) benzoyl] pyrazole (7),
[300] 5-amino-4- [3- (3-dimethylaminoprop-1-ynyl) benzoyl] -1- (4-fluorophenyl) -pyrazoleHCl (12), and
[301] 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxy-3-methyl-but-1-ynyl) benzoyl] pyrazole (87) was obtained, respectively.
[302] 4-fluorophenyl-hydrazine to 2,4-difluorophenylhydrazine in step 3 of Example 1 and 4- (prop-2-ynyl) morpholine to 3-ethynylpyridine in step 4 above 5-amino-1- (2,4-difluorophenyl) -4- [3- (3-pyridylethynyl) benzoyl] pyrazole was carried out as described in Example 1 except for the substitution. (88) is obtained,
[303] 5-amino-1- (2,4-difluorophenyl) -4- [3- [3 substituted by 3- (S, S-dioxo-thiomorpholin-4-yl) -1-propyne -(S, S-dioxo-thiomorpholin-4-yl) -1-propynyl] benzoyl] pyrazole (89)
[304] 5-amino-1- (2,4-difluorophenyl) -4- [3- [2- (1-hydroxycyclopentyl) ethynyl] benzoyl] pyrazole, substituted with 1-ethynylcyclopentanol (94) was obtained.
[305] Example 2
[306] 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl] pyrazole hydrochloride (6)
[307]
[308] 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylprop-1-ynyl) -benzoyl] pyrazole in ethanol (20 mL) (0.45 g, 1.0 mmol) (prepared as described in Example 1) and 5% Pd / C (0.07 g) were stirred under hydrogen atmosphere. After 16 h, the reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (Elution gradient, EtOAc-15% MeOH / EtOAc with 0.2% NH ₄ OH). The product was converted to hydrochloric acid salt and recrystallized from a mixture of methanol / ethyl acetate to give 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl as a solid. ] Pyrazole.HCl (0.3 g, mp 211.9-212.6 ° C.) was obtained.
[309] In Example 2, 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylprop-1-ynyl) benzoyl] pyrazole,
[310] 5-amino-1- (4-fluorophenyl) -4- [3- [3- (4-methylpiperazin-1-yl) prop-1-ynyl] benzoyl] pyrazole,
[311] 5-amino-1- (4-fluorophenyl) -4- [3- (3-piperidin-1-yl) prop-1-ynyl] benzoyl] pyrazole,
[312] 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxyprop-1-ynyl) benzoyl] pyrazole,
[313] 5-amino-4- [3- (3-dimethylaminoprop-1-ynyl) benzoyl] -1- (4-fluorophenyl) pyrazole,
[314] 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxy-3-methyl-1-butynyl) benzoyl] pyrazole,
[315] 5-amino-1- (2,4-difluorophenyl) -4- [3- (3-pyridylethynyl) benzoyl] pyrazole,
[316] 5-amino-1- (2,4-difluorophenyl) -4- [3- [3- (S, S-dioxo-thiomorpholin-4-yl) -1-propynyl] benzoyl] pyra Sol,
[317] 5-amino-1- (4-fluorophenyl) -4- [3- [2- (1-hydroxycyclopentyl) ethynyl] benzoyl] pyrazole, and
[318] In Example 2, except that 5-amino-1- (2,4-difluorophenyl) -4- [3- [2- (1-hydroxycyclopentyl) ethynyl] benzoyl] pyrazole was replaced By performing as described,
[319] 5-amino-1- (4-fluorophenyl) -4- [3- [3- (4-methylpiperazin-1-yl] propyl] benzoyl] pyrazole (30),
[320] 5-amino-1- (4-fluorophenyl) -4- [3- (3-piperidin-1-ylpropyl) benzoyl] pyrazole (32),
[321] 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxypropyl) benzoyl] pyrazole,
[322] 5-amino-4- [3- (3-dimethylaminopropyl) benzoyl] -1- (4-fluorophenyl) pyrazole,
[323] 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxy-3-methylbutyl) benzoyl] pyrazole (90),
[324] 5-amino-1- (2,4-difluorophenyl) -4- [3- (3-pyridylethyl) benzoyl] pyrazole (91),
[325] 5-amino-1- (2,4-difluorophenyl) -4- [3- [3- (S, S-dioxo-thiomorpholin-4-yl) propyl] benzoyl] pyrazole (92) ,
[326] 5-amino-1- (4-fluorophenyl) -4- [3- [2- (1-hydroxycyclopentyl) ethyl] benzoyl] pyrazole (93), and
[327] 5-amino-1- (2,4-difluorophenyl) -4- [3- [2- (1-hydroxycyclopentyl) ethyl] benzoyl] pyrazole 94 was obtained, respectively.
[328] Example 3
[329] 5-amino-1- (4-fluorophenyl) -4- [3- [2- (morpholin-4-yl) ethoxy] benzoyl] pyrazole hydrochloride (14)
[330]
[331] Step 1
[332] Mixture of methyl 3-hydroxybenzoate (8.0 g, 56 mmol), 4- (2-chloroethyl) -morpholine hydrochloride (15.7 g, 84 mmol) and potassium carbonate (11.5 g, 83 mmol) in toluene (50 mL) Was heated to reflux. After 4 days, the reaction mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water and then extracted with diluted hydrochloric acid. The acidic layer was separated, basified with 5N sodium hydroxide and the product extracted with ethyl acetate. The organic solution is removed in vacuo and the residue is purified by flash chromatography (elution gradient, 3% acetone / methylene chloride) to give methyl 3- (2-morpholin-4-ylethoxy) benzoate (9.0 as oil). g) was obtained.
[333] Step 2
[334] Lithium diisopropylamide (18.8 mL, 37 mmol, 2.0 M solution in heptane / tetrahydrofuran / ethylbenzene) was added dropwise to a solution of acetonitrile (1.58 g, 37 mmol) in anhydrous tetrahydrofuran (50 mL) at −78 ° C. It was. After the reaction mixture was stirred for 30 minutes, a solution of methyl 3- (2-morpholin-4-ylethoxy) benzoate in anhydrous tetrahydrofuran (50 mL) was added dropwise over 10 minutes. After 15 minutes, water was added and the reaction mixture was allowed to warm to room temperature. The aqueous layer was separated and acidified with diluted hydrochloric acid to pH 7. The product was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. The organic solution was removed under vacuum to afford 2- [3- (2-morpholin-4-ylethoxy) phenyl] acetonitrile (5.0 g) as an oil which was used in the next step without further purification.
[335] Step 3
[336] Mixture of 2- [3- (2-morpholin-4-ylethoxy) phenyl] acetonitrile (5.0 g) and N, N-diphenylformamidine (5.0 g, 25.5 mmol) in xylene (150 mL) Was heated at 100 ° C. under a nitrogen atmosphere. After 3 hours, the reaction mixture was cooled to room temperature and diluted with hexane to give 2- [3- (2-morpholin-4-ylethoxy) -benzoyl] -3-phenylamino-acrylonitrile (5.0 g) as a solid. ) Was obtained.
[337] Step 4
[338] 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2- [3- (2-morpholin-4-ylethoxy) -benzoyl] -phenylaminoacrylonitrile (2.0 g, in ethanol (30 mL) 5.3 mmol) was heated under reflux under a nitrogen atmosphere. After 6 hours, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH ₂ Cl ₂ -3% MeOH / CH ₂ Cl ₂ ) to 5-amino-1- (4-fluorophenyl) -4- [3- (2-morpholine-4 -Ylethoxy) benzoyl] pyrazole was obtained and converted to the hydrochloride salt (0.7 g, mp 191.6-192.5 ° C.).
[339] In step 4, 4-fluorophenylhydrazine is replaced with 2-fluorophenylhydrazine and 2,6-dichlorophenylhydrazine, respectively.
[340] 5-amino-1- (2-fluorophenyl) -4- [3- (2-morpholin-4-ylethoxy) benzoyl] pyrazole (97), and
[341] 5-amino-1- (2,6-dichlorophenyl) -4- [3- (2-morpholin-4-ylethoxy) benzoyl] pyrazole (98) was obtained.
[342] Example 4
[343] 5-amino-1- (4-fluorophenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (20)
[344]
[345] Step 1
[346] 5-amino-4- (3-bromobenzoyl) -1- (4-fluorophenyl) pyrazole (0.9 g, 2.5 mmol) in dioxane (20 mL) (prepared as described in Example 1 above) Mixture of pyridine-3-boronic acid, 1,3-propanediol cyclic ester (0.5 g, 3 mmol), potassium phosphate (0.8 g, 3.73 mmol) and tetrakistriphosphine palladium (0.3 g, 0.25 mmol) Was heated at 85 ° C. under argon. After 16 hours, the reaction mixture was cooled to room temperature and poured into brine. The product was extracted with ethyl acetate, dried over sodium sulfate and filtered. The organic layer was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 40-80% ethyl acetate / hexanes) to give 5-amino-1- (4-fluorophenyl) -4- [3- ( Pyridin-3-yl) benzoyl] -pyrazole (0.50 g) was obtained and recrystallized from ethyl acetate (mp 222.2-223.0).
[347] 5-amino-1- (4-fluorophenyl) -4- [3- (pyridin-3-yl) benzoyl] -pyrazole was treated with methyl iodide in ethyl acetate to give 5-amino-1- (4-fluoro Rophenyl) -4- [3- (N-methylpyridinium-3-yl) benzoyl] pyrazole iodide (59) was obtained.
[348] In step 1, 5-amino-4- (3-bromobenzoyl) -1- (4-fluorophenyl) pyrazole is replaced with 5-amino-4- (3-bromobenzoyl) -1- (2,4 -Difluorophenyl) pyrazole and substituted with hydrochloric acid salt to convert 5-amino-1- (2,4-difluorophenyl) -4- [3- (pyridin-3-yl) benzoyl] pyra Sol.HCl (99) was obtained.
[349] Example 5
[350] 5-amino-4- [3- (2-aminosulfonylethyl) benzoyl] -1- (4-fluorophenyl) pyrazole (50)
[351]
[352] Step 1
[353] 5-amino-4- (3-bromobenzoyl) -1- (4-fluorophenyl) pyrazole (1.5 g, 4.14 mmol) in dimethylformamide (18 mL) (as described in Example 1 above) Prepared), a mixture of vinylsulfonamide (1.33 g, 12.4 mmol), bis (triphenylphosphine) palladium chloride (0.3 g, 0.42 mmol) and triethylamine (6 ml, 43 mmol) were heated at 100 ° C. under argon. . After 16 hours, the reaction mixture was cooled to room temperature and poured into 1N hydrochloric acid. The product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The organic layer was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 40-80% ethyl acetate / hexanes) to give 5-amino-4- [3- (2-aminosulfonylethenyl) benzoyl] -1- (4-fluorophenyl) pyrazole was obtained and recrystallized from a mixture of methanol / ethyl acetate / hexanes to give the desired product (0.78 g).
[354] Step 2
[355] 5-amino-4- [3- (2-aminosulfonylethenyl) benzoyl] -1- (4-fluorophenyl) -pyrazole (2.1 g, 5.43 mmol) and palladium hydroxide in methanol (150 mL) The mixture of side (0.6 g) was shaken at 50 psi under hydrogen atmosphere in a Parr apparatus. After 4 days, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was filtered by flash chromatography (elution gradient: 40-100% ethyl acetate / hexanes) to afford the crude product and recrystallized from methanol / ethyl acetate / hexanes to give 5-amino-4- [3- (2-amino-sulfonylethyl) benzoyl] -1- (4-fluorophenyl) pyrazole (0.95 g, mp 170-170.4 ° C.) was obtained.
[356] Replacing vinyl sulfonamide with vinyl methyl sulfone in step 1 to obtain 5-amino-4- [3- (2-methylsulfonylethyl) benzoyl] -1- (4-fluorophenyl) pyrazole (100). It was.
[357] Example 6
[358] 5-amino-1- (4-fluorophenyl) -4- [3- (morpholin-4-ylmethylcarbonyl) benzoyl] pyrazole (18)
[359]
[360] Step 1
[361] 5-amino-4- (3-bromobenzoyl) -1- (4-fluorophenyl) pyrazole (3.5 g, 9.7 mmol) in dimethylformamide (25 mL) (as described in Example 1 above) Prepared), tributyl- (1-ethoxyvinyl) tin (4.3 mL, 12.36 mmol) and tetrakis (triphenylphosphine) palladium (1.0 g, 0.87 mmol) were heated at 95 ° C. under argon. After 16 hours, the reaction mixture was cooled to room temperature and 10% aqueous hydrochloric acid solution (25 mL) was added slowly. After 30 minutes, the reaction mixture was diluted with ethyl acetate and filtered through celite. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 10-60% ethyl acetate / hexanes) to give 5-amino-4- [3- (1-ethoxyvinyl) benzoyl] -1- (4-fluorophenyl Pyrazole was obtained and dissolved in tetrahydrofuran (50 mL). 1N hydrochloric acid (20 mL) was added and the reaction mixture was stirred at rt for 16 h. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (elution gradient: 20-50% ethyl acetate / hexanes) and then recrystallized from a mixture of ethyl acetate / hexanes to give 5-amino-4- [3-acetylbenzoyl] -1- ( 4-fluorophenyl) pyrazole (2.0 g) was obtained.
[362] Step 2
[363] 5-amino-4- [3-acetylbenzoyl] in methylene chloride (25 mL) in a reflux suspension of copper bromide (2.2 g, 9.85 mmol) in a mixture of ethyl acetate / methylene chloride (1: 1) (100 mL) A solution of -1- (4-fluorophenyl) pyrazole (1.6 g, 4.95 mmol) was added under argon. After 16 h, the reaction mixture was concentrated and the residue was partitioned between aqueous sodium bisulfite solution and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 10-40% ethyl acetate / hexanes) to give 5-amino-4- [3- (2-bromoacetyl) -benzoyl] -1- (4- as a solid. Fluorophenyl) pyrazole (0.47 g) was obtained.
[364] Step 3
[365] To a solution of morpholine (0.25 mL, 2.79 mmol) in dimethylformamide (5 mL) 5-amino-4- [3- (2-bromoacetyl) benzoyl] -1- (in dimethylformamide (5 mL) A solution of 4-fluorophenyl) pyrazole (0.22 g, 0.56 mmol) was added. After 16 h, the reaction mixture was poured into brine and the product extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: ethyl acetate-10% methanol / ethyl acetate) to give 5-amino-1- (4-fluorophenyl) -4- [3- (morpholine-4 as solid). -Ylmethylcarbonyl) benzoyl] pyrazole (0.05 g) was obtained.
[366] Example 7
[367] 5-amino-1- (4-fluorophenyl) -4- [3- (2-hydroxyethyl) benzoyl] pyrazole (118)
[368]
[369] Step 1
[370] To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) in tetrahydrofuran (100 mL) was added diborane (70 mL, 1.0 M solution in tetrahydrofuran) at 0 ° C. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled to 0 ° C and water (50 mL) was added dropwise. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-60% ethyl acetate / hexanes) to afford 3- (2-hydroxyethyl) bromobenzene (9.0 g).
[371] Step 2
[372] To a solution of 3- (2-hydroxyethyl) bromobenzene (4.0 g, 20 mmol) in methylene chloride (100 mL) t-butyldimethylsilyl chloride (3.6 g, 24 mmol), dimethylaminopyridine (0.61 g) at 0 ° C. , 5 mmol) and triethylamine (3.6 mL, 25.9 mmol) were added. After 1 h, the reaction mixture was washed with brine, saturated aqueous ammonium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 0-10% hexanes / ethyl acetate) to give 3- (2-t-butyl-dimethylsiloxyethyl) bromobenzene (6.0 g).
[373] Step 3
[374] A mixture of ethyl (ethoxymethylene) cyanoacetate (26 mL, 154 mmol) and 4-fluorophenyl hydrazine (19.4 g, 154 mmol) in ethanol (125 mL) was heated under reflux. After 16 hours, the reaction mixture was cooled to room temperature. The solid was filtered and dried to give 5-amino-4-ethylcarboxy-1- (4-fluorophenyl) pyrazole (28 g), which was added to a mixture of 1N lithium hydroxide (100 mL) and methanol (250 mL). Suspended. The reaction mixture was heated to reflux. After 16 h, the reaction mixture was filtered through a sinter funnel and the filtrate was acidified with 2N hydrochloric acid (65 mL). The solid was filtered and dried to give 5-amino-4-carboxy-1- (4-fluorophenyl) pyrazole (21 g).
[375] Step 4
[376] 5-amino-4-carboxy-1- (4-fluorophenyl) pyrazole (15 g, 68 mmol), aldothiol-2 (14.9 g, 68 mmol) and triphenylphosphine (17.8 g) in acetonitrile (2 L) , 68 mmol) was stirred at room temperature. After 16 hours, the product was filtered and dried to afford 5-amino-1- (4-fluorophenyl) -4- (2-pyridylthiocarboxy) -pyrazole (14 g).
[377] Step 5
[378] In an oven-dried flask containing magnesium turning (0.386 g, 15.9 mmol) and tetrahydrofuran (10 mL), 3- (2-t-butyldimethylsiloxyethyl) -bromobenzene (5.0 g) 15.9 mmol) was added and the reaction mixture was heated to reflux. After 3 hours, the reaction mixture was cooled to room temperature, 5-amino-1- (4-fluorophenyl) -4- (2-pyridylthiocarboxy) pyrazole (2.37 g, 7.6 mmol) was added, Stir for hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous ammonium chloride solution and brine and dried over sodium sulfate. The organic solution is removed in vacuo and the residue is purified by flash chromatography (elution gradient: 10-30% ethyl acetate / hexanes) to give 5-amino-1- (4-fluorophenyl) -4- [3- (2-t-butyldimethyl-siloxyethyl) benzoyl] pyrazole (1.20 g) was obtained.
[379] Step 6
[380] 5-amino-1- (4-fluorophenyl) -4- [3- (2-t-butyldimethyl-siloxyethyl) -benzoyl] pyrazole (1.2 g, 3.0 mmol in tetrahydrofuran (25 mL) To a solution of) tetrabutyl-ammonium fluoride (3.6 mL, 3.6 mmol, 1 M solution in tetrahydrofuran) was added. After 1 hour, the reaction mixture was poured into brine and the product extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40 to 100% ethyl acetate / hexanes) to afford 5-amino-1- (4-fluorophenyl) -4- [3- (2-hydroxyethyl) benzoyl ] Pyrazole (0.8 g) was obtained.
[381] Example 8
[382] 5-amino-1- (4-fluorophenyl) -4- [3- [4-methylpiperazin-1-yl) ethyl) benzoyl] pyrazole dihydrochloride (31)
[383]
[384] Step 1
[385] Methanesulfonyl chloride in a solution of 5-amino-1- (4-fluorophenyl) -4- [3- (2-hydroxyethyl) benzoyl] pyrazole (0.8 g, 2.5 mmol) in pyridine (10 mL) (0.29 mL, 3.7 mmol) was added. After 2 hours, the reaction mixture was poured into 2N hydrochloric acid (40 mL) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40 to 100% ethyl acetate / hexanes) to give 5-amino-1- (4-fluorophenyl) -4- [3- (2-methanesulfonyloxyethyl ) Benzoyl] pyrazole (0.87 g) was obtained.
[386] Step 2
[387] 5-amino-1- (4-fluorophenyl) -4- [3- (2-methanesulfonyloxy-ethyl) benzoyl] pyrazole (0.22 g, 0.55 mmol), N in dimethylformamide (10 mL) A mixture of methylpiperazine (0.18 mL, 1.64 mmol) and potassium carbonate (0.22 g, 1.64 mmol) was heated at 70 ° C. After 4 hours, the reaction mixture was cooled to room temperature, poured into water and the product extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: ethyl acetate-20% methanol / ethyl acetate) to give 5-amino-1- (4-fluorophenyl) -4- [3- [4-methylpiperazin- 1-yl) ethyl) benzoyl] pyrazole was obtained and converted to the hydrochloride salt (mp 272.9-273.9).
[388] Example 9
[389] 5-amino-4- [3- (2-aminoethyl) benzoyl] -1- (4-fluorophenyl) -pyrazole hydrochloride (47)
[390]
[391] Step 1
[392] 5-amino-1- (4-fluorophenyl) -4- [3- (2-methanesulfonyloxyethyl) -benzoyl] pyrazole (0.40 g, 0.99 mmol) in dimethylformamide (15 mL), sodium A mixture of azide (0.19 mL, 2.97 mmol) and potassium carbonate (0.41 g, 2.97 mmol) was stirred at room temperature. After 16 h, the reaction mixture was poured into brine and the product extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 20-50% ethyl acetate / hexanes) to give 5-amino-1- (4-fluorophenyl) -4- [3- (2-azidoethyl) benzoyl ] Pyrazole (0.32 g) was obtained.
[393] Step 2
[394] Triphenyl in a solution of 5-amino-1- (4-fluorophenyl) -4- [3- (2-azidoethyl) benzoyl] pyrazole (0.31 g, 0.9 mmol) in tetrahydrofuran (15 mL) Phosphine (3.55 g, 1.36 mmol) was added. After 48 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in 2N aqueous sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was converted to hydrochloride and recrystallized from a mixture of methanol-ethyl acetate to give 5-amino-4- [3- (2-aminoethyl) benzoyl] -1- (4-fluorophenyl) pyrazole hydrochloride (0.22 g) was obtained.
[395] Example 10
[396] 5-amino-4- [3- (t-butoxycarbonylmethyloxy) benzoyl] -1- (4-fluorophenyl) pyrazole
[397]
[398] Step 1
[399] 3-bromoanisole (3.1 g, 17 mmol) was added to an oven-dried flask containing magnesium turning (0.408 g, 17 mmol) and tetrahydrofuran (10 mL) and the reaction mixture was heated to reflux. After 2 hours, the reaction mixture was cooled to room temperature, 5-amino-1- (4-fluorophenyl) -4- (2-pyridylthiocarboxy) pyrazole (1.5 g, 4.8 mmol) was added, 1 Stir for hours. The reaction was quenched with water and the product extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine, and dried over sodium sulfate. The organic solution was removed in vacuo and the residue was filtered and washed with hexane to give 5-amino-1- (4-fluorophenyl) -4- (3-methoxybenzoyl) pyrazole (1.20 g). .
[400] Step 2
[401] Boron tribromide in an ice-cooled solution of 5-amino-1- (4-fluorophenyl) -4- (3-methoxybenzoyl) -pyrazole (3.0 g, 10.0 mmol) in methylene chloride (25 mL) (51 mL, 51 mmol, 1 M solution in methylene chloride) was added. After 1 hour, the reaction mixture was poured into brine and the product extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-amino-1- (4-fluorophenyl) -4- [3-hydroxybenzoyl] -pyrazole (2.4 g).
[402] Step 3
[403] 5-amino-1- (4-fluorophenyl) -4- [3-hydroxybenzoyl] pyrazole (1.0 g, 3.3 mmol), t-butyl bromoacetate (1.4 g, 7.2 mmol) in acetonitrile and A mixture of potassium carbonate (1 g, 7.2 mmol) was heated at 70 ° C. overnight. The reaction mixture was cooled down, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (elution gradient: 10% acetone / hexane) to give 5-amino-4- [3- (t-butoxycarbonylmethyloxy) benzoyl] as a solid. -1- (4-fluorophenyl) pyrazole (1.2 g) was obtained.
[404] Example 11
[405] 5-amino-4- [3-carboxymethyloxy) benzoyl] -1- (4-fluorophenyl) -pyrazole (119)
[406]
[407] Step 1
[408] 5-amino-4- [3- (t-butoxycarbonylmethyloxy) benzoyl] -1- (4-fluorophenyl) pyrazole (1.0 g, 3.3 mmol) and trifluoro in methylene chloride (15 mL) A mixture of roacetic acid (15 mL, 194 mmol) was stirred at rt overnight. The organic liquid was removed in vacuo and the residue was dissolved in toluene. The solution was concentrated and the residue triturated with ethyl acetate and hexanes to give 5-amino-4- [3- (carboxymethyloxy) benzoyl] -1- (4-fluorophenyl) -pyrazole (0.8 g as a solid). ) Was obtained.
[409] Example 12
[410] 5-amino-1- (4-fluorophenyl) -4- [3- (methylaminocarbonylmethyloxy) benzoyl] pyrazole (34)
[411]
[412] Step 1
[413] Carbonyl di in a solution of 5-amino-4- [3- (carboxymethyloxy) benzoyl] -1- (4-fluorophenyl) -pyrazole (0.5 g, 1.43 mmol) in tetrahydrofuran (10 mL) Imidazole (0.3 g, 1.85 mmol) was added and the reaction mixture was heated at 60 ° C. After 1 hour methylamine (10 mL, 5 mmol, 0.5 M solution in tetrahydrofuran) was added and reacted overnight at 60 ° C. The reaction mixture was cooled down and diluted with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. The organic solution was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 20-30% acetone / hexane) to give 5-amino-1- (4-fluorophenyl) -4- [3 as a solid. -(Methylaminocarbonyl-methyloxy) benzoyl] pyrazole (0.25 g, mp 195.6-196.3 ° C.) was obtained.
[414] 5-amino-1- (4-fluorophenyl) -4- [3- (morpholine-) was carried out as described in Example 12, except that methylamine was replaced with morpholine in Example 12 above. 4-ylcarbonyl-methyloxy) benzoyl] pyrazole 35 was obtained.
[415] Example 13
[416] 5-amino-1- (4-fluorophenyl) -4- [3- [3- (morpholin-4-yl) propylamino] benzoyl] pyrazole (48)
[417]
[418] Step 1
[419] Benzoylacetonitrile (14.5 g, 10 mmol) was added portionwise to cold fuming nitric acid (50 mL) over 10 minutes. The reaction mixture was stirred for 15 minutes and then poured on ice. The solid was filtered and recrystallized from ethanol to give 2- (3-nitrobenzoyl) -acetonitrile (5.4 g) as a brown solid.
[420] Step 2
[421] A mixture of 2- (3-nitrobenzoyl) acetonitrile (13.75 g, 72.3 mmol) and N, N-diphenylformamidine (14.2 g, 72.3 mmol) in xylene (200 mL) was heated under reflux in a nitrogen atmosphere. . After 3 hours, the reaction mixture was cooled to room temperature and diluted with xylene to give 2- (3-nitrobenzoyl) -3-phenylamino-acrylonitrile (15.7 g) as a yellow solid.
[422] Step 3
[423] A mixture of 4-fluorophenylhydrazine (2.24 g, 15.57 mmol) and 2- (3-nitrobenzoyl) -3-phenylaminoacrylonitrile (4.15 g, 14.16 mmol) in ethanol (50 mL) was refluxed in a nitrogen atmosphere. Under heating. After 1 hour, the reaction mixture was cooled to room temperature and stirred for a further 3 hours. The solid was filtered and dried to afford 5-amino-1- (4-fluorophenyl) -4- (3-nitrobenzoyl) pyrazole (4.5 g) as a solid.
[424] Step 4
[425] 5-amino-1- (4-fluorophenyl) -4- (3-nitrobenzoyl) pyrazole (4.0 g, 24.52 mmol) in ethanol (135 mL) and water (64 mL), Fe powder (3.84 g, 68 mmol) and ammonium chloride (3.84 g, 71.78 mmol) were heated under reflux in a nitrogen atmosphere. After 1 hour, the reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5-amino-4- (3-amino-benzoyl) -1- (4-fluoro-phenyl) pyrazole (3.5 g) as a solid. Obtained.
[426] Step 5
[427] 5-amino-4- (3-aminobenzoyl) -1- (4-fluorophenyl) pyrazole (0.5 g, 1.6 mmol), 1-bromo-3-chloropropane (25 mL) in dimethylformamide (25 mL) 0.26 g, 1.6 mmol) and cesium carbonate (0.52 g, 1.6 mmol) were heated at 80 ° C. After 2 days, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 20% acetone / hexane) to give 5-amino-4- [3- (3-chloropropylamino) benzoyl] -1- (4-fluorophenyl) as a solid. Pyrazole (0.2 g) was obtained.
[428] Step 6
[429] 5-amino-4- [3- (3-chloropropylamino) benzoyl] -1- (4-fluorophenyl) -pyrazole (0.05 g, 0.13 mmol) in acetonitrile (3 mL), morpholine (0.1 ML, 1.1 mmol), a mixture of potassium carbonate (0.1 g) and potassium iodide (0.1 g) was heated under reflux. After 2 days, the reaction mixture was poured into brine and the product was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 3% MeOH / CH ₂ Cl ₂ ) to give 5-amino-1- (4-fluorophenyl) -4- [3- [3- (morpholine as solid). -4-yl) propylamino] -benzoyl] -pyrazole was obtained.
[430] Example 14
[431] 5-amino-1- (4-fluorophenyl) -4- [3- [2- (piperidin-1-yl) ethoxy] benzoyl] pyrazole HCl Salt (81)
[432]
[433] Step 1
[434] 5-amino-1- (4-fluorophenyl) -4- [3-hydroxybenzoyl] pyrazole (1.5 g, 5.05 mmol) prepared from Example 10, step 2 was mixed with toluene (50 mL). . After addition of 2-bromoethanol (1.79 mL, 25.23 mmol), the reaction mixture was cooled to 0 ° C. Triphenylphosphine (5.425 g, 20.69 mmol) and diethyl azodicarboxylate (3.26 mL, 20.69 mmol) were added. The reaction was warmed to room temperature. After stirring for 16 hours, the reaction was quenched with a saturated aqueous solution of NH ₄ Cl, extracted with ethyl acetate, dried (MgSO ₄ ), filtered and concentrated in vacuo. Column with 40: 1 CH ₂ Cl ₂ / MeOH on silica gel with product (5-amino-1- (4-fluorophenyl) -4- [3- (2-bromoethoxy) benzoyl] pyrazole) After purification by chromatography, it was stirred in ether for 20 minutes, filtered and dried to give 0.785 g of product.
[435] Step 2
[436] 5-amino-1- (4-fluorophenyl) -4- [3- (2-bromoethoxy) benzoyl] pyrazole (0.6 g, 1.48 mmol) was converted to piperidine (1.47 mL, 14.8 mmol) and ethanol. (10 mL) and heated at reflux for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between saturated aqueous solution of NaHCO ₃ and ethyl acetate and extracted three times with ethyl acetate. Dry the organic extract, and (MgSO _4), filtered, concentrated in vacuo and 16 on silica gel was purified by column chromatography using a CH ₂ Cl ₂ / MeOH 1.
[437] After dissolving the product in ethyl acetate, hydrochloric acid (1.0 M, 1.0 equiv) was added to form the hydrochloride salt, which was filtered and dried to 5-amino-1- (4-fluorophenyl) -4- [3- 0.413 g of [2- (piperidin-1-yl) ethoxy] benzoyl] pyrazole.HCl (mp 210.2-211.2 ° C.) was obtained.
[438] The piperidine in step 2 is diethanolamine, dimethylamine, N-methylpiperazine, 2-aminoethanol, bis (2-methoxyethyl) amine, diethylamine, methylamine, ammonia and 3-oxopyridazine The following compounds were obtained in the same manner as in Step 2 except that the residue was replaced with.
[439]
[440] Example 15
[441] 5-amino-1- (4-fluorophenyl) -4- [3- (pyridin-2-ylmethoxy) benzoyl] pyrazole (82)
[442]
[443] 5-amino-1- (4-fluorophenyl) -4- [3-hydroxybenzoyl] pyrazole (0.5 g, 1.68 mmol), 2-pyridylcarbinol (0.81) prepared from Example 10, step 2 ML, 8.41 mmol), triphenylphosphine (1.81 g, 6.9 mmol) and diethylazodicarboxylate (1.09 mL, 6.9 mmol) were mixed with toluene (50 mL). The reaction mixture was stirred for 16 hours, then quenched with saturated aqueous solution of NH ₄ Cl and extracted three times with ethyl acetate. The product was then extracted from ethyl acetate with 10% aqueous HCl solution. The aqueous layer was neutralized with NaOH and extracted with ethyl acetate. The organic extract was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with 1: 1 hexanes / ethyl acetate and then 5-amino-1- (4-fluorophenyl) -4- [3- (pyridin-2-ylme Oxy) benzoyl] pyrazole (mp 176.1-177.3 ° C.) was obtained.
[444] 2-pyridylcarbinol was replaced with glycolic acid, 1- (2-hydroxyethyl) -2-pyrrolidinone and 4-hydroxypiperidine to afford the following compounds.
[445]
[446] Example 16
[447] 5-amino-1- (4-fluorophenyl) -4- [3-isopropylaminocarbonyloxybenzoyl] pyrazole (83)
[448]
[449] 5-amino-1- (4-fluorophenyl) -4- [3-hydroxybenzoyl] pyrazole (0.30 g, 1.01 mmol) prepared from Example 10, step 2 was dissolved in K ₂ CO ₃ (0.418 g, 3.03 mmol) and THF (6 mL). After the mixture was cooled in an ice bath, isopropyl isocyanate (0.12 mL, 1.21 mmol) was added. The reaction was warmed to rt and stirred for 16 h. The reaction was quenched with water, extracted with ethyl acetate, dried (MgSO ₄ ), filtered and concentrated to dryness. The residue was stirred for 1 h in methanol and dichloromethane and then filtered to give 5-amino-1- (4-fluorophenyl) -4- [3-isopropylaminocarbonyloxybenzoyl] pyrazole (mp 225.2- 0.118 g) was obtained.
[450] Isopropyl isocyanate was replaced with ethyl isocyanate to yield 5-amino-1- (4-fluorophenyl) -4- [3-ethylaminocarbonyloxybenzoyl] pyrazole (84). m.p. 201.2-202.8 ° C.
[451] Example 17
[452] 5-amino-1- (4-fluorophenyl) -4- [3-iodobenzoyl] pyrazole
[453]
[454] Step 1
[455] n-butyllithium (30.5 mL, 76 mmol, 2.5 M solution in hexane) was added dropwise to a cooled solution (0 ° C.) of diisopropylamine (10.6 mL, 76 mmol) in anhydrous tetrahydrofuran (10 mL). Once the addition was complete, the solution was held at 0 ° C. for 10 minutes and then cooled to −50 ° C. The cooled LDA solution was added to a 50 ° C. solution of acetonitrile (2.37 mL, 45.3 mmol) and ethyl 4-iodobenzoate (10.0 g, 36.2 mmol) in anhydrous tetrahydrofuran (18 mL). Once the addition was complete, the reaction was stirred at −50 ° C. for 3 hours and then warmed to 0 ° C. Saturated aqueous ammonium chloride solution (20 mL) was added and the reaction mixture was allowed to warm to room temperature. The product was extracted with ether and washed with 1N hydrochloric acid (50 mL). The organic solution was washed with brine (50 mL), dried over MgSO ₄ and concentrated in vacuo to a red oil. The oil was purified through a small plug of silica gel using 3: 1 to 2: 1 hexanes / ethyl acetate as eluent. The column fractions were concentrated in vacuo to afford 2- (3-iodobenzoyl) -acetonitrile (8.3 g) as a yellow oil.
[456] Step 2
[457] A mixture of 2- (3-iodobenzoyl) acetonitrile (36.2 g, 133.5 mmol) and N, N-diphenylformamidine (26.2 g, 133.5 mmol) in toluene (200 mL) was heated under reflux in a nitrogen atmosphere. It was. After 8 hours, the reaction mixture was cooled to room temperature and diluted with ether to give 2- (3-iodobenzoyl) -3-phenylaminoacrylonitrile (31.2 g) as a solid.
[458] Step 3
[459] A mixture of 4-fluorophenylhydrazine (26.6 g, 211 mmol) and 2- (3-iodobenzoyl) -3-phenylaminoacrylonitrile (79 g, 211 mmol) in ethanol (400 mL) was heated under reflux in a nitrogen atmosphere. It was. After 30 minutes, the reaction mixture was cooled to room temperature and diluted with hexanes to give 5-amino-4- (3-iodobenzoyl) -1- (4-fluorophenyl) pyrazole (75.1 g) as a solid. It was.
[460] 4-fluorophenylhydrazine in step 3, 4-methylphenylhydrazine, 3-methoxyphenylhydrazine, 4-sulfamoylphenylhydrazine, 2,4-dimethylphenylhydrazine, 2-methylphenylhydrazine, 4-chloro-2-methylphenyl By replacing with hydrazine, 4-methylsulfonylphenylhydrazine, 2-ethylphenylhydrazine, and 2,4-difluorophenylhydrazine,
[461] 5-amino-4- (3-iodobenzoyl) -1- (4-methylphenyl) pyrazole,
[462] 5-amino-4- (3-iodobenzoyl) -1- (3-methoxyphenyl) pyrazole,
[463] 5-amino-4- (3-iodobenzoyl) -1- (4-sulfamoylphenyl) pyrazole,
[464] 5-amino-4- (3-iodobenzoyl) -1- (2,4-dimethylphenyl) pyrazole,
[465] 5-amino-4- (3-iodobenzoyl) -1- (2-methylphenyl) pyrazole,
[466] 5-amino-4- (3-iodobenzoyl) -1- (4-chloro-2-methylphenyl) pyrazole,
[467] 5-amino-4- (3-iodobenzoyl) -1- (4-methylsulfonylphenyl) pyrazole,
[468] 5-amino-4- (3-iodobenzoyl) -1- (2-ethylphenyl) pyrazole, and
[469] 5-amino-4- (3-iodobenzoyl) -1- (2,4-difluorophenyl) pyrazole was obtained, respectively.
[470] Example 18
[471] 5-amino-1- (4-fluorophenyl) -4- [3- (1,2-dihydroxyethyl) benzoyl] pyrazole (85)
[472]
[473] Step 1
[474] To a solution of 5-amino-1- (4-fluorophenyl) -4- [3-iodobenzoyl] pyrazole (10 g, 24.6 mmol) in dimethylformamide (100 mL), vinyltributytin (8.57 g, 27.0 mmol) and tetrakistriphenylphosphine palladium (0) (1.42 g, 1.23 mmol) were added. The resulting solution was degassed with argon and subsequently warmed to 100 ° C. for 12 hours.
[475] The reaction mixture was cooled to room temperature, poured into 500 mL of distilled water and extracted three times with 100 mL of 1: 1 ether / ethyl acetate. The organic solution was washed with brine (150 mL), dried over MgSO ₄ and concentrated in vacuo to brown oil. The oil was prepared by flash column chromatography using 5: 1 to 4: 1 hexanes / ethyl acetate to remove impurities and 3: 1 to 2: 1 hexanes / ethyl acetate to elute the desired product. Purified. The column fractions were concentrated in vacuo to afford 5-amino-1- (4-fluorophenyl) -4- [3-vinylbenzoyl] pyrazole (4.48 g) as a white solid.
[476] Step 2
[477] N- in distilled water (50 mL) in a suspension of 5-amino-1- (4-fluorophenyl) -4- [3-vinylbenzoyl] pyrazole (4.48 g, 13.95 mmol) in t-butanol (50 mL). Methylmorpholine N-oxide (1.79 g, 15.35 mmol) was added. To the mixture was added a 2.5% osmium tetraoxide solution (5.25 mL, 0.42 mmol) in t-butanol at room temperature. After 5 hours, the homogeneous reaction was diluted with ethyl acetate (25 mL), the organic solution was separated, washed with brine (25 mL), dried over MgSO ₄ and concentrated in vacuo to brown oil. The oil was purified by flash column chromatography using 1: 1 hexanes / ethyl acetate to remove impurities and ethyl acetate to elute the desired product. Concentrate the column fraction in vacuo to afford 5-amino-1- (4-fluorophenyl) -4- [3- (1,2-dihydroxyethyl) benzoyl] pyrazole (4.48 g) as a white foam. It was. The foam was triturated from solid hexane to a solid (2.36 g).
[478] In step 1, 5-amino-1- (4-fluorophenyl) -4- [3-iodobenzoyl] pyrazole is replaced with 5-amino-1- (2,4-difluorophenyl) -4- [ 5-amino-1- (2,4-difluorophenyl) in place of 3-iodobenzoyl] pyrazole and 5-amino-1- (2-methylphenyl) -4- [3-iodobenzoyl] pyrazole -4- [3- (1,2-dihydroxyethyl) benzoyl] pyrazole (103) and 5-amino-1- (2-methylphenyl) -4- [3- (1,2-dihydroxyethyl ) Benzoyl] pyrazole 109 was obtained respectively.
[479] Example 19
[480] 5-amino-1- (2,4-difluorophenyl) -4- [3- (1-piperidinylmethyl) benzoyl] pyrazole (86)
[481]
[482] Step 1
[483] 5-amino-1- (2,4-difluorophenyl) -4- [3- (1,2-dihydroxyethane) benzoyl] pyrazole (10.1 g, 28 mmol) in t-butanol (100 mL) To a suspension of distilled water (100 mL) and sodium periodate (18.06 g, 84 mmol) were added. After 2 hours, the solid precipitate was collected by vacuum filtration, washed with distilled water (300 mL) and dried under vacuum to yield 5-amino-1- (2,4-difluorophenyl) -4- [as a white solid. 8.28 g of 3-formylbenzoyl] pyrazole were obtained.
[484] Step 2
[485] 5-amino-1- (2,4-difluorophenyl) -4- [3-formylbenzoyl] pyrazole (0.3 g, 0.92 mmol) in 1,2-dichloroethane (5 mL), piperidine ( 0.1 ml, 1.0 mmol) and sodium triacetoxyborohydride (0.29 g, 1.37 mmol) were added to a solution of acetic acid (0.05 mL). After stirring for 12 hours at room temperature, the reaction was diluted with 10% hydrochloric acid and ethyl acetate (10 mL). The aqueous layer was separated, neutralized to pH 9 with sodium hydroxide and then extracted with ethyl acetate. The combined organics were separated, washed with brine (25 mL), dried over MgSO ₄ and concentrated in vacuo to brown oil. The oil was purified by flash column chromatography using 1: 1 hexanes / ethyl acetate to remove impurities and ethyl acetate to elute the desired product. The column fractions were concentrated in vacuo to afford 5-amino-1- (4-fluorophenyl) -4- [3- (1-piperidinylmethyl) -benzoyl] pyrazole (0.211 g) as an oil. The compound was triturated from hexane / ethyl acetate to a solid.
[486] Piperidine in step 1 is morpholine, N-methylpiperazine, 4-hydroxypiperidine, 2-aminopyridine, 3-aminopyridine, 4-methylimidazole, 3-aminopyrazole and 2- Substitution with methylimidazole afforded the following compounds.
[487]
[488] Example 20
[489] 5-amino-1- (3-methylphenyl) -4- [3- [N-oxidopyridin-3-yl] benzoyl] pyrazole (70)
[490]
[491] 5-amino-4- (3-iodobenzoyl) -1- (2-methylphenyl) pyrazole (0.98 g, 2.4 mmol), pinacol diborone (0.68 g) prepared from Example 17 in DMF (10 mL) , 2.7 mmol), a mixture of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (0.2 g, 0.24 mmol) and potassium acetate (0.72 g, 7.3 mmol) was heated at 80 ° C. under argon. After 2 hours, the reaction mixture was cooled to room temperature, 3-bromo-pyridine N-oxide (0.47 g, 2.7 mmol), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (0.2 g , 0.24 mmol) and 2M sodium carbonate (6.1 mL, 12.2 mmol) were added and heated to 80 ° C. After 16 h, the reaction mixture was cooled to rt, poured into brine and the product extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the solution was evaporated to dryness. The residue was purified by flash chromatography (elution gradient: 100% ethyl acetate to 20% methanol / ethyl acetate) and recrystallized from methanol / ethyl acetate / hexanes before 5-amino-1- (3-methylphenyl) -4 -[3- (N-oxidopyridin-3-yl) benzoyl] pyrazole (0.57 g, mp 190.5-191.2 ° C.) was obtained.
[492] 5-amino-4- (3-iodobenzoyl) -1- (2-methylphenyl) pyrazole / 3-bromopyridine N-oxide
[493] 5-amino-4- (3-iodobenzoyl) -1- (4-methylphenyl) pyrazole / 3-bromopyridine,
[494] 5-amino-4- (3-iodobenzoyl) -1- (3-methoxyphenyl) pyrazole / 3-bromopyridine,
[495] 5-amino-4- (3-iodobenzoyl) -1- (4-sulfamoylphenyl) pyrazole / 3-bromopyridine,
[496] 5-amino-4- (3-iodobenzoyl) -1- (2,4-dimethylphenyl) pyrazole / 3-bromopyridine,
[497] 5-amino-4- (3-iodobenzoyl) -1- (2-methylphenyl) pyrazole / 3-bromopyridine-N-oxide,
[498] 5-amino-4- (3-iodobenzoyl) -1- (4-chloro-2-methylphenyl) pyrazole / 3-bromopyridine,
[499] 5-amino-4- (3-iodobenzoyl) -1- (4-methylsulfonylphenyl) pyrazole / 3-bromopyridine,
[500] 5-amino-4- (3-iodobenzoyl) -1- (2-ethylphenyl) pyrazole / 3-bromopyridine, and
[501] Replacing with 5-amino-4- (3-iodobenzoyl) -1- (2,4-difluorophenyl) pyrazole / 3-bromoimidazole,
[502] 5-amino-1- (4-methylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (65),
[503] 5-amino-1- (3-methoxyphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (66),
[504] 5-amino-1- (4-sulfamoylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (68),
[505] 5-amino-1- (2,4-dimethylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (69),
[506] 5-amino-1- (2-methylphenyl) -4- [3- (N-oxidopyridin-3-yl) benzoyl] pyrazole (70),
[507] 5-amino-1- (4-chloro-2-methylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (73),
[508] 5-amino-1- (4-methylsulfonylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (75),
[509] 5-amino-1- (2-ethylphenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (76), and
[510] 5-amino-1- (2,4-difluorophenyl) -4- [3- (imidazol-2-ylbenzoyl] pyrazole (77) with hydrochloric acid salts thereof is also obtained, respectively.
[511] Example 21
[512] 5-amino-1- (2,4-difluorophenyl) -4- [N-oxidopyridin-3-yl] benzoyl] pyrazole (60)
[513]
[514] To a solution of 5-amino-1- (2,4-difluorophenyl) -4- [3- (pyridin-3-yl) benzoyl] pyrazole (4.6 g, 12.2 mmol) in dichloromethane (100 mL) 3-chloroperoxybenzoic acid (5.6 g, 18.3 mmol) was added and the mixture was stirred at room temperature. After 4 hours, 10% aqueous sodium sulfate solution (50 mL) was added. After 0.5 h, the organic layer was separated, washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness and the residue was purified by flash chromatography (elution gradient: 100% ethyl acetate to 30% methanol / ethyl acetate), recrystallized from methanol, and then 5-amino-1- (2,4-di Fluorophenyl) -4- [3- (N-oxidopyridin-3-yl) benzoyl] pyrazole (1.3 g, mp 251.1-251.7 ° C.) was obtained.
[515] Example 22
[516] 5-amino-1- (2,4-difluorophenyl) -4-[(pyridin-4-yl) benzoyl] pyrazole (61)
[517]
[518] 5-amino-4- (3-bromobenzoyl) -1- (2,4-difluorophenyl) pyrazole (0.93 g, 2.5 mmol), 4-tributylstannylpyridine in DMF (15 mL) 1.0 g, 2.7 mmol) and a mixture of bis (triphenylphosphine) palladium chloride (0.17 g, 2.5 mmol) were heated at 100 ° C. under argon. After 16 hours, the reaction mixture was cooled to room temperature and an aqueous solution of 10% potassium fluoride (30 mL) was added. After 1 h, the reaction mixture was poured into brine, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash chromatography (elution gradient: 50-100% ethyl acetate / hexanes to 5% methanol / ethyl acetate) and recrystallized from methanol / ethyl acetate before 5-amino-1- (2,4- Difluorophenyl) -4- [3- (pyridin-4-yl) benzoyl] pyrazole (0.42 g, mp 218-226 ° C.) was obtained.
[519] Example 23
[520] 5-amino-1- (2,4-dimethylphenyl) -4- [3- (pyridin-3-yl) benzoylpyrazole HCl salt (69)
[521]
[522] Step 1
[523] A solution of n-butyl lithium (165 mL, 264 mmol) in butyl ether (250 mL) was added 3-bromopyridine (25.4 mL, 264 mmol) at −78 ° C. under nitrogen. After 1 hour, diethylmethoxyborane (52 mL, 396 mmol) was added. The mixture was allowed to warm to room temperature. After 16 h, water and brine were added, the organic layer was separated, dried over sodium sulfate and concentrated. The resulting slurry was dissolved in isopropanol (500 mL), cooled and separated by filtration to give diethyl (3-pyridyl) borane (29.8 g).
[524] Step 2
[525] Diethyl (3-pyridyl) borane (176.4 g, 1.2 mole), methyl-3-iodobenzoate (262 g, 1 mole), potassium phosphate (318.4 g, 1.5 mole) and tetraquistri in DMF (1000 mL) A mixture of phenylphosphine palladium (0) (57.8 g, 0.05 mole) was heated at 80 ° C. under argon. After 10 h the mixture was diluted with water and extracted with ethyl acetate. The organic layer was filtered and washed with water. To the organic fractions was added concentrated HCl (65 mL). The organic layer was separated and extracted with an aqueous HCl solution. The combined acid extracts were treated with ethyl acetate followed by 50% aqueous sodium hydroxide solution (55 mL). The organic layer was separated, washed with water and saturated sodium bicarbonate solution and dried over sodium sulfate. The solution was filtered and concentrated to give methyl-3- (pyridin-3-yl) benzoate (145.3 g).
[526] Step 3
[527] To a solution of methyl-3- (pyridin-3-yl) benzoate (126.2 g, 0.59 mole) in THF (600 mL) was added acetonitrile (37 mL, 0.71 mole) and the reaction was cooled to 40 ° C. Lithium diisopropyl amide solution (590 mL, 1.18 mole) was added dropwise. After 30 minutes, methanol (25 mL) was added and after another 30 minutes water (110 mL) was added. The reaction mixture was warmed to 10 ° C. and ethyl acetate was added. The layers were separated and the aqueous layer was acidified with 1M HCl. The aqueous layer was extracted with ethyl acetate, diluted with hexanes and washed with brine. The organic layer was concentrated and then mixed with N, N'-diphenylformanidine (120 g, 0.61 mole) in 800 mL ethyl acetate. The mixture was stirred at room temperature. After 3 days, the product was collected by filtration and recrystallized from isopropanol, hexanes to give 2- (3-pyridin-3-yl) phenyl-3-phenylacrylonitrile (100 g).
[528] Step 4
[529] A solution of 2- (3-pyridin-3-ylphenyl) -3-phenylacrylonitrile (1.0 g, 3 mmol) and 2,4-dimethylphenylhydrazine (0.4 g, 3 mmol) in ethanol (30 mL) was added under nitrogen. Heated to reflux. After 6 hours, the reaction was cooled to room temperature, concentrated to dryness and the residue was purified by flash column chromatography (elution gradient: 40-100% ethyl acetate / hexanes to 10% methanol / ethyl acetate). The purified residue was dissolved in ethyl acetate and salts were prepared by addition of HCl / ether. After recrystallization from methanol / ethyl acetate, 5-amino-1- (2,4-dimethylphenyl) -4- [3- (pyridin-3-yl) benzoylpyrazole hydrochloride salt (0.74 g, mp 250.7-251.8 ) Was separated.
[530] In step 4, 2,4-dimethylphenylhydrazine is substituted with phenyl hydrazine, 2-methyl-4-chlorophenylhydrazine, 4-methoxyphenylhydrazine, 4-methylsulfonylphenylhydrazine, 2-ethylphenylhydrazine, 4-isopropyl As in Example 23, with the exception of phenylhydrazine, 2-methoxyphenylhydrazine, 3-chloro-4-methylphenylhydrazine, 3-fluorophenylhydrazine, and 3-fluoro-6-methylphenylhydrazine, respectively. The following compounds were obtained by carrying out.
[531]
[532] Example 24
[533] 5-amino-1- (4-fluorophenyl) -4- [3- [2 (R), 3-dihydroxypropoxy] benzoyl] pyrazole (106)
[534]
[535] Step 1
[536] D-α, β-isopropyl in a solution of 5-amino-4- (3-hydroxybenzoyl) -1- (4-fluorophenyl) pyrazole (0.5 g, 1.68 mmol) in 5 ml of anhydrous dimethylformamide. Lidenglycerol-γ-tosylate (0.72 g, 2.52 mmol) was added and anhydrous potassium carbonate (0.695 g, 5.04 mmol) was added. The reaction was warmed to 80 ° C. under argon. After 24 hours, the reaction was cooled to room temperature, additionally 500 mg of D-α, β-isopropylideneglycerol-γ-tosylate were added and the reaction was again warmed to 80 ° C. under argon. After another 8 hours, the reaction was cooled to room temperature, diluted with distilled water (50 mL) and the product was extracted with ether. The collected organic solution was washed with brine (50 mL), dried over MgSO ₄ and concentrated in vacuo to a yellow oil. The oil was purified by flash column chromatography using 2: 1 to 1: 1 hexanes / ethyl acetate as eluent. The column fractions were concentrated in vacuo to afford 556 mg of the desired acetal.
[537] Step 2
[538] To a solution of acetal (0.556 g, 1.35 mmol) formed above in methanol (10 mL) was added distilled water (2 mL) and p-toluenesulfonic acid monohydrate (5 mg). The solution was warmed to 80 ° C. under argon atmosphere. After 2 hours, the reaction mixture was cooled to room temperature, concentrated in vacuo to a yellow oil and redissolved in ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over MgSO ₄ , and concentrated to a white solid under vacuum. Recrystallization from hexane / ethyl acetate gave 196 mg of the desired diol (mp 150.2-153.0 ° C).
[539] Example 25
[540] 5-amino-1- (4-fluorophenyl) -4- [3-[(2,2-dimethyl-1,3-dioxolan-4 (S) -yl) methoxy] benzoyl] pyrazole (170 )
[541]
[542] 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3-dihydroxypropoxy] benzoyl] pyrazole (0.6 g, 1.6 mmol) in acetone (30 mL) Zinc chloride (0.34 g, 2.6 mmol) was added to the solution. The reaction mixture was stirred and heated at reflux. After 13 h, the reaction mixture was concentrated to dryness and the product was purified by flash column chromatography on silica gel using 40% EtOAc / hexanes as eluent. The product was stirred in 1: 1 ether / hexanes and 5-amino-1- (4-fluorophenyl) -4- [3-[(2,2-dimethyl-1,3-dioxolane-5 (S 125 mg of) -yl) methoxy] benzoyl] pyrazole was obtained.
[543] 5-Amino-1- (4-fluorophenyl) -4- [3-[(2,2-diethyl) as described above except that acetone was replaced with 3-pentanone and methylethyl ketone -1,3-dioxolane-4 (S) -yl) methoxy] benzoyl] pyrazole (173) and 5-amino-1- (4-fluorophenyl) -4- [3-[(2-methyl -2-ethyl-1,3-dioxolane-4 (S) -yl) methoxy] benzoyl] pyrazole 174 was obtained, respectively.
[544] Example 26
[545] 5-amino-1- (4-fluorophenyl) -4- [3-[(2 (S), 3- (diacetoxy) propoxy] benzoyl] pyrazole (165)
[546]
[547] Of 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3-dihydroxypropoxy] benzoyl] pyrazole (1 g, 2.7 mmol) in pyridine (5 mL) Acetic anhydride (0.5 mL, 5.4 mmol) and DMAP (0.066 g, 0.5 mmol) were added to the solution, and the reaction was stirred at room temperature. After 16 h, the reaction mixture was poured into brine, extracted with EtOAc, dried over sodium sulfate, concentrated to dryness and purified by flash chromatography (elution gradient, 20-60% EtOAc / hexanes). The product was recrystallized from EtOAc / hexanes to give 0.75 g of 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3- (diacetoxy) propoxy] benzoyl] pyrazole. Obtained.
[548] 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S) was carried out as described above except that acetic anhydride was replaced with isobutanoyl chloride and pivaloyl chloride. , 3- (diisobutanoyloxy) propoxy] benzoyl] pyrazole (166) and 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3- (dipi Valoyloxy) propoxy] benzoyl] pyrazole 167 was obtained, respectively.
[549] Example 27
[550] 5-amino-1- (4-fluorophenyl) -4- [3-[(2 (S), 3- (dimethoxycarbonyloxy) propoxy] benzoyl] pyrazole (168)
[551]
[552] Of 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3-dihydroxypropoxy] benzoyl] pyrazole (1 g, 2.7 mmol) in pyridine (5 mL) To the solution was added methyl chloroformmate (2 mL, 25.4 mmol). After 4 days, the reaction mixture was poured into brine, extracted with EtOAc, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (elution gradient, 40-80% EtOAc / hexanes) to give 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3- ( 0.55 g of dimethoxycarbonyloxy) propoxy] benzoyl] pyrazole was obtained.
[553] Example 28
[554] 5-amino-1- (4-fluorophenyl) -4- [3-[(1,3-dioxolan-2-one-4 (R) -yl) methoxy] benzoyl] pyrazole (171)
[555]
[556] Suspension of 5-amino-1- (4-fluorophenyl) -4- [3- [2 (S), 3-dihydroxypropoxy] benzoyl] pyrazole (15.0 g, 40.4 mmol) in 150 mL THF To this was added triethylamine (17 mL, 168 mmol). The mixture was cooled to -5 ° C and 18 mL of phosgene (20% in toluene) was added over 30 minutes while maintaining the reaction temperature below 0 ° C. After the addition was complete, the reaction was stirred at 0 ° C. for an additional hour. 20 ml of distilled water were then added, and 5% HCl was added until the solution had a pH of 5-6. After 30 minutes, ethyl acetate was added and the organic layer was separated, washed with brine and dried over MgSO ₄ . Filtration and concentration in vacuo gave a yellow oil which was purified by flash column chromatography using hexanes / ethyl acetate of 1: 1 to 1: 2 as eluent. Concentration of the column fractions precipitated the desired carbonate to yield 7.38 g of the desired product.
[557] Example 29
[558] 5-amino-1- (4-fluorophenyl) -4-tenoyl-pyrazole (114)
[559]
[560] In Example 1, step 2, step 2 was performed by replacing 2- (3-bromo-benzoyl) acetonitrile with 2- (2-tenoyl) acetonitrile, followed by step 3 to carry out 5-amino-1 -(4-fluorophenyl) -4- (2-tenoyl) -pyrazole was obtained.
[561] In Example 1, step 2, step 2 was performed by replacing 2- (3-bromo-benzoyl) acetonitrile with 2- (2-furanoyl) acetonitrile, followed by step 3 to carry out 5-amino-1 -(4-fluorophenyl) -4- (2-furanoyl) -pyrazole 115 was obtained.
[562] In Example 1, step 2, 2- (3-bromo-benzoyl) acetonitrile was replaced with 2- (2-methyl-3-furanoyl) acetonitrile, and in step 3 4-fluorophenylhydrazine was replaced with 2, Except for the substitution with 4-difluorophenylhydrazine, it was carried out as described in Example 1, Step 2 and Step 3 to 5-amino-1- (2,4-difluorophenyl) -4- ( 2-Methylfuran-3-oil) -pyrazole 116 was obtained.
[563] Example 1, Step 2 replaced 2- (3-bromo-benzoyl) acetonitrile with 2- (6-quinolinoyl) acetonitrile, and step 3 replaced 4-fluorophenylhydrazine with 2,4-di 5-amino-1- (2,4-difluorophenyl) -4- (6-quine as described in Examples 1, 2 and 3 except that it was replaced by fluorophenylhydrazine Nolinoyl) -pyrazole.HCl (117) (mp 220-259.2 ° C.) was obtained.
[564] Example 30
[565] The following is a representative pharmaceutical formulation containing a compound of formula (I).
[566] Tablet formulation
[567] The following ingredients were mixed directly and pressed into multiple tablets, one by one.
[568] ingredientmg / 1 tablet Compound of the Invention400 Corn starch50 Croscarmellose sodium25 Lactose120 Magnesium stearate5
[569] Capsule Blend
[570] The following ingredients were mixed directly and loaded into hard-shell gelatin capsules.
[571] ingredientmg / 1 capsule Compound of the Invention200 Lactose, spray-dried148 Magnesium stearate2
[572] Suspension formulation
[573] The following ingredients were mixed to prepare a suspension for oral administration.
[574] ingredientamount Compound of the Invention1.0 g Fumaric acid0.5g Sodium chloride2.0 g Methyl paraben0.15 g Profile paraben0.05g Granulated Sugar25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.)1.0 g Spice0.035 ml coloring agent0.5mg Distilled waterFit to 100ml
[575] Injectable Formulations
[576] The following components were mixed to prepare an injectable formulation.
[577] ingredientamount Compound of the Invention0.2 g Sodium acetate buffer solution (0.4M)2.0 ml HCl (1N) or NaOH (1N)Fit to the right pH Water (distilled water, sterilized water)Fit to 20ml
[578] All of the above components except water were mixed and heated to 60-70 ° C. with stirring. A sufficient amount of water was added to emulsify the components with vigorous stirring at 60 ° C., then water was added to 100 g.
[579] Suppository Formulations
[580] A total of 2.5 g suppository by mixing the compound of the present invention with Bitepsol® H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) It manufactured and has the following composition.
[581] Compound of the Invention500 mg Bitepsol H-15Remainder
[582] Example 31
[583] In Vitro Assay-Inhibition of p38 (MAP) Kinase
[584] In vitro, p38 MAP kinase inhibitory activity of the compounds of the present invention is described by Ahn, NG et al ., J. Biol. Chem. Vol. 266 (7), 4220-4227, (1991), using a slightly modified method of Myelin Basic Protein (MBP) in γ- ³³ P-ATP by p-38 kinase. Was determined by measuring the delivery of γ-phosphate.
[585] The phosphorylated form of the recombinant p38 MAP kinase was expressed by SEK-1 and MEKK in this E. Coli and purified by affinity chromatography using a Nickel column.
[586] Phosphorylated p38 MAP kinase to kinase buffer solution (20 mM 3- (N-morpholino) propanesulfonic acid, pH 7.2, 25 mM β-glycerol phosphate, 5 mM ethylene glycol-bis (beta-aminoethyl ether) -N , N, N ', N'-tetraacetic acid, 1 mM sodium vanadate, 1 mM dithiothreitol, 40 mM magnesium chloride). Only test compound or DMSO (control) dissolved in DMSO was added and the samples were incubated at 30 ° C. for 10 minutes. Kinase reactions were initiated by adding a substrate cocktail containing MBP and γ- ³³ P-ATP. After further incubating at 30 ° C. for 20 minutes, the reaction was terminated by adding 0.75% phosphoric acid. Subsequently, phosphorylated MBP was separated from residual γ- ³³ P-ATP using a phosphocellulose membrane (Millipore, Bedford, Mass.), And a scintillation instrument (Packard, Meriden, Conn.) Quantification using
[587] Compounds of the invention were active in this assay. The p-38 inhibitory activity (expressed as IC ₅₀ and analyzed as a concentration that inhibits 50% of the p-38 enzyme) of some compounds of the invention is as follows:
[588] Number of compoundsIC ₅₀ (μM)Compound numberIC ₅₀ (μM) One1.81191.45 23.29212.18 31.78272.72 46.18331.12 61.74386.31 91.32436.52 141.27501.25
[589] Example 32
[590] In Vitro Assay-Inhibition of TNF-α Production Induced by LPS in THP1 Cells
[591] The ability of compounds of the present invention to inhibit TNF-α release is described by Blyld et al., Transplantation, Vol. 51 (2), 498-503, (1991)] using a slightly modified method of the method described.
[592] (a) Induction of TNF biosynthesis
[593] THP-1 cells were suspended in medium [RPMI (15% Fetal Bovine Serum, 0.02 mM 2-mercapto-ethanol) (Gibco-BRL, Galessusburg, MD) at a concentration of 2.5 × 10 ⁶ cells / ml. After plating, they were plated in 96 well plates (0.2 ml aliquots per well). Test compounds were dissolved in DMSO and then diluted with medium to a final DMSO concentration of 5%. A 2 ml aliquot of the test solution or medium containing only DMSO (control) was added to each well. The cells were incubated at 37 ° C. for 30 minutes. LPS (Sigma, St. Louis, MO) was added to the wells to a final concentration of 0.5 μg / ml and the cells were incubated for an additional 2 hours. At the end of the culture, the culture supernatants were harvested and the amount of TNF-α present was measured using the ELISA assay described below.
[594] (b) ELISA assay
[595] The amount of human TNF-α present can be found in Reimund, JM et al ., CUT. Vol. 39 (5), 684-689 (1996), measured by specific trapping ELISA assay using two anti-TNF-α antibodies (2TNF-H22 and 2TNF-H34).
[596] Polystyrene 96 well plates were coated with 50 μl per well of antibody 2TNF-H22 in PBS (10 μg / ml) and incubated in a wet room at 4 ° C. overnight. The plates were washed with PBS, then blocked with 5% skim milk powder in PBS for 1 hour at room temperature and washed with 0.1% BSA (bovine serum albumin) in PBS.
[597] TNF standards were prepared from stock solutions of human recombinant TNF-α (R & D system, Minneapolis, Minn.). Standard concentrations in the assay were serially diluted six times to ½ log values starting at 10 ng / ml.
[598] Only 25 μl aliquots of the culture supernatant, TNF standard or medium (control) mixed with 25 μl aliquots of the biotinylated monoclonal antibody 2TNF-H34 (2 μg / ml in PBS containing 0.1% BSA). Then added to each well. Samples were incubated for 2 hours at room temperature with gentle shaking and then washed three times with 0.1% BSA in PBS. 50 μl of a peroxidase-streptovidin solution (Zymed, San Francisco, Calif.) Containing 0.416 μg / ml peroxidase streptavidin and 0.1% BSA in PBS was added to each well. Samples were incubated for an additional hour at room temperature and then washed four times with 0.1% BSA in PBS. 50 μl of O-phenylenediamine solution (1 μg / ml O-phenylene-diamine and 0.23% hydrogen peroxide in 0.2 M citrate buffer) was added to each well and the samples incubated in the dark for 30 minutes at room temperature. It was. The optical density and control of the sample were read at 450 nm and 650 nm, respectively. TNF-α values were determined from a graph showing the relationship between optical density at 450 nm versus concentration used.
[599] IC ₅₀ values were defined as the concentration of test compound corresponding to a half decrease in maximum at 450 nm absorbance. Compounds of the invention were active in this assay. The activities of the selected compounds are as follows:
[600] Number of compoundsIC ₅₀ (μM)Compound numberIC ₅₀ (μM) One1.77210.61 26.30270.83 41.26330.14 61.04380.69 101.62430.17 130.77500.51 190.17
[601] Example 33
[602] In Vivo Assay-Inhibition of TNF-α Production Induced by LPS in Rats
[603] The ability of the compounds of the invention to inhibit TNF-α release in vivo is described by Zanetti, G. and Heumann, D. et al., "Cytokine production after intravenous or peritoneal Gram-negative bacterial challenge. in mice ", J. Immunol. , 148, 1890, (1992) and Sekut, L., Menius, JA et al., "Evaluation of the significance of elevated levels of systemic and localized tumor necrosis factor in different animal models of inflammation ", J. Lab. Clin. Med. , 124, 813, (1994)] using a slightly modified method of the method described.
[604] Female Sprague-Dawley rats (Charles River, Hollister, Calif.) Weighing between 110 and 140 grams were acclimated for one week. The test compound dissolved in an aqueous vehicle containing 0.9% sodium chloride, 0.5% sodium carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol (CMC vehicle), or vehicle was added to the group containing 8 mice each. (Control) was administered orally. After 30 minutes, mice were injected intraperitoneally with 50 μg / kg LPS (Sigma, St. Louis, MO). After 1.5 hours, mice were killed by CO ₂ inhalation and blood was obtained by cardiac puncture. The blood was sorted by centrifugation at 15,600 × g for 5 minutes, the serum was transferred to clean tubes according to the manufacturer's protocol, and TNF-α by ELISA assay (Biosource International, Camarillo, CA). Frozen at −20 ° C. until analysis.
[605] Determination of TNF-α inhibitory activity of selected compounds of the present invention, ie, the amount of TNF-α in the test group for the 30 mg vehicle treated group (control), is as follows:
[606] Number of compounds% InhibitionNumber of compounds% Inhibition 3961976 8863475 1686
[607] Example 34
[608] In Vivo Assay-Adjuvant Arthritis Analysis in Rats
[609] Anti-inflammatory activity of the compounds of the present invention was measured using adjuvant induced arthritis in rats. Briefly, female Sprague Dawley rats (Charles River, Hollister, Calif.) Weighing 120-155 g were acclimated at home for about a week before use. On the first day, animals were treated with heat-sterilized and dried Mycobacterium Butyricum (Difco, Bacto, Des., Lot 115979JA / EXP9 / 99) at a concentration of 1 mg / 0.1 ml. 0.1 ml of the suspension in mineral oil (Sigma, St. Louis, Missouri) was injected intradermal into a quarter of the tail close to the base.
[610] On day 7, test compounds in the CMC vehicle were administered until day 18. On day 18, the compounds were administered and the animals weighed. Clinical values were obtained to assess the degree of edema in the four feet and tail. The values were 0-4 at each foot, 0-3 at the tail and a maximum of 19. In animals with polyarthritis, levels are not observed when inflammatory symptoms (swelling and redness) are not observed in any small joints (intra-palmated, metacarpal, metatarsal) or large joints (wrist / elbow, ankles / foot bones). 0. If the animal had a slight inflammation, the values were 1, moderate edema was observed 2, severe edema was observed 3, and very severe edema was observed. If no signs of edema or necrotic tissue are observed in the tail, the value is zero; if some edema appears at the site of inoculation injection and adjacent surrounding tissue, 1, if about 1/4 of the tail is inflamed or shows necrotic tissue, 2, It was 3 if more than 1/4 of the tail showed severe necrosis or edema. According to the clinical value, the distal tibia of the hind paw, immediately adjacent to the ankle joint, was cut. The left and right hind paws were weighed and recorded respectively.
[611] The compounds of the present invention showed anti-inflammatory activity as a result of testing the assay.
[612] The invention has been described in more detail by way of description and examples in order to clarify the invention and to aid the understanding of the invention. It will be apparent to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should not be determined with reference to the above specification, but should be determined with reference to the appended claims and the full scope equivalent to which such claims are claimed.
[613] All patents, patent applications, and publications cited therein are hereby incorporated by reference in their entirety for the entire purpose to the same extent as they each individually mean.

权利要求:
Claims (44)
[1" claim-type="Currently amended] A compound selected from the group of compounds of formula (I), their precursors, individual isomers, mixtures of isomers or pharmaceutically acceptable salts:
Formula I

Where
R ¹ is hydrogen or acyl;
R ² is hydrogen or alkyl;
A is an aryl or heteroaryl ring;
B is an aryl or heteroaryl ring;
R ³ is
(a) amino, alkylamino or dialkylamino;
(b) acylamino;
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl;
(h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(l) optionally substituted heterocyclylalkynyl;
(m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) optionally substituted cycloalkylamino;
(r) -NHSO ₂ R ⁶ , wherein R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(s) -NHSO ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently of each other hydrogen, alkyl or heteroalkyl;
(t) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O-, -NH- or -S (O) _n- , where n is an integer from 0 to 2, and R ⁹ is cyano, optionally substituted heteroaryl, -COOH, -COR ¹⁰ , -COOR ¹¹ , -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or- NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹⁰ is alkyl or optionally substituted heterocycle, R ¹¹ is alkyl, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ is independently of each other hydrogen, alkyl or heteroalkyl);
(u) —C (═NR ²⁰ ) (NR ²¹ R ²² ), wherein R ²⁰ , R ²¹ and R ²² are independently hydrogen, alkyl or hydroxy, or R ²⁰ and R ²¹ together are — (CH ₂ ) _n -where n is 2 or 3 and R ²² is hydrogen or alkyl;
(v) -NHC (X) NR ²³ R ²⁴ , wherein X is -O- or -S- and R ²³ and R ²⁴ are independently of each other hydrogen, alkyl or heteroalkyl;
(w) -CONR ²⁵ R ²⁶ wherein R ²⁵ and R ²⁶ are independently of each other hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl or heterocyclyl optionally substituted with the nitrogen to which they are attached; To form a ring);
(x) -S (O) _n R ²⁷ where n is an integer from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, or -NR ²⁸ R ²⁹ wherein R ²⁸ and R ²⁹ are, independently from each other, hydrogen, alkyl, or heteroalkyl;
(y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, which are optionally substituted with alkyl, halo, hydroxy or amino;
(z) arylaminoalkylene or heteroarylaminoalkylene;
(aa) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² , wherein Z is -NH-, -N- (alkyl)-or -O-, and R ³⁰ , R ³¹ and R ³² Are independently of each other hydrogen, alkyl or heteroalkyl;
(bb) —OC (O) -alkylene-CO ₂ H or —OC (O) —NR′R ″ wherein R ′ and R ″ are independently hydrogen or alkyl;
(cc) heteroarylalkenylene or heteroarylalkynylene;
(dd) X- (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] where X is -O-, -NH-, -NR- (where , R is alkyl, or -S (O) _p- , where p is an integer from 0 to 2; R ⁴⁰ is acyl, C (O) OR ⁴¹ , wherein R ⁴¹ is hydrogen, alkyl or cyclo Alkyl), C (O) ONR ⁴¹ R ⁴² , wherein R ⁴¹ is as defined above and R ⁴² is hydrogen or alkyl, or C (O) NR ⁴¹ R ⁴² , wherein R ⁴¹ and R ⁴² Are as defined above; R 'and R "are independently hydrogen or alkyl; m and n are independently an integer from 0 to 3, provided that m and n are not simultaneously 0;
(ee) X- (alkylene) -CH (OH) CH ₂ NHR ⁵⁰ , wherein X is -O-, -NH-, -NR- (where R is alkyl) or S (O) _n- ( Wherein n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen or alkyl being);
(ff) X- (alkylene) -CH (NR ⁵⁰ ) -CH ₂ OH, wherein X is -O-, -NH-, -NR- (where R is alkyl) or S (O) _n- Where n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen or Alkyl)
Selected from the crowd consisting of;
R ⁴ is
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) alkoxy; And
(e) hydroxy
Selected from the crowd consisting of;
R ⁵ is
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino;
(j) heteroalkyl;
(k) optionally substituted heterocycle;
(l) optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;
(p) heteroalkoxy; And
(q) carboxy
Selected from the crowd consisting of;
R ⁶ is
(a) hydrogen;
(b) halo;
(c) alkyl; And
(d) alkoxy
It is chosen from a crowd consisting of.
[2" claim-type="Currently amended] The method of claim 1,
R ³ is
(a) optionally substituted heterocyclyl;
(b) halo, alkyl, amino, alkoxy, carboxy, lower alkoxy carbonyl, SO ₂ R 'where R' is alkyl, or SO ₂ NHR'R ", where R 'and R" are independently hydrogen Or alkyl; aryl or heteroaryl optionally substituted with a substituent selected from;
(c) heteroalkyl;
(d) heteroalkenyl;
(e) heteroalkylamino;
(f) heteroalkoxy;
(g) optionally substituted heterocyclylalkyl, heterocyclyloxy; Cycloalkoxy or cycloalkylalkyloxy;
(h) optionally substituted heterocyclylalkenyl;
(i) optionally substituted heterocyclylalkynyl;
(j) optionally substituted heterocyclylalkoxy;
(k) optionally substituted heterocyclylalkylamino or cycloalkylamino;
(l) optionally substituted heterocyclylalkylcarbonyl;
(k) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ^17, or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are mutually Independently hydrogen, alkyl or heteroalkyl);
(l) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, which are optionally substituted with alkyl, halo, hydroxy or amino;
(m) arylaminoalkylene or heteroarylaminoalkylene; or
(n) Z-alkylene-NR ³⁰ R ³¹ , wherein Z is -NH-, -N (alkyl)-or -O-, and R ³⁰ and R ³¹ are independently of each other hydrogen, alkyl or heteroalkyl Phosphorus compounds.
[3" claim-type="Currently amended] The method of claim 2,
R ¹ and R ² are hydrogen; B is phenyl.
[4" claim-type="Currently amended] The method of claim 3, wherein
A is phenyl.
[5" claim-type="Currently amended] The method of claim 4, wherein
R ⁴ is hydrogen; R ⁵ is halo or alkyl.
[6" claim-type="Currently amended] The method of claim 5,
R ⁵ is chloro, fluoro or methyl; R ⁶ is hydrogen, chloro, fluoro, methyl or methoxy.
[7" claim-type="Currently amended] The method of claim 5,
R ³ is optionally substituted heteroaryl.
[8" claim-type="Currently amended] The method of claim 7, wherein
Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yl, N-oxidopyridin-3-yl, N-oxido, wherein R ³ is optionally substituted Compounds that are pyridin-4-yl or pyridone-2-yl.
[9" claim-type="Currently amended] The method of claim 8,
R ³ is in the 3-position.
[10" claim-type="Currently amended] The method of claim 9,
R ⁵ is 4-F and R ⁶ is hydrogen.
[11" claim-type="Currently amended] The method of claim 9,
R ⁵ is 2-Me and R ⁶ is hydrogen.
[12" claim-type="Currently amended] The method of claim 5,
R ³ is optionally substituted phenyl.
[13" claim-type="Currently amended] The method of claim 12,
R ³ is 3-sulfamoylphenyl, 3-methylsulfonylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl.
[14" claim-type="Currently amended] The method of claim 13,
R ³ is in the 3-position.
[15" claim-type="Currently amended] The method of claim 14,
R ⁵ is 4-F and R ⁶ is hydrogen.
[16" claim-type="Currently amended] The method of claim 5,
R ³ is
(a) heteroalkyl;
(b) heteroalkoxy;
(c) heteroalkylamino;
(d) optionally substituted heterocyclylalkyl;
(e) optionally substituted heterocyclylalkoxy, cycloalkoxy or cycloalkylalkyloxy;
(f) optionally substituted heterocyclylalkylamino;
(g) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ^17, or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are mutually Independently hydrogen, alkyl or heteroalkyl); or
(h) Z-alkylene-NR ³⁰ R ³¹ wherein Z is -NH-, -N (alkyl)-or -O-, and R ³⁰ and R ³¹ are independently of each other hydrogen, alkyl or heteroalkyl Phosphorus compounds.
[17" claim-type="Currently amended] The method of claim 16,
R ³ is heteroalkyl.
[18" claim-type="Currently amended] The method of claim 17,
R ³ is in the 3-position, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1 A compound selected from the group consisting of -butyl or 3-hydroxybutyl.
[19" claim-type="Currently amended] The method of claim 18,
R ⁵ is 2-F and R ⁶ is 4-F.
[20" claim-type="Currently amended] The method of claim 18,
R ⁵ is 4-F and R ⁶ is hydrogen.
[21" claim-type="Currently amended] The method of claim 18,
R ⁵ is 2-Me and R ⁶ is hydrogen.
[22" claim-type="Currently amended] The method of claim 16,
R ³ is heteroalkoxy or heteroalkylamino.
[23" claim-type="Currently amended] The method of claim 22,
R ³ is in the 3-position, 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 2,2- (dihydroxymethyl) A compound selected from the group consisting of ethoxy, 2-dimethylaminoethylamino and 3-dimethylaminopropylamino.
[24" claim-type="Currently amended] The method of claim 23,
R ⁵ is 4-F or 2-Me and R ⁶ is hydrogen.
[25" claim-type="Currently amended] The method of claim 16,
R ³ is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy or optionally substituted heterocyclylalkylamino.
[26" claim-type="Currently amended] The method of claim 25,
R ³ is in the 3-position, 3- (morpholin-4-yl) propoxy, 2- (morpholin-4-yl) ethoxy, 2- (2-oxo-pyrrolidin-1-yl) Ethoxy, 3- (morpholin-4-yl) propyl, 2- (morpholin-4-yl) ethyl, 4- (morpholin-4-yl) butyl, 3- (morpholin-4-yl) propyl Amino, 3- (morpholin-4-yl) ethylamino, 4- (hydroxypiperidinylmethyl, 2- (S, S-dioxo-thiamorpholin-4-yl) ethyl, 3- (S, S-dioxo-thiamorpholin-4-yl) propyl and N-methylpiperazinylmethyl.
[27" claim-type="Currently amended] The method of claim 26,
R ⁵ is 4-F or 2-Me and R ⁶ is hydrogen.
[28" claim-type="Currently amended] The method of claim 25,
R ³ is in the 3-position, (2,2-dimethyl-1,3-dioxolan-4 (S) -yl) methoxy, (1,3-dioxolan-2-one-4 (R)- Yl) methoxy, (2-thioxo-1,3-dioxolan-4-yl) methoxy, (2,2-diethyl-1,3-dioxolan-4 (S) -yl) methoxy, (2,2-Diethyl-1,3-dioxolan-4 (S) -yl) methylamino and (2-methyl-2-ethyl-1,3-dioxolan-4 (S) -yl) methoxy Compound selected from the crowd consisting of.
[29" claim-type="Currently amended] The method of claim 28,
R ⁵ is 4-F or 2-Me and R ⁶ is hydrogen.
[30" claim-type="Currently amended] The method of claim 16,
R ³ is -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are Independently of one another are hydrogen, alkyl or heteroalkyl).
[31" claim-type="Currently amended] The method of claim 30,
Y is a single bond, and R ⁹ is SO ₂ R ¹⁴ or SO ₂ NR ¹⁵ R ¹⁶ .
[32" claim-type="Currently amended] The method of claim 31, wherein
R ³ is methylsulfonylethyl or sulfamoylethyl.
[33" claim-type="Currently amended] The method of claim 32,
R ⁵ is 4-F or 2-Me and R ⁶ is hydrogen.
[34" claim-type="Currently amended] The method of claim 1,
R ³ is
(a) -S (O) _n R ²⁷ where n is an integer from 0 to 2; R ²⁷ is alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, or -NR ²⁸ R ²⁹ , wherein R ²⁸ and R ²⁹ are, independently of each other, hydrogen, alkyl, or heteroalkyl;
(b) X- (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] where X is -O-, -NH-, -NR-, wherein , R is alkyl, or -S (O) _p- , where p is an integer from 0 to 2; R ⁴⁰ is acyl, C (O) OR ⁴¹ , wherein R ⁴¹ is hydrogen, alkyl or cyclo Alkyl), C (O) ONR ⁴¹ R ⁴² , wherein R ⁴¹ is as defined above and R ⁴² is hydrogen or alkyl, or C (O) NR ⁴¹ R ⁴² , wherein R ⁴¹ and R ⁴² Are as defined above; R 'and R "are independently hydrogen or alkyl; m and n are independently an integer from 0 to 3, provided that m and n are not simultaneously 0;
(c) X- (alkylene) -CH (OH) CH ₂ NHR ⁵⁰ , wherein X is -O-, -NH-, -NR-, where R is alkyl, or -S (O) _n -Wherein n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen Or alkyl);
(d) X- (alkylene) -CH (NR ⁵⁰ ) -CH ₂ OH, wherein X is -O-, -NH-, -NR (where R is alkyl), or -S (O) _n -Wherein n is an integer from 0 to 2; R ⁵⁰ is C (O) OR ⁵¹ and C (O) NR ⁵¹ R ⁵² , wherein R ⁵¹ is hydrogen, alkyl or cycloalkyl, and R ⁵² is hydrogen Or alkyl).
[35" claim-type="Currently amended] The method of claim 34, wherein
R ³ is in the 3-position,
X (alkylene) CH [(CR'R ") _m OR ⁴⁰ ] [(CR'R") _n OR ⁴⁰ ] where X is -O-, -NH-, -NR- (where R is alkyl Is -S (O) _p- , where p is an integer from 0 to 2; R ⁴⁰ is acyl, C (O) OR ⁴¹ , wherein R ⁴¹ is hydrogen, alkyl or cycloalkyl, C (O) ONR ⁴¹ R ⁴² , wherein R ⁴¹ is as defined above and R ⁴² is hydrogen or alkyl, or C (O) NR ⁴¹ R ⁴² , wherein R ⁴¹ and R ⁴² are as defined above R 'and R "are independently hydrogen or alkyl; m and n are independently an integer from 0 to 3, provided that m and n are not 0 at the same time.
[36" claim-type="Currently amended] 36. The method of claim 35 wherein
R ³ is in the 3-position and is selected from the group consisting of (diacetoxy) propoxy, (diisobutanoyloxy) propoxy and (dipivaloyloxy) propoxy, (dimethoxycarbonyloxy) propoxy compound.
[37" claim-type="Currently amended] The method of claim 36,
R ⁴ is hydrogen, R ⁵ is 4-F or 2-Me, and R ⁶ is hydrogen.
[38" claim-type="Currently amended] The method of claim 37,
R ¹ and R ² are hydrogen and A and B are phenyl.
[39" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable excipient.
[40" claim-type="Currently amended] A method of treating a disease in a mammal that is treatable by administration of a p38 MAP kinase inhibitor comprising administering to the mammal a therapeutically effective amount of the compound of claim 1.
[41" claim-type="Currently amended] The method of claim 40,
The method of treatment wherein the disease is an inflammatory disease.
[42" claim-type="Currently amended] 42. The method of claim 41 wherein
Method of treatment, in which the disease is arthritis.
[43" claim-type="Currently amended] (i) reacting 2-keto-3-phenylaminoacrylonitrile of Formula 1 with hydrazine of Formula 2 to provide a compound of Formula I wherein R ¹ is hydrogen;
(ii) reacting 2-keto-3-phenylaminoacrylonitrile of Formula 3 with hydrazine of Formula 2 to provide a compound of Formula 4, and then converting the Z group of Formula 4 to the desired R ³ group Providing a compound of formula I wherein ¹ is hydrogen;
(iii) optionally modifying any R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ group;
(iv) optionally treating the compound of formula (I) prepared in step (i), (ii) or (iii) with an acid to convert to the corresponding acid addition salt;
(v) optionally treating the compound of formula (I) prepared in step (i), (ii) or (iii) with a base to convert to the corresponding free base;
(vi) optionally separating the stereoisomeric mixtures of the compounds of formula (I) prepared in steps (i) to (v) to provide one stereoisomer,
A process for preparing a compound of formula (I) selected from the compounds of claim 1:




Where
R ³ , R ⁴ , R ⁵ or R ⁶ are as defined in claim 1,
Z is a hydroxy, nitro or halo group.
[44" claim-type="Currently amended] (i) a compound of Formula 5 Reacting with an organometallic reagent of which M is a metal moiety to provide a compound of formula I wherein R ¹ is hydrogen;
(ii) optionally modifying any R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ group;
(iii) optionally treating the compound of formula (I) prepared in step (i) or (ii) with an acid to convert to the corresponding acid addition salt;
(iv) optionally converting the compound of formula (I) prepared in step (i) or (ii) with a base to convert to the corresponding free base;
(v) optionally separating the stereoisomeric mixtures of the compounds of formula (I) prepared in steps (i) to (iv) to provide one stereoisomer,
A process for preparing a compound of formula (I) selected from the compounds of claim 1:

Where
L is a leaving group under the organometallic substitution reaction conditions,
R ³ , R ⁴ , R ⁵ or R ⁶ are as defined in claim 1.

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同族专利:

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JP2003509495A|2003-03-11|

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MXPA02002382A|2002-08-20|

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BR0014225A|2002-05-21|

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WO2001021591A1|2001-03-29|

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TR200200778T2|2002-06-21|

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EP1218346A1|2002-07-03|

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CA2385447A1|2001-03-29|

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US6316466B1|2001-11-13|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-09-22|Priority to US09/401,141

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1999-09-22|Priority to US09/401,141

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2000-09-14|Application filed by 프리돌린 클라우스너, 롤란드 비. 보레르, 에프. 호프만-라 로슈 아게

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2000-09-14|Priority to PCT/EP2000/008981

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2002-04-22|Publication of KR20020030124A

优先权:

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申请号 | 申请日 | 专利标题

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US09/401,141|US6316466B1|1998-05-05|1999-09-22|Pyrazole derivatives P-38 MAP kinase inhibitors|

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US09/401,141|1999-09-22|

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PCT/EP2000/008981|WO2001021591A1|1999-09-22|2000-09-14|Pyrazole derivatives|