Pyrrolo [2,3-b] pyridines and pyrrolo [2,3-b] pyrimidines substituted with heteroaryl as Janus kinas

专利摘要:

公开号:ES2543904T9
申请号:ES11152708.1T
申请日:2006-12-12
公开日:2017-05-29
发明作者:James D. Rodgers；Stacey Shepard；Thomas P. Maduskuie；Haisheng Wang；Nikoo Falahatpisheh；Maria Rafalski；Argyrios G. Arvanitis；Louis Storace；Ravi Kumar Jalluri；Jordan S. Fridman；Krishna Vaddi
申请人:Incyte Holdings Corp；
IPC主号:

专利说明:

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In some embodiments, p is 0.
In some embodiments, p is 1. 5 In some embodiments, p is 2.
In some embodiments, q is 0.
10 In some embodiments, q is 1.
In some embodiments, q is 2.
In some embodiments, one of p and q is 0 and the other of p and q is 1, 2 or 3.
In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2- alkynyl 4, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C (O) Rb, C (O) NRcRd, C (O) ORn, OC (O) b , OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORe, C (= NRi) NRcRd, NRcC (= NRi) NRcRd,
20 S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (Q) 2Rb and S (O) 2NRcRd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C14 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C (O) Rb, C (O) NRcRd, C (O) ORa,
OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRc = C (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O ) 2Rb, NRcS (O) 2Rb and S (O) 2NRcRd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1 haloalkyl
30 4, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O ) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb and S (O ) 2NRcRd.
In some embodiments, Z is 5 or 6 membered phenyl or heteroaryl, each optionally substituted.
35 with 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1 , CN, NO2, ORa, SRa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O ) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb and S (O) 2NRcRd.
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1 hydroxyalkyl -4, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb and S (O) 2NRcRd.
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1 haloalkyl -4, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O ) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb,
50 NRcS (O) 2Rb and S (O) 2NRcRd.
In some embodiments, Z is substituted with at least one substituent comprising at least one CN group.
In some embodiments, Cy1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, haloalkyl C1-4, CN, NO2, ORa "SRa", C (O) Rb ", C (O) NRc" Rc ", C (O) ORa", OC (O) Rb ", OC (O) NRc" Rd ", NRc" Rd ", NRc" C (O) Rb ", NRc" C (O) ORa ", S (O) Rb", S (O) NRc "Rd", S (O) 2Rb "and S ( O) 2NRc "Rd".
In some embodiments, Cy1 is independently selected from cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN , NO2, ORa ", SRa", C (O) Rb ", C (O) NRc" Rd ", C (O) ORa", OC (O) Rb ", OC (O) NRc" Rc "Rd", NRc "Rd", NRc "C (O) Rb", NRc "C (O) ORa", S (O) Rd ", S (O) NRc" Rd ", S (O) 2Rb" and S (O) 2NRc "Rd".
In some embodiments, R5 is H, halo, C1-4 alkyl, C1-4 haloalkyl, halosulfanyl, CN or NR9R10.
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In some embodiments, the compound has Formula IV:
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In some embodiments, the compound has Formula Va:
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In some embodiments, the compound has Formula Vb:
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In some embodiments, the compound has Formula VIa:
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In some embodiments, the compound has Formula VIb:
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suitable for providing the protected compound 1-7, which is subsequently subjected to a Suzuki coupling with a boric acid 1-8 to provide the 1-9a nuclei containing pyrazole which can further react with the reagent L- (Y) nZ ( wherein L is a leaving group) to give the compounds of the invention 19b. Alternatively, the N-oxide 1-2 can be halogenated with a halogenating agent, such as MeSO2Cl to form a 4-halo 1-4 compound, such as a 4-chloro compound while the N-oxide is reduced at the same time. . The 4-halo 1-4 compound may be coupled to a bromine compound substituted with bromine 1-5 under suitable conditions, such as heating to provide the pyrazole-containing core 1-6, which may contain some functional groups, such as bromine. or cyano suitable for additional chemical modification.
Similarly, an imidazole 1-11 core can be synthesized by coupling the 4-halo 1-4 compound in an imidazole 1-10 derivative under suitable conditions, such as heating to provide the imidazole 1-11 containing core, which It may contain some functional groups, such as bromine or cyano suitable for further chemical modification.
Scheme 1
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As shown in Scheme 2, nuclei 2-3, 2-5 and 2-6 containing pyrazole can be synthesized from a bromine derivative substituted with bromine 2-1 (a compound 1-6 in Scheme 1 in which one of R5 is Br). The bromine derivative substituted with bromine 2-1 can be coupled to an aromatic species containing boron, such as a 2-2 aromatic boric acid using Suzuki coupling, in which Ar is aryl or heteroaryl, each of which may be optionally substituted with one or more substituents, such as alkyl, aryl, CN, nitro, alkoxy, etc. Alternatively, a compound containing alkene or alkyne, such as a compound containing alkene 2-5 can be obtained by coupling the pyrazol derivative substituted with bromine 2-1 to an unsaturated compound, such as an alkene 2-4 in the presence of a metal catalyst, such as bis (triphenylphosphine) palladium (II) chloride in which t can be 0.1, 2 and the like; and R may be a substituent, such as alkyl, aryl, CN, nitro, alkoxy, etc. The alkene group of compound 2-5 can be reduced by hydrogenation to
65 provide the corresponding compound 2-6.


Scheme 2
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As shown in Scheme 3, nuclei containing imidazole 3-7 can be synthesized by starting
of an N-protected 4-bromo-pyrrolo [2,3-b] pyridine or a 3-1 N-protected pyrimidine [2,3-b] pyrimidine in which P
it is a suitable amine protecting group, such as {[2- (trimethylsilyl) ethoxy] methyl} (SEM). Compound 3-1 can
30 reacted with a Grignard reagent, such as isopropyl magnesium chloride to generate an aromatic anion through ion exchange. Subsequent addition of a chloroacetyl-containing compound, such as 2-chloro-N-methoxy-N-methylacetamide 3-2 to the anion will typically provide the 3-3 chloroacetyl derivative. Derivative 3-3 can be reacted with an organic acid salt, such as a cesium salt R5CO2Cs to provide a compound 3-4. In the presence of a suitable ammonia source, such as ammonium acetate, the
Compound 3-4 can react with ammonia under suitable conditions, such as at a high temperature to form the imidazole ring of compound 3-5. The amine-free nitrogen of the imidazole derivative 3-5 may undergo further modification, such as reacting with a compound X- (Y) nZ, wherein X is a leaving group such as chlorine, bromine or iodine in order to provide compound 3-6. The protecting group of compound 3-6 can be removed by an appropriate procedure according to the nature of the protecting group for
40 produce compound 3-7. It should be noted that if there are functional groups present in the group R, R5 and - (Y) n-Z, a further modification can be made. For example, a CN group can be hydrolyzed to provide an amide group; a carboxylic acid can be converted into an ester, which, in turn, can be further reduced to give an alcohol, which, in turn, can be further modified. One skilled in the art will recognize additional appropriate modifications.
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Scheme 3
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As shown in Scheme 4, nuclei containing thiazole 4-3 can be synthesized from
a 4-1 N-protected chloroacetyl derivative in which P is a suitable amine protecting group, such as SEM. He
compound 4-1 can be reacted with a thioamide 4-2 to form the thiazole ring followed by deprotection
25 of the amine nitrogen of the pyrrole ring by removing the group P to provide compound 4-3. Various thioureas 4-5 (equivalent to compound 4-2 can be made in which - (Y) nZ is NR'R "; and R 'and R" are H, alkyl, aryl or the like; or R' and R "together with the N atom to which they are attached form a heterocycloalkyl) useful in the preparation of thiazole compounds 4-3 from secondary amines 4-4. A secondary amine 4-4 can be reacted with 1,1'- thiocarbonyldiimidazole; and the resulting intermediate can be reacted
30 additionally with ammonia to provide a thiourea 4-5.
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As shown in Scheme 5, nuclei containing thiazole 5-5 can be synthesized from
a thiazole compound 5-1. Compound 5-1 can be reacted with a metal alkyl, such as n-butyllithium.
through ion exchange to generate an aromatic anion in situ. The subsequent addition of trimethyl acid ester
Boric followed by hydrolysis will typically provide boric acid 5-2. Boric acid 5-2 can undergo Suzuki coupling with an N-protected 4-bromo-pyrrolo [2,3-b] pyridine or a 5-3-protected bromo-pyrrolo [2,3-b] pyrimidine in the that P is a suitable amine protecting group, such as SEM. The protecting group P of the coupling product 5-4 can be removed by an appropriate method according to the nature of the protecting group to produce the compound of the invention 5-5.
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Scheme 5
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6-1 in which P is a suitable amine protecting group, such as SEM can be reacted with L- (Y) nZ, in which L represents a leaving group, such as halo, triflate or the like to provide compound 6 -2 in
30 basic conditions. If there are several functional groups present in the Y and / or Z group, an additional modification can be made. For example, a CN group can be hydrolyzed to provide an amide group; a carboxylic acid can be converted into an ester, which, in turn, can be reduced to give an alcohol. One skilled in the art will recognize the additional modifications, when appropriate. In addition, compound 6-1 can be reacted with alkene 6-3 (where R 'and R "can be H, alkyl,
Cycloalkyl and the like; and Z 'can be an electron acceptor group, such as an ester or CN) to provide compound 6-4. In addition, the substitution can be made on alkene 6-3 in the alpha position (alpha with respect to Z ') to generate a substituted derivative of the product, 6-4 (see, for example, Example 68). Compounds 6-2 and 6-4 can be deprotected by appropriate procedures according to the nature of the protecting group used to provide their corresponding unprotected counterpart.
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Scheme 8
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As shown in Scheme 9, the 1,2,4-oxadiazole compound 9-6 can be prepared from the N-protected bromine compound 9-1 by treatment with zinc cyanide in DMF in the presence of a catalyst, such 15 as bis (tributyl) palladium to give the N-protected cyano compound 9-2. The N-hydroxy carboximidamide 9-3 compound can be prepared by heating the N-protected cyano compound 9-2 with hydroxylamine hydrochloride in an appropriate solvent, such as ethanol and a base, such as potassium carbonate at a temperature below the point boiling solvent. The N-protected 1,2,4-oxadiazole compound can be prepared by treating the N-hydroxy carboximidamide 9-3 compound with an acid chloride compound
Properly substituted 9-4 in a solvent, such as pyridine at a temperature sufficient to complete the closure of the ring. If there are several functional groups present in the Y and / or Z group, an additional modification can be made. For example, a CN group can be hydrolyzed to provide an amide group; a carboxylic acid can be converted into an ester, which, in turn, can be reduced to give an alcohol. A person skilled in the art will recognize additional modifications when appropriate.
25 Scheme 9
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As shown in Scheme 10, the 3-and 4-arylpyrazolo compounds 10-9 can be prepared by reacting the respective 3-arylpyrazolo compound 10-4 or the 4-aryl pyrazolo compound 10-7 with a bromine compound appropriately substituted 10-8, as previously described. The 3-aryl pyrazolo 10-4 compound can be prepared by reacting an appropriately substituted aryl group containing a halogen, such as bromine or a triflate with the N-protected boronic acid compound or 10-2 boronic acid pyrazole ester in
55 conditions similar to Suzuki known in the literature. The N-protecting group of 10-3 can be removed by conditions previously described and known in the literature to eliminate groups, such as SEM.
The 4-arylpyrazolo compounds 10-7 can be prepared by reacting the compound of
Properly substituted acetophenone 10-5 with DMF acetal in DMF at elevated temperatures to give the dimethylamino compound 10-6. The 4-arylpyrazolo 10-7 compounds can be prepared by treating the dimethylamino compound 10-6 with hydrazine in a solvent, such as ethanol.
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1H NMR (400 MHz, CDCl3): δ 9.7 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.7 (1H, s); 7.59 (1H, t); 7.4 (1H, d); 7.35 (1H, t); 7.21 (1H, d); 6.75 (1H, d); 6.25 (1 H, m); 4.4 (1 H, m); 3.9-4.15 (2H, m); 2.55 (2H, m); 1.63 (3H, d). MS (M + H) +: 306.
The following compounds in Table 1 were manufactured by procedures analogous to the 5 procedures indicated above. "Purification A" indicates that the product followed by deprotection was purified by preparative HPLC under the following conditions: C18 eluting with a gradient of MeCN / H2O containing 0.15% NH4OH.
Table 1
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Ex. Nº. StructureNameMS (M + H)Ex Prep. No.
4 image44 1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1-pyrazol-4-carboxylic acid ethyl ester 256 1
5 image45 4- (3-Methyl-4-phenyl-pyrazol-1-yl) -1 H -pyrrolo [2,3-b] pyridine 274 1
6 image46 4- (3-Phenyl-pyrazol-1-yl) -1H-pyrrolo [2,3-b] pyridine 260 1
7 4- (4-Bromo-imidazol-1-yl) -1H-pyrrolo [2,3-b] pyridine26213
8 4- (4-Bromo-3-methyl-pyrazol-1-yl) -1H-pyrrolo [2,3-b] pyridine262one

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Ex. Nº. StructureNameMS (M + H)Ex Prep. No.
9 3- [3-Methyl-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] -benzonitrile299one
10 4- [3-Methyl-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] -benzonitrile299one
16 4- [4- (3-Fluoro-phenyl) -3-methyl-pyrazol-1-yl] -1H-pyrrolo [2,3-b] pyridine292one
17 4- [4- (3,5-Bis-trifluoromethyl-phenyl) -3-methyl-pyrazol-1-yl] 1 H -pyrrolo [2,3-b] pyridine410one
18 4- [4- (3,5-Difluoro-phenyl) -3-methyl-pyrazol-1-yl] -1H-pyrrolo [2,3-b] pyridine310one

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Ex. Nº. StructureNameMS (M + H)Ex Prep. No.
19 {3- [3-Methyl-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] phenyl} -methanol304one
twenty 4- (3-Methyl-4-pyrimidin-5-yl-pyrazol-1-yl) -1H-pyrrolo [2,3-b] pyridine276one
twenty-one image47 4- [3-Methyl-4- (1-methyl-1H-indol-5-yl) -pyrazol-1-yl] -1H-pyrrolo [2,3-b] pyridine 327 1
22 4- (3-Methyl-4-thiophene-3-yl-pyrazol-1-yl) -1H-pyrrolo [2,3-b] pyridine280one
2. 3 N, N-Dimethyl-4- [3-methyl-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpyrazol-4-yl] -benzenesulfonamide381one

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Ex. Nº. StructureNameMS (M + H)Ex Prep. No.
24 N- {4- [3-Methyl-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] -phenyl} -acetamide331one
26 3-tert-Butyl-1- (1H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazole-4carbonitrile265one
27 4-Bromo-1- (1H-pyrrolo [2,3-b] -pyridin-4-yl) -1H-pyrazol-3carbonitrile287one
28 4- (3-Cyano-phenyl) -1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpyrazol-3-carbonitrile310one
29 3- [1- (1 H-Pyrrolo [2,3-b] pyridin-4-yl) -3-trifluoromethyl-1 Hpyrazol-4-yl] -propan-1-ol254one
30 3- [3-Methyl-1- (1H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazol-4-yl] prop-2-en-1-ol310one

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Ex. Nº. StructureNameMS (M + H)Ex Prep. No.
31 2- [4-Bromo-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-3-yl] -isoindolo-1,3-dione408one
32 4- [4- (2,6-Dimethyl-phenyl) -3-methyl-pyrazol-1-yl] -1H-pyrrolo [2,3-b] pyridine302one
33 image48 3- [3-Amino-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol 4-yl] -benzonitrile 300 1
3. 4 image49 3- [3-Benzylamino-1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpyrazol-4-yl] -benzonitrile 390 1.15
35 N- [4- (3-Cyano-phenyl) -1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpirazol-3-yl] -acetamide3421.14
36 3- [4- (1H-Pirrolo [2,3-b] pyridin-4-yl) -pyrazol-1-yl] -propan1-ol24258 Purification A

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Ex. Nº. StructureNameMS (M + H)Ex Prep. No.
37 3- [4- (1H-Pirrolo [2,3-b] pyridin-4-yl) -pyrazol-1-yl] -butan-1ol25658 Purification A
38 image50 4- [4- (1H-Pyrrolo [2,3-b] pyridin-4-yl) -pyrazol-1-yl] pentanonitrile 265 59 Purification A
39 image51 4- [4- (1H-Pyrrolo [2,3-b] pyridin-4-yl) pyrazol-1-yl] -pentanoic acid amide 283 60 Purification A
41 4- [1- (3-Imidazol-1-yl-1-methyl-propyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridine30642
43 4-Cyclopentyl-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -pyrazol-1-yl] -butyronitrile31959 Purification A


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44 4-Cyclopentyl-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) pyrazol-1-yl] -butyramide33760 Purification A
Four. Five 3-Cyclopropyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -propionitrile27961 Purification A
Example 46: 4- (2-tert-Butyl-1-methyl-1 H -imidaxol-4-yl) -1 H -pyrrolo [2,3-b] pyridine trifluoroacetate salt
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Step 1. 4- (2-tert-Butyl-1H-imidazol-5-yl) -1- [2- (trimethylsilyl) ethoxy] methyl-1H-pyrrolo [2,3-b] pyridine
To a solution of trimethylacetic acid (0.169 ml, 0.00147 mol) in ethanol (6 ml, 0.1 mol) was added
cesium carbonate (0.24 g, 0.00073 mol) and the resulting mixture was stirred for 2 hours. The solvent was removed at
empty, providing cesium pivalate.
To a solution of 2-chloro-1- (1- [2- (trimethylsilyl) ethoxy] methyl-1 H -pyrrolo [2,3-b] pyridin-4-yl) ethanone (prepared, for example, as in the Ex. 50, Step 1) (0.054 g, 0.00017 mol) in DMF (1.8 ml, 0.023 mol), cesium pivalate (0.0389 g, 0.000166 mol) was added and the reaction was stirred at room temperature for 16 hours. Ammonium acetate (0.45 g, 0.0058 mol) was added and the reaction was heated in the microwave at 170 ° C for 5 minutes. Water was added and the product was extracted with MTBE. The combined organic extracts were dried over sodium sulfate and then filtered and concentrated. The crude residue was purified by flash column chromatography (2.5% MeOH / DCM), yielding 4- (2-tert-butyl-1H-imidaxol-5-yl) -1- [2- (trimethylsilyl) ethoxy ] methyl-1H-pyrrolo [2,3b] pyridine (32 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 8.31 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.37 (d, 1H), 6.94 ( d, 1H), 5.69 (s, 2H), 3.52
55 (dd, 2H), 1.46 (s, 9H), 0.90 (dd, 2H), -0.08 (s, 9H); MS (ES): 371 (M + 1).
Step 2. 4- (2-tert-Butyl-1-methyl-1H-imidazol-4-yl) -1- [2- (trimethylsilyl) ethoxy] methyl-1H-pyrrolo- [2,3-b] pyridine
To a mixture of 4- (2-tert-butyl-1 H -imidazol-5-yl) -1- [2- (trimethylsilyl) ethoxy] methyl-1 H -pyrrolo [2,3-b] pyridine (0.019 g, 0 , 000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in DMF (3 ml, 0.04 mol) was added in two portions methyl iodide (0.01 ml, 0.00015 mol) during 48 hours. Then, water was added and the product was extracted with MTBE. The combined extracts were dried with sodium sulfate, filtered, concentrated in vacuo and then purified by chromatography on silica gel (20% ethyl acetate / hexanes) to provide 4- (2-tert-butyl-1-methyl-1H -imidazol-4-yl) -1- [2- (trimethylsilyl) ethoxy] methyl-1 H -pyrrolo [2,3-b] pyridine (10 mg, 51%).
65 1H NMR (400 MHz, CDCl3): δ 8.37 (d, 1H), 7.54 (d, 1H), 7.44-7.22 (m, 2H), 7.19 (d, 1H) , 5.78 (s, 2H), 3.93 (s, 3H), 3.60 (dd, 2H), 1.61 (s, 9H), 0.98 (dd, 2H), 0.00 ( s, 9H); MS (ES): 385 (M + 1).
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Table 4
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Ex. Nº NameRMS (ES) (M + 1)Preparation and chiral separation procedure
62 3- [4- (1H-Pyrrolo [2,3-b] pyridin-4-yl) 1H-pyrazol-1-yl] propanonitrile trifluoroacetate saltH238Ex 61
63 (3S) -3- [4- (1H-pyrrolo [2,3-b] pyridin4-yl) -1H-pyrazol-1-yl] hexanonitrile trifluoroacetate salt and trifluoroacetate (3R) -3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] hexanonitrilePr280Ex. 61 Procedure B
64 trifluoroacetate salt of (3S) -3-cyclopentyl-3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -propanonitrile and trifluoroacetate salt of (3R) - 3-cyclopentyl-3- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazol-1-yl] -propanonitrile306Ex. 61 Procedure C
64th (35) -3-cyclohexyl-3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpyrazol-1-yl] -propanonitrile and (3R) -3-cyclohexyl-3- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazol-1-yl] -propanonitrile320Ex. 61 Procedure D
Example 65: Trifluoroacetate salt of (3R) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] hexanonitrile and trifluoroacetate salt of (3S) - 3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] hexanonitrile
35
Four. Five
Step 1. 4-Chloro-7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidine
To a solution of 4-chloropyrrolo [2,3-d] pyrimidine (0.86 g, 0.0056 mol) in DMF (20 ml, 0.2 mol) at 0 ° C was added in several portions sodium hydride (0 , 27 g, 0.0067 mol). The reaction mixture was stirred for a further 45 minutes followed by a dropwise addition of β- (trimethylsilyl) ethoxy] -methyl chloride (1.2 ml, 0.0067 mol). The resulting reaction mixture was stirred at 0 ° C for 45 min, then quenched with water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and concentrated, giving an oil. The crude residue was purified by flash column chromatography (0-15% ethyl acetate / hexanes), yielding 4-chloro-7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d ] pyrimidine (1.40 g, 88%).
1 H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H), 5.71 (s, 2H), 3.59 (dd, 2H), 0.97 (dd, 2H), 0.00 (s, 9H); MS (ES): 284 (M + 1).
Step 2. 4- (1H-Pirazol-4-yl) -7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidine
To a mixture of 4-chloro-7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidine (1.4 g, 0.0049 mol) and 4 (4.4.5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.4 g, 0.0074 mol) in DMF (40 ml, 0.5 mol) was added potassium carbonate (2 , 0 g, 0.015 mol) in 15 ml of water. The mixture was purged with a continuous stream of nitrogen for 15 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.41 g, 0.00036 mol) was added and the reaction was heated at 125 ° C for 30 min. The mixture was allowed to cool and then diluted with ethyl acetate. The diluted reaction mixture was washed with water and brine, dried over Na2SO4 and concentrated, giving a solution in a small volume of DMF (approximately 2-3 ml). Water was added, causing the material to form a rubber on the
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Table 5
5
fifteen
25
35
Ex. Nº NameR ', R "MS (ES) (M + 1)Preparation and chiral separation procedure
66 trifluoroacetate salt of (3R) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanonitrile and trifluoroacetate salt of (3S) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] butanonitrileMe, h253Example 65, Procedure A
67 (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] propanonitrile and (3S) -3-cyclopentyl-3 - [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile307Example 67
68 2-methyl-3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetate saltH, Me253Example 65, Not Separated
68th (3R) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] pentanonitrile and (3S) -3- [4- (7H-pyrrolo [2 , 3-d] pyrimidin4-yl) -1 H -pyrazol-1-yl] pentanonitrileEt, H267Example 65, modification G, Procedure E
68b (3R) -5-methyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1Hpyrazol-1-yl] hexanonitrile and (3S) -5-methyl-3- [ 4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] hexanonitrile295Example 65, modification G, Procedure A
68c (3R) -3-cyclohexyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] propanonitrile and (3S) -3-cyclohexyl-3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile321Example 65, modification G, Procedure A
68d (3R) -4-cyclopropyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] butanonitrile and (3S) -4-cyclopropyl-3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanonitrile279Example 65, modification G, Procedure F
Example 69: 4- {1 - [(1 S) -1-methylbutyl] -1H-pyrazol-4-yl} -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetate salt and 4- {1- trifluoroacetate salt [(1R) -1-methylbutyl] -1H-pyrazol-4-yl} -7H-pyrrolo [2,3-d] pyrimidine
Four. Five
55
A solution of 4- (1 H -pyrazol-4-yl) -7- [2- (trimethylsilyl) ethoxy] methyl-7 H -pyrrolo [2,3-d] -pyrimidine (0.050 g, 0.00016 mol) in DMF (2 ml, 0.02 mol) was cooled in an ice bath and sodium hydride (0.013 g, 0.00032 mol) was added thereto. The resulting mixture was stirred for 10 minutes followed by an addition of 2-bromopentane (0.030 ml, 0.00024 mol). Then, the cooling bath was removed and the reaction was stirred at room temperature for 3 hours, at which time a portion more than 2-bromopentane (0.015 ml, 0.00012 mol) was added. After 45 minutes, water was added and the reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was stirred with TFA (3 ml, 0.04 mol) and DCM (3 ml, 0.05 mol) for 3.5 hours and then the solvent was removed in vacuo. Then, the residue was stirred with NH4OH (1.5 ml) in MeOH (4 ml) for 16 hours. The solvent was evaporated and the
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Table 5c
Ex. Nº NameRMS (ES) (M + 1)Preparation Procedure
79 5-methyl-3- [5- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,3-thiazol-2-yl] hexanonitrile312Ex 77
80 3-pyridin-3-yl-3- [5- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1,3thiazol-2-yl] -propanonitrile image72 333 Ex. 78
81 3- (5-bromopyridin-3-yl) -3- [5- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1,3thiazol-2-yl] propanonitrile411,413Ex 77
82 5-2-cyano-1- [5- (7H-pyrrolo [2,3d] -pyrimidin-4-yl) -1,3-thiazol-2-yl] ethylnicotinonitrile image73 358 Ex. 77 to Stage 4, then Ex. 431 excluding purification, then Ex. 77, Stage 5
83 3- [5- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1,3-thiazol-2-yl] butanonitrileI270Ex. 86, Stage 3 subject to the conditions of Ex. 77, Stages 4 to 5
83A 3-pyridin-4-yl-3- [5- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,3thiazol-2-yl] propanonitrile image74 333 Ex. 78
83B 4-2cyano-1- [5- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,3-thiazol-2-yl] ethylpyridine-2-carbonitrile trifluoroacetate salt image75 358 Ex. 77 to Step 3, then Ex. 431 excluding purification, then Ex. 78, purified by prep./EM HPLC using H2O / ACN containing 0.1% TFA
83C 3-pyridin-2-yl-3- [5- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1,3thiazol-2-yl] -propanonitrile image76 333 Ex. 78
Example 84: (2S) -y (2R) -2- [5- (7H-Pirrolo [2,3-d] pyrimidin-4-yl) -1,3-thiazol-2-yl] pentane-nitrile
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Stage 1. (2S) -y (2R) -2- [5- (7- [2- (Trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1.3 -thiazol-2-yl] pentanonitrile
To a mixture of 1- [5- (7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,3-thiazol-2-yl] butan -1-one (prepared as in Example 77) (101 mg, 0.251 mmol) and p-tolylsulfonyl methyl isocyanide (147 mg, 0.753 mmol) in a mixture of DMSO (5.0 ml) and ethanol (61 µl ) 1.0 M potassium tert-butoxide in THF (753 µl) was added. Then, the mixture was heated at 45 ° C for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of saturated ammonium chloride, followed by water. The product was extracted with
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Table 5e
Ex. Nº StructureNameMS (M + H)Prep. Ex. Nº
94 5,5-Dimethyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -hexanonitrile30861 modification G
95 4- [1- (2-Methanesulfonyl-ethyl) -1H-pyrazol-4-yl] -7Hpyrrolo [2,3-d] pyrimidine29161 modification G
96 5,5,5-Trifluoro-4- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -pentanonitrile32059 modification G
Example 97: 3- (2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl) cyclopentane-carbonitrile trifluoroacetate
Stage 1: 3- (Dimethoxymethyl) cyclopentanecarbaldehyde
In a 3-round round bottom flask, 2-norbornene (5,500 g, 0.05841 mol) was dissolved in DCM (198.0 ml) and methanol (38.5 ml) and cooled to -78 ° C. Ozone was passed through the reaction until it turned blue and stirred at -78 ° C for 30 minutes. Then, nitrogen was passed through for 20 minutes and ptoluenesulfonic acid (0.95 g, 0.0055 mol) was added. The reaction was allowed to warm to 20 ° C and stirred for 90 minutes. To the reaction was added sodium bicarbonate (1.67 g, 0.0199 mol) and the resulting mixture was stirred at 20 ° C for 30 minutes and dimethyl sulfide (9.4 ml, 0.13 mol) was added. The reaction was stirred for 16 hours and reduced by rotary evaporation to give ~ 50 ml. The reaction was extracted with DCM, the organic extracts were washed with water and brine, dried (MgSO4) and removed in vacuo. The reaction was distilled at 135 ° C (bath temperature) at high pump vacuum, giving the product (7.5 g) as a ~ 2: 1 mixture of diastereomers. 1H NMR (300 MHz, CDCl3): 9.64 and 9.62 (d, 1H), 4, 15 and 4.12 (s, 1H), 3.35 and 3.34 (s, 6H), 2, 77 m, 1H), 2.34 (m, 1H), 1.35-2.00 (m, 6H).
Stage 2. (2E, Z) -3- [3- (Dimethoxymethyl) cyclopentyl] acrylonitrile
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1H), 8.98 (s, 1H), 8.57 (s, 1H), 8.31 (d, 1H, J = 7.0), 8.08 (s, 1H), 7.89 (d , 1H, J = 10), 7.66 (d, 1H, J = 10), 7.63 (m, 1H), 7.55 (d, 1H), 7.07 (m, 1H), 2, 4 (s, 3H).
Additional exemplary compounds are provided in Tables 7, 8, 9, 10 and 11 indicated below. The compounds listed in Tables 7, 8, 9, 10 and 11 are racemic unless the enantiomers are indicated separately.
Table 7 Table 8 Table 9 (continued) Table 10 (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) Table 11 (continued) (continued) (continued) (continued) (continued) ( continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued)
Ex. Nº RMS (M + H) +NamePreparation
101 2392- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -4,5,6,7 tetrahydro-2H-indazoleEx 100
102 2805-nitro-2- (1H-pyrrolo [2,3-b] -pyridin-4-yl) 2H-indazolEx 100
103 2806-nitro-2- (1H-pyrrolo [2,3-b] -pyridin-4-yl) 2H-indazolEx 100
104 2863- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1Himidazol-4-yl] -benzonitrileEx 100
105 2914- [4- (3-Methoxyphenyl) -1H-imidazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 100
108 2774- (5-phenyl-2-thienyl) -1H-pyrrolo [2,3b] pyridineEx 107
Ex. Nº - (Y) n-ZMS (M + H) +NamePreparation
121 2794- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 120
122 3064- [3- (3-nitrophenyl) -1H-pyrazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 120
123 2954- [3- (4-chlorophenyl) -1H-pyrazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 120
124 2914- [3- (4-methoxyphenyl) -1H-pyrazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 120
125 2864- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpirazol-3-yl] benzonitrileEx 120
126 2763- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpirazol-3-yl] anilineEx 120
129 2914- [3- (3-Methoxyphenyl) -1H-pyrazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 128
130 316{3- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpirazol-3-yl] -phenoxy} acetonitrileEx 128
131 3432-cyano-N- {3- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-3-yl] phenyl} acetamideEx 128
132 image99 405 3-cyano-N- {3- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-3-yl] phenyl} benzamide Ex. 128
Ex. Nº - (Y) n-ZSpec. mass (M + H) +NamePrep.
150 3064- [4- (4-nitrophenyl) -1H-pyrazol-1-yl] -1H-pyrrolo [2,3b] pyridineEx 153
151 2764- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] anilineEx 153
152 2614- (4-phenyl-1H-pyrazol-1-yl) -1H-pyrrolo [2,3-b] pyridineEx 153
154 2624- (4-pyridin-3-yl-1H-pyrazol-1-yl) -1H-pyrrolo [2,3b] pyridineEx 153
155 2862- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] benzonitrileEx 153
156 300{2- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] phenyl} acetonitrileEx 153
157 3064- [4- (3-nitrophenyl) -1H-pyrazol-1-yl] -1H-pyrrolo [2,3b] pyridineEx 153
158 2763- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] anilineEx 153
159 300{3- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] phenyl} acetonitrileEx 153
160 2864- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] benzonitrileEx 153
161 2773- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] phenolEx 153
162 3193- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] methyl benzoateEx 153
163 300{4- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] phenyl} acetonitrileEx 153
Ex. Nº - (Y) n-ZSpec. mass (M + H) +NamePrep.
164 3432-cyano-N- {3- [1- (1 H -pyrrolo [2,3-b] -pyridin-4-yl) 1 H -pyrazol-4-yl] -phenyl} acetamideEx 153
165 2774- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) 1 H -pyrazol-4-yl] phenolEx 153
166 2875- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-4-yl] nicotinonitrileEx 153
167 image100 316 {4- [1- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol 4-yl] phenoxy} acetonitrile Ex. 153
168 2654- (4-cyclohex-1-en-1-yl-1H-pyrazol-1-yl) -1Hpyrrolo [2,3-b] pyridineEx 172
169 2914- [4- (4-methoxyphenyl) -1H-pyrazol-1-yl] -1Hpyrrolo [2,3-b] pyridineEx 153
171 2634- (4-pyrimidin-4-yl-1H-pyrazol-1-yl) -1Hpyrrolo [2,3-b] pyridineEx 171
174 image101 316 3- {hydroxy [1- (1 H -pyrrolo [2,3-b] -pyridin-4-yl) -1 Hpyrazol-4-yl] -methyl} benzonitrile Ex. 172
175 2794- [4- (cyclohex-1-en-1-ylmethyl) -1H-pyrazol-1-yl] 1H-pyrrolo [2,3-b] pyridineEx 172
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Ex. Nº MS (M + H) +- (Y) n-ZNamePrep.
202 335 image103 4- [1- (3,5-Dimethoxybenzyl) -1H-pyrazol-4-yl] -1Hpyrrolo [2,3-b] pyridine Ex. 201
203 2894- [1- (1-Phenylethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
204 2814- [1- (cyclohexylmethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
205 3003 - {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] methyl} benzonitrileEx 201
206 3002 - {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] methyl} benzonitrileEx 201
207 3004 - {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] methyl} benzonitrileEx 201
208 3031-phenyl-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] ethanoneEx 201
209 283 image104 3,3-Diniethyl-1- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpirazol-1-yl] butan-2-one Ex. 201
210 280 image105 4- {1 - [(5-methylisoxazol-3-yl) methyl] -1H-pyrazol-4-yl} -1Hpyrrolo [2,3-b] pyridine Ex. 201
211 2834- [1- (tetrahydro-2H-pyran-2-ylmethyl) -1H-pyrazol-4-yl] 1H-pyrrolo [2,3-b] pyridineEx 201
212 2654- (1-Cyclohex-2-en-1-yl-1H-pyrazol-4-yl) -1Hpyrrolo [2,3 b] pyridineEx 201
213 2554- [1- (1-ethylpropyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
Ex. Nº MS (M + H) +- (Y) n-ZNamePrep.
214 2674- (1-Cyclohexyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3b] pyridineEx 201
215 2422- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] acetamideEx 201
216 3764 '- {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] methyl} biphenyl-2-carbonitrileEx 201
217 3204- [1- (2-Nitrobenzyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
218 397, 3994- {1- [2,6-Dichloro-4- (trifluoromethyl) phenyl] -1H-pyrazol-4il} -1H-pyrrolo [2,3-b] pyridineEx 201
220 3204- [1- (3-Nitrobenzyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
221 353,3554- [1- (2-Bromobenzyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
222 332N-phenyl-2- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazol-1-yl] propanamideEx 201
223 3594- {1- [3- (trifluoromethoxy) benzyl] -1H-pyrazol-4-yl} -1Hpyrrolo- [2,3b] pyridineEx 201
224 3614- {1- [2-Fluoro-5- (trifluoromethyl) -benzyl] -1H-pyrazol-4il} -1H-pyrrolo [2,3-b] pyridineEx 201
225 3434- {1- [3- (trifluoromethyl) benzyl] -1H-pyrazol-4-yl} -1Hpyrrolo [2,3-b] pyridineEx 201
226 2764- [1- (pyridin-3-ylmethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
227 3174 - {- [(1S) -1-phenylbutyl] -1H-pyrazol-4-yl} -1H-pyrrolo [2,3b] pyridineEx 201
228 3174- {1 - [(1R) -1-phenylbutyl] -1H-pyrrole-4-yl} -1H-pyrrolo [2,3b] pyridineEx 201
229 3171-phenyl-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] propan-1-oneEx 201
230 343, 345 image106 4- [1- (2,6-Dichlorobenzyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridine Ex. 201
232 2894- [1- (2,6-Dimethylphenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 231
233 3542- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -5 (trifluoromethyl) -benzonitrileEx 286
2. 3. 4 393, 3954- [1- (4-Bromo-3,5,6-trifluoropyridin-2-yl) -1H-pyrazol-4-yl] 1H-pyrrolo [2,3-b] pyridineEx 286
235 2394- [1- (cyclopropylmethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 201
236 2894- [1- (2,5-Dimethylphenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 231
237 2754- [1- (2-methylphenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 231
238 2914- [1- (2-Methoxyphenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 231
239 3143- {1- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] ethyl} benzonitrileEx 250
240 3203-Chloro-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
241 2954- [1- (1-Cyclohexylethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
242 3044-fluoro-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
243 3042-fluoro-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
244 304 image107 3-fluoro-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrile Ex. 286
245 3574- (1- {1- [3- (trifluoromethyl) -phenyl] ethyl} -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridineEx 250
246 2894- [1- (3,5-Dimethylphenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridineEx 231
247 2864- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 231
248 300{4- [4- (11H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazol-1-yl] phenyl} acetonitrileEx 231
249 2834- [1- (1-methylhexyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridineEx 250
251 2414- (1-sec-butyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridineEx 250
252 3034- [1- (1-Phenylpropyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridineEx 250
253 3674- (1- {1- [4- (methylsulfonyl) -phenyl] ethyl} -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridineEx 250
254 3374- {1- [1- (3-Fluoro-4-methoxy-phenyl) ethyl] -1H-pyrazol-4-yl} -1H-pyrrolo [2,3-b] pyridineEx 250
255 3574- (1- {1- [2- (trifluoromethyl) -phenyl] ethyl} -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridineEx 250
256 4254- (1- {1- [3,5-bis (trifluoromethyl) -phenyl] ethyl} -1 H -pyrazol-4-yl) 1 H -pyrrolo [2,3-b] pyridineEx 250
257 3144- {1- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] ethyl} benzonitrileEx 250
258 3744- {1- [4-nitro-2- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} -1Hpyrrolo [2,3-b] pyridineEx 286
259 3003-methyl-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
260 295, 2974- [1- (2-Chlorophenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 231
261 364, 3663-Bromo-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1-pyrazol-1-yl] benzonitrileEx 286
262 3334- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] ethyl benzoateEx 286
263 408,4104- {1- [2-Chloro-6-nitro-4- (triftuoro-methyl) phenyl] -1H-pyrazol4-yl} -1H-pyrrolo [2,3-b] pyridineEx 286
264 3574- (1- {1- [4- (trifluoromethyl) -phenyl] ethyl} -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridineEx 250
265 3014- [1- (2,3-dihydro-1H-inden-1-yl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridineEx 250
266 3154- [1- (1,2,3,4-tetrahydronaphthalen-1-yl) -1H-pyrazol-4-yl] 1H-pyrrolo [2,3-b] pyridineEx 250
267 391 image108 4- (1- {1- [2-Chloro-5- (trifluoromethyl) -phenyl] ethyl} -1H-pyrazol4-yl) -1H-pyrrolo [2,3-b] pyridine Ex. 250
268 3754- {1- [1- (2,4-Dichloro-5-fluoro-phenyl) ethyl] -1H-pyrazol-4-yl} 1H-pyrrolo [2,3-b] pyridineEx 250
269 2814- [1- (1-Cyclopentylethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
270 3174- [1- (1-methyl-3-phenylpropyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
271 2674- [1- (1-Cyclobutylethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
272 368[2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -5 (trifluoromethyl) phenyl] acetonitrileEx 286
273 368[5- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -2 (trifluoromethyl) phenyl] acetonitrileEx 286
274 2534- {1 - [(3E) -pent-3-en-1-yl] -1H-pyrazol-4-yl} -1H-pyrrolo [2,3b] pyridineEx 250
275 2382- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] propanonitrileEx 250
276 3154- {1 - [(3E) -4-phenylbut-3-en-1-yl] -1H-pyrazol-4-yl} -1Hpyrrolo [2,3-b] pyridineEx 250
277 2806- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] hexanonitrileEx 250
278 314Ethyl 3-amino-2 - {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -methyl propanoateEx 250
279 285Ethyl 2- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -1H-pyrazol-1-yl] propanoateEx 250
280 2834- [1- (1-Propylbutyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
281 2524- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] butanonitrileEx 250
282 402, 404[3-Chloro-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -5- (trifluoromethyl) phenyl] acetonitrileEx 286
283 354 image109 5- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -2 (trifluoromethyl) -benzonitrile Ex. 286
284 363, 3654- {1- [2-Chloro-4- (trifluoromethyl) -phenyl] -1H-pyrazol-4-yl} -1H-pyrrolo [2,3-b] pyridineEx 286
285 3544- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -2 (trifluoromethyl) -benzonitrileEx 286
287 2862- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
288 320, 3223-Chloro-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
289 3624-amino-5,6-difluoro-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 Hpyrazol-1-yl] isophthalonitrileEx 286
290 2641 - {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] methyl} cyclopropanecarbonitrileEx 250
291 2805- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] hexanonitrileEx 250
292 3082,2-dimethyl-6- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -hexanonitrileEx 250
293 2694 - [- (1-ethyl-2-methylpropyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
294 364, 3665-Bromo-2- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
295 3543- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -4 (trifluoromethyl) -benzonitrileEx 286
296 3542- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -3 (trifluoromethyl) -benzonitrileEx 286
297 372 image110 3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -4 (trifluoromethyl) -benzamide Ex. 286
298 2813- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] cyclohexanoneEx 61
299 2832- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] cyclohexanolEx 250
300 360 image111 4- (1 {[1- (methylsulfonyl) piperidin-4-yl] methyl} -1 H -pyrazol-4-yl) 1 H -pyrrolo [2,3-b] pyridine Ex. 250
301 2922- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] cyclohexanecarbonitrileEx 61
302 3294- {1- [2- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} -1H-pyrrolo [2,3b] pyridineEx 286
303 329, 3314- [1- (2,6-Dichlorophenyl) -1 H -pyrazol-4-yl] -1 H -pyrrolo [2,3b] pyridineEx 286
304 311 image112 (4 - {[4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] methyl} cyclohexyl) methanol Ex. 250
305 2694- [1- (tetrahydrofuran-2-ylmethyl) -1H-pyrazol-4-yl] -1Hpyrrolo [2,3-b] pyridineEx 250
306 2954- [1- (1-Cyclopentylpropyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 250
307 2694- [1- (tetrahydrofuran-3-ylmethyl) -1H-pyrazol-4-yl] -1Hpyrrolo [2,3-b] pyridineEx 250
308 3202-Chloro-3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrileEx 286
309 3213- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -3- (1,3-thiazol-5-yl) -propanonitrileEx 61
310 3721-benzyl-4 - {[4- (1H-pyrrolo [2,3-b] -pyridin-4-yl) -1H-pyrazol-1-yl] methyl} pyrrolidin-2-oneEx 250
311 3183- (1-methyl-1H-imidazol-5-yl) -3- [4- (1H-pyrrolo [2,3-b] pyridin-4il) -1H-pyrazol-1-yl] propanonitrileEx 61
312 3203- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] -3- (3-thienyl) propanonitrileEx 61
313 292{1- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] cyclopentyl} acetonitrileEx 61
314 320,322 image113 4-Chloro-3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzonitrile Ex. 286
315 3114- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] phthalonitrileEx 286
316 3033-methyl-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] benzaldehydeEx 286
317 3204- [1- (2-methyl-4-nitrophenyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3b] pyridineEx 286
318 2673- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] cyclopentanoneEx 201
319 265 image114 4- [1- (3-Furylmethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridine Ex. 201
320 2654- [1- (2-Furylmethyl) -1H-pyrazol-4-yl] -1H-pyrrolo [2,3-b] pyridineEx 201
321 3393- {2-cyano-1- [4- (1 H -pyrrolo [2,3-b] -pyridin-4-yl) -1 H -pyrazol-1-yl] ethyl} -benzonitrileEx 61
322 305{3-methyl-4- [4- (1 H -pyrrolo [2,3-b] -pyridin-4-yl) -1 H -pyrazol-1-yl] phenyl} methanolEx 286
323 2834-methyl-4- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1 H -pyrazol-1-yl] pentan-2-oneEx 61
324 354 image115 3- (1-Benzofuran-2-yl) -3- [4- (1 H -pyrrolo [2,3-b] pyridin-4-yl) -1-Hpyrazol-1-yl] propanonitrile trifluoroacetate Ex. 61
325 3043- (3-furyl) -3- [4- (1 H -pyrrolo [2,3-b] -pyridin-4-yl) -1 H -pyrazol-1-yl] -propanonitrileEx 61
326 314{3-methyl-4- [4- (1 H -pyrrolo [2,3-b] -pyridin-4-yl) -1 H -pyrazol-1-yl] phenyl} acetonitrileEx 286
 image116
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
400 image117 301 4-methyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] benzonitrile trifluoroacetate Ex. 286
401 image118 296 4- [1- (1-Cyclopentylpropyl) 1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetate Ex. 201
402 image119 293 {1- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1-Hirozol-1-yl] cyclopentyl} acetonitrile trifluoroacetate Ex. 61
403R 3403 - {(1R) -2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} benzonitrile trifluoroacetateEx 61
403S 3403 - {(1S) -2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} benzonitrile trifluoroacetateEx 61
404 image120 321 3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] -3- (3-thienyl) propanonitrile trifluoroacetate Ex. 61
405 321, 3234-Chloro-3- [4- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1Hyrazol-1-yl] benzonitrileEx 286
406 image121 305 3- (3-furyl) -3- [4- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1Hyrazol-1-yl] propanonitrile Ex. 61
407 2783- [4- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1Hyrazol-1-yl] pentanedinitrileEx 407
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
408 3073- {1- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] cyclopentyl} propanonitrileEx 61
409 307{1- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] cyclohexyl} -acetonitrile trifluoroacetateEx 61
410 306{3-methyl-4- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -phenyl} methanol trifluoroacetateEx 286
411 3163-pyridin-4-yl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1Hpyrazol-1-yl] propanonitrileEx 61
412 3163-Pyridin-3-yl-3- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
413 image122 360 3- [4- (methylthio) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetate Ex. 61
414 3. 4. 53- (3-Methoxyphenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
415 3. 4. 53- (4-methoxyphenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] propanonitrileEx 61
416 314{3-methyl-4- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -phenyl} acetonitrile trifluoroacetateEx 153
417 3763- [4- (methylsulfinyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
418 3923- [4- (methylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
419 3693- [3- (cyanomethoxy) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
420 349 3513- (6-Chloropyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1Hpyrazol-1-yl] propanonitrileEx 61
421 3405- {2-Cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} pyridine-2-carbonyl trifluoroacetateEx 421
422 3343- (3,5-Dimethylisoxazol-4-yl) -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
423 image123 384 3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -3- [6- (trifluoromethyl) pyridin-3-yl] propanonitrile trifluoroacetate Ex. 61
424 3. 4. 53- (6-Methoxypyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
425 3163-pyridin-2-yl-3- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1Hpyrazol-1-yl] propanonitrileEx 61
426 394 3963- (6-Bromopyridin-2-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
427 3416- {2-Cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -ethyl} pyridine-2-carbonyl trifluoroacetateEx 421
428 image124 306 4- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] heptanedinitrile Ex. 428
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
429 393 3953- (5-bromopyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] propanonitrileEx 429
430 image125 288 4- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] heptanedinitrile Ex. 430
431 3405- {2-Cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} nicotinonitrile trifluoroacetateEx 431
432 3. 4. 53- (2-Methoxypyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
433 3693- [4- (cyanomethoxy) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
434 3693- [2- (cyanomethoxy) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
435 4733- (3,5-dibromophenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] propanonitrileEx 61
436 3655- {2-Cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} isophthalonitrile trifluoroacetateEx 431
437 image126 359 3- [6- (dimethylamino) pyridin-2-yl] -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile ex. 421 trifluoroacetate
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
438 401 3993- (4-Bromo-2-thienyl) -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
439 3465- {2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} thiophene-3-carbonitrile trifluoroacetateEx 431
440 410 4123- (5-Bromo-2-fluorophenyl) -3 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
441 3593- (3-Nitrophenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
442 422 4243- (5-Bromo-2-methoxyphenyl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
443 3693- {2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -4methoxybenzonitrile trifluoroacetateEx 61
444 392 3943- (3-Bromophenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
445 3573- {2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -4fluorobenzonitrile trifluoroacetateEx 61
446 447 4493- [5-Bromo-2- (cyanomethoxy) -phenyl] -3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
447 385 3833- (4-Bromo-2-furyl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
448 3944- (cyanomethoxy) -3- {2-cyano-1- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzonitrile trifluoroacetateEx 61
449 396 3943- (4-bromopyridin-2-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
450 3412- {2-Cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} isonicotinonitrile trifluoroacetateEx 431
451 3305- {2-Cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -ethyl} -3-furonitrile trifluoroacetateEx 431
452 447 4493- [2-Bromo-5- (cyanomethoxy) -phenyl] -3- [4- (7H-pyrrolo [2,3d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] -propanonitrileEx 61
453 3944- (cyanomethoxy) -2- {2-cyano-1- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzonitrile trifluoroacetateEx 61
454 3173-pyrimidin-5-yl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
455 396 3943- (2-Bromopyridin-4-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
456 3414- {2-Cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} pyridine-2-carbonyl trifluoroacetateEx 421
457 3463- (5-Methoxypyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
458 3483- (3-Chlorophenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
459 3823- [4- (7H-Pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -3- [3 (trifluoromethyl) phenyl] -propanonitrile trifluoroacetateEx 61
460 4063- (3-Phenoxyphenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
461 3983- [4- (7H-Pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -3- [3 (trifluoromethoxy) phenyl] propane-nitrile trifluoroacetateEx 61
462 image127 373 3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} methyl benzoate Ex. 61
463 image128 359 3- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] ethyl} benzoic acid Ex. 61
464 3803- [3- (1H-pyrazol-4-yl) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 482
467 3293- (3-Aminophenyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile bis trifluoroacetateEx. 467
468 371N- (3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) -acetamide trifluoroacetateEx 468
469 407N- (3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4yl) -1H-pyrazol-1-yl] ethyl} phenyl) -methanesulfonamideEx 468
470 3464- {2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} thiophene-2-carbonyl trifluoroacetateEx 470
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
471 3465- {2-Cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} thiophene-2-carbonyl trifluoroacetateEx 471
472 4283- [3- (morpholin-4-ylcarbonyl) -phenyl] 3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 472
475 image129 401 N- (2-aminoethyl) -3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzamide trifluoroacetate Ex 472
476 3493- (5-formyl-3-thienyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 61
477 3723- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -Nmethylbenzamide trifluoroacetateEx 472
478 3962-cyano-N- (3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) acetamide trifluoroacetateEx 472
479 434N- (3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) nicotinamide bis trifluoroacetateEx 478
480 image130 414 N- (3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) N'-isopropylurea trifluoroacetate Ex 468
481 image131 415 (3- {2-cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) -isopropyl trifluoroacetate Ex. 468
482 image132 392 3- (5-phenylpyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetate Ex. 482
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
483 3933- (3,3'-bipyridin-5-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 482
484 3943- (5-pyrimidin-5-ylpyridin-3-yl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 482
485 3963- [5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) trifluoroacetate - 1 Hpirazol-1-yl] -propanonitrileEx 482
486 image133 339 3- (5-ethynylpyridin-3-yl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetate Ex. 486
488 4243- [5- (phenylthio) pyridin-3-yl] -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx 488
489 402 4003- (2-Bromo-1,3-thiazol-5-yl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
490 300Ethyl 3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] -butanoateEx 61
491 4013- (5-morpholin-4-ylpyridin-3-yl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 491
492 3193- (1-methyl-1H-pyrazol-4-yl) -3- [4 (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 61
493 image134 357 4- {1- [1-phenyl-2- (1H-1,2,4-triazol1-yl) ethyl] -1H-pyrazol-4-yl} -7H-pyrrolo [2,3-d] pyrimidine Ex. 250
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
494 3574- {1- [1-Phenyl-2- (4H-1,2,4-triazol-4-yl) ethyl] -1Hpirazol-4-yl} -7H-pyrrolo [2,3-d] pyrimidineEx 250
495 3923- (3-pyridin-3-ylphenyl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 482
496 image135 440 3- [5- (phenylsulfinyl) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] propane-nitrile trifluoroacetate Ex. 496
497 image136 456 3- [5- (Phenylsulfonyl) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] propane-nitrile trifluoroacetate Ex. 497
498 2723- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1Hpirazol-1-yl] pentan-1-olEx 498
499 3303- [4- (7H-Pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] -pentyl carbonateEx 499
500 (a) 285(1E) -3- [4- (7 H -pyrrolo [2,3-d] -pyrimidin-4-yl) -1 Hpirazol-1-yl] -pentanal oximeEx 500
501 299(1E) -3- [4- (7 H -pyrrolo [2,3-d] -pyrimidin-4-yl) -1 Hpirazol-1-yl] -pentanal O-methyl oximeEx 501
502 299(1Z) -3- [4- (7 H -pyrrolo [2,3-d] -pyrimidin-4-yl) -1 Hpirazol-1-yl] -pentanal O-methyl oximeEx 502
503 4264- [1- (4,4-dibromo-1-ethylbut3-en-1-yl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3d] pyrimidine trifluoroacetateEx 503
504 4313- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -3- [5- (1,3-thiazol-2-ylthio) pyridine bis (trifluoroacetate) -3-yl] -propanonitrileEx 488
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
505 3763- [5- (ethylthio) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 488
506 2664- [1- (1-Ethylbut-3-in-1-yl) 1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetateEx 506
507 2954- {1- [1-methyl-2- (1H-1,2,4-triazol-1-yl) ethyl] -1Hpirazol-4-yl} -7H-pyrrolo [2,3-d] pyrimidineEx 250
508 2704- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] pentan-2-one trifluoroacetateEx 61
509 3181-phenyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] propan-1-oneEx 250
510 3923- [5- (ethylsulfinyl) pyridin-3-yl] -3- [4- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 496
511 4083- [5- (ethylsulfonyl) pyridin-3-yl] -3- [4- (7Hpyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 497
512 4303- [5- (cyclohexylthio) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 488
513 of No. 1 3201-phenyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] propan-1-olEx 509
513 of No. 2 3201-phenyl-2- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) 1H-pyrazol-1-yl] -propan-1-olEx 509
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
514 3753- [3- (ethylthio) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4yl) -1H-pyrazol-1-yl] propanonitrileEx. 516
515 image137 391 3- [3- (ethylsulfinyl) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile Ex. 516
516 ee No. 1 image138 407 3- [3- (ethylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile Ex. 516
516 ee No. 2 image139 407 3- [3- (ethylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile Ex. 516
517 4623- [5- (cyclohexylsulfonyl) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 497
518 4463- [5- (cyclohexylsulfinyl) pyridin-3-yl] -3- [4- (7Hpyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 496
519 3044- [1- (1-methyl-2-phenylethyl) -1H-pyrazol-4-yl] -7Hpyrrolo [2,3-d] -pyrimidineEx 250
520 3104- {1- [1-methyl-2- (3-thienyl) ethyl] -1H-pyrazol-4-yl} -7Hpyrrolo- [2,3-d] pyrimidineEx 250
521 3153- {1- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] -ethyl} benzonitrileEx 250
522 image140 294 4- {1- [2- (1 H -imidazol-1-yl) -1-methyl ethyl] -1 H -pyrazol-4-yl} -7 H -pyrrolo [2,3-d] pyrimidine Ex. 250
523 3104- {1- [1-methyl-2- (3-methyl-1,2,4-oxadiazol-5-yl) ethyl] -1Hpyrazol-4-yl} -7H-pyrrolo [2,3-d] pyrimidineEx 250
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
524 3933- [3- (methylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx. 516
525 3923- (3-pyridin-4-ylphenyl) -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 482
526 2684- [1- (1-ethylbut-3-en-1-yl) -1H-pyrazol-4-yl] -7Hpyrrolo [2,3-d] -pyrimidineEx 526
527 2684- [1- (1,3-Dimethylbut-3-en-1-yl) -1 H -pyrazol-4-yl] -7 H -pyrrolo [2,3-d] pyrimidineEx 526
528 image141 390 3- [5- (isopropylthio) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile Ex. 488
529 4063- [5- (isopropylsulfinyl) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 496
530 4223- [5- (isopropylsulfonyl) pyridin-3-yl] -3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 497
531 e.e. No. 1 3843- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -4H-pyrazol-1-yl] -3- [5- (trifluoromethyl) pyridin-3-yl] -propanonitrileEx 431
531 e.e. No. 2 3843- [4- (7 H -pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] -3- [5- (trifluoromethyl) pyridin-3-yl] -propanonitrileEx 431
532 4012- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -N- [3- (trifluoromethyl) phenyl] -propanamideEx 250
533 383N-2-Naphthyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1Hyrazol-1-yl] propanamideEx 250
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
534 383N-1-naphthyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] propanamideEx 250
535 358N- (3-cyanophenyl) -2- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanamideEx 250
536 347N-benzyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] propanamideEx 250
537 347N-Phenyl-2- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) 1H-pyrazol-1-yl] -butanamideEx 250
538 439N- (4-phenoxyphenyl) -2- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanamideEx 250
539 397N-2-naphthyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] butanamideEx 250
540 372N- (3-cyanophenyl) -2- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanamideEx 250
541 423N-biphenyl-4-yl-2- [4- (7H-pyrrolo [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] butanamideEx 250
542 image142 437 N- (biphenyl-4-ylmethyl) -2- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanamide Ex. 250
543 image143 437 N- (biphenyl-3-ylmethyl) -2- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanamide Ex. 250
544 image144 372 N- (4-cyanophenyl) -2- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] butanamide Ex. 250
Ex. Nº - (Y) n-ZMS (M + H) +NamePrep.
545 397N-1-Naphthyl-2- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1 Hpirazol-1-yl] butanamideEx 250
546 4355- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N-phenylnicotinamide trifluoroacetateEx 431
547 image145 430, 432 4- {1- [1- (5-bromopyridin-3-yl) -4,4-difluorobut-3-en-1il] 1H-pyrazol-4-yl} -7H-pyrrolo [2,3- d] pyrimidine Ex. 717
548 image146 378 5- {4,4-difluoro-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] but-3-en-1-yl} nicotinonitrile Ex. 717
Example 407: 3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] pentanedinitrile
image147
Stage 1: 3- [4- (7 - {[2- (trimethylsilyl) ethoxy] methyl} -7 H -pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] dimethyl pentanedioate
4- (1 H -pyrazol-4-yl) -7- [2- (trimethylsilyl) ethoxy] methyl-7 H -pyrrolo [2,3-d] pyrimidine (31.0 g, 0.0983 mol) was suspended in ACN (620 ml, 12 mol) and DBU (9.3 ml, 0.062 mol) was added under a nitrogen atmosphere. The reaction was heated to 65 ° C and was added in 5 ml portions of dimethyl (2E) -pent-2-enodioate (16 ml, 0.12 mol) for 2 h. After stirring overnight, the reaction was complete. The reaction was allowed to cool to room temperature and concentrated in vacuo, giving a dark oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HCl and brine, dried over magnesium sulfate and then concentrated, giving a dark oil. The viscous oil was triturated with 3 x 500 ml ethyl ether, giving a dark precipitate. The oil was taken up in ethyl acetate, forming a solid. The solids were collected, washed with ethyl ether and dried, giving 3- [4- (7 - {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl ) -1 H -pyrazol-1-yl] dimethyl pentanedioate in the form of a white powder (29.5 g, 64%), LC / MS (M + H) +: 474, 1 H NMR (DMSO-d6) δ 9.1 (s, 1H), 9.02 (s, 1H), 8.65 (s, 1H), 8.11 (d, 1H), 7.42 (d, 1H), 5.78 ( s, 2H), 5.27 (m, 1H), 3.65 (m, 8H), 3.15 (m, 4H), 0.95 (t, 2H), 0.1 (s, 9H).
Stage 2: 3- [4- (7- [2- (trimethylsilyl) ethoxy] methyl-7 H -pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] -pentanedioic acid
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Table 12
Ex. Nº NameRMS (ES) (M + 1)Preparation and chiral separation procedure
501 3- [3- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -, 1H-pyrrol1-yl] butanonitrileCH3252Ex 500, non-separated enantiomers
The following compounds in Table 13 were prepared as indicated in the column marked "Prep procedure." and the details of certain exemplary synthetic procedures are provided in the following Table 13.
Table 13 (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued)
Ex. Nº R1R2M + 1NamePrep procedure
601 CH2CN502N- (3- {2-cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) 3- (trifluoromethyl) benzamideEx 468
602 H image164 463 N- (3 - {[4- (7 H -pyrrolo [2,3-d] pyrimidin-4-yl) 1 H -pyrazol-1-yl] methyl} phenyl) -3 (trifluoromethyl) benzamide Ex. 468
603 e.e. No. 1 CH2CNSO2CH33933- [3- (methylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] -propanonitrileEx. 516
603 e.e. No. 2 CH2CNSO2CH33933- [3- (methylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] -propanonitrileEx. 516
604 H431N- (3 - {[4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) 1H-pyrazol-1-yl] methyl} phenyl) benzenesulfonamideEx 469
605 H4633 - {[4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1Hpyrazol-1-yl] methyl} -N- [3- (trifluoromethyl) phenyl] benzamideEx 472
Ex. Nº R1R2M + 1NamePrep procedure
606 e.e. No. 1 CH2CN4223- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N, N-dimethylbenzenesulfonamideEx 649
606 e.e. No. 2 CH2CN image165 422 3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N, N-dimethylbenzenesulfonamide Ex. 649
607 CH2CN484N-benzyl-3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} benzene-sulfonamide trifluoroacetateEx 649
608 CH2CN448N-benzyl-3- {2-cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzamideEx 472
609 CH2CN4343- {2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N-phenylbenzamide trifluoroacetateEx 472
610 CH2CN5023- {2-Cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- [3- (trifluoromethyl) phenyl] trifluoroacetate - benzamideEx 472
611 H420N- (3-cyanophenyl) -3 - {[4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] methyl} benzamideEx 472
612 H409N-benzyl-3 - {[4- (7H-pyrrolo- [2,3-d] pyrimidin4-yl) -1 H -pyrazol-1-yl] methyl} benzamideEx 472
613 H445N-1-naphthyl-3 - {[4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] methyl} benzamideEx 472
614 H image166 445 N-2-naphthyl-3 - {[4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] methyl} -benzamide Ex. 472
615 H image167 445 N- (3 - {[4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] methyl} phenyl) -2-naphthamide Ex. 468 trifluoroacetate
Ex. Nº R1R2M + 1NamePrep procedure
616 H445N- (3 - {[4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1-pyrazol-1-yl] methyl} phenyl) -1-naphthamide trifluoroacetateEx 468
617 H4092-phenyl-N- (3 - {[4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] methyl} -phenyl) acetamide trifluoroacetateEx 468
618 H image168 429 3-Chloro-N- (3 - {[4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] methyl} phenyl) -benzamide trifluoroacetate Ex. 468
619 CH2CN484N- (3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} phenyl) -2-naphthamide trifluoroacetateEx 468
620 CH2CN484N- (3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} phenyl) -1-naphthamide trifluoroacetateEx 468
621 CH2CN448N- (3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] -ethyl} phenyl) -2-phenylacetamide trifluoroacetateEx 468
622 CH2CN4593-cyano-N- (3- {2ciano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) benzamide trifluoroacetateEx 468
623 CH2CN image169 434 N- (3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} -phenyl) benzamide trifluoroacetate Ex. 468
624 CH2CN502N- (3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} phenyl) -4 (trifluoromethyl) trifluoroacetate benzamideEx 468
625 CH2CN449N- (3- {2-cyano-1 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} phenyl) -N'-phenylurea trifluoroacetateEx 480
626 CH2CN5023- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N- [4 (trifluoromethyl) phenyl] trifluoroacetate -benzamideEx 472
Ex. Nº R1R2M + 1NamePrep procedure
627 CH2CN4483- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N- (4-methylphenyl) benzamide trifluoroacetateEx 472
628 CH2CN459N- (4-cyanophenyl) 3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzamide trifluoroacetateEx 472
629 CH2CN image170 484 3- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-Hirozol-1-yl] ethyl} -N-2-naphthylbenzamide trifluoroacetate Ex. 472
630 CH2CN image171 484 3- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N-1-naphthylbenzamide trifluoroacetate Ex. 472
631 CH2CN3863- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N, N-dimethylbenzamide trifluoroacetateEx 472
632 CH2CN4353- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N-pyridine-3-benzamide trifluoroacetateEx 472
633 CH2CN4483- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N-methyl-N-phenylbenzamide trifluoroacetateEx 472
634 CH2CN4403- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -Ncyclohexylbenzamide trifluoroacetateEx 472
635 CH2CN5263- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N- (4-phenoxyphenyl) benzamide trifluoroacetateEx 472
636 CH2CN459N- (3-cyanophenyl) 3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzamide trifluoroacetateEx 472
637 CH2CN510N-biphenyl-4-yl-3- {2cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} benzamide trifluoroacetate trifluoroacetateEx 472
Ex. Nº R1R2M + 1NamePrep procedure
638 CH2CN468N- (4-chlorophenyl) -3- {2ciano-1- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) 1H-pyrazol-1-yl] ethyl} benzamide trifluoroacetateEx 472
639 CH2CN image172 462 3- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (3,4-dimethylphenyl) trifluoroacetate benzamide Ex. 472
640 CH2CN4643- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (3-methoxyphenyl) benzamide trifluoroacetateEx 472
641 CH2CN4643- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (4-methoxyphenyl) benzamide trifluoroacetateEx 472
642 CH2CN4253- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N-isoxazol-3-ylbenzamide trifluoroacetateEx 472
643 CH2CN4843- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] ethyl} -N-methyl-N-phenylbenzenesulfonamideEx 649
644 CH2CN4363- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] ethyl} -N-PropylbenzenesulfonamideEx 649
645 CH2CN4703- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] ethyl} -N-phenylbenzenesulfonamideEx 649
646 CH2CN5203- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] ethyl} -N-2-naphthylbenzenesulfonamideEx 649
647 CH2CN4343- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] ethyl} -N-cyclopropylbenzenesulfonamideEx 649
648 CH2CN4623- [3- (piperidin-1-ylsulfonyl) -phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 649
649 CH2CN4643- [3- (morpholin-4-ylsulfonyl) -phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 649
650 CH2CN4843- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (4-methylphenyl) benzene sulfonamide trifluoroacetateEx 649
Ex. Nº R1R2M + 1NamePrep procedure
651 CH2CN4983- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] ethyl} -N- (3,4-dimethylphenyl) benzenesulfonamide trifluoroacetateEx 649
652 CH2CN5003- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (3-methoxyphenyl) benzenesulfonamide trifluoroacetateEx 649
653 CH2CN image173 500 3- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (4-methoxyphenyl) benzenesulfonamide trifluoroacetate .649
654 CH2CN4943- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (3,5-dimethoxyphenyl) benzamide trifluoroacetateEx 472
655 CH2CN4773- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- [4- (dimethylamino) phenyl] trifluoroacetate benzamideEx 472
656 CH2CN4693- [3- (benzylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] -propanonitrileEx. 516
657 CH2CN4373- [3- (benzylthio) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-ylpropanonitrileEx 514
658 CH2CN4944 - {[(3- {2-cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) sulfonyl] methyl} benzonitrileEx. 516
659 CH2CN4083- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl-Nmethyl-benzenesulfonamideEx 649
660 CH2CN5203- {2-cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N-1naphthylbenzenesulfonamideEx 649
661 CH2CN image174 546 N-biphenyl-4-yl-3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] ethyl} -benzenesulfonamide Ex. 649
662 CH2CN5183- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- [4- (trifluoromethoxy) phenyl] trifluoroacetate benzamideEx 472
Ex. Nº R1R2M + 1NamePrep procedure
663 CH2CN image175 464 3- {2-Cyano-1- [4- (7H-Pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (2-methoxyphenyl) benzamide trifluoroacetate .472
664 CH2CN4213- [3- (benzyloxy) phenyl] -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 514
665 CH2CN4763- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} N-cyclohexylbenzenesulfonamide trifluoroacetateEx 649
666 CH2CN5103- [3- (3,4-dihydroisoquinolin-2 (1H) -ylsulfonyl) phenyl] -3 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] trifluoroacetate propane nitrileEx 649
667 CH2CN4523- {2-Cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- (2-methoxyethyl) benzenesulfonamide trifluoroacetateEx 649
668 CH2CN4503- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N, NdiethylbenzenesulfonamideEx 649
669 CH2CN4913- {3 - [(4-ethylpiperazin-1-yl) -sulfonyl] phenyl} -3 [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1Hpirazol-1-yl] propanonitrileEx 649
670 CH2CN image176 514 N-1,3-benzodioxol-5-yl-3- {2-cyano-1- [4 (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1Hyrazol-1-yl] ethyl } benzenesulfonamide Ex. 649
671 CH2CN4993- {3 - [(3-methoxybenzyl) -sulfonyl] phenyl} -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1Hpyrazol-1-yl] -propanonitrileEx. 516
672 CH2CN4993- {3 - [(4-methoxybenzyl) -sulfonyl] phenyl} -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] -propanonitrileEx. 516
673 CH2CN4923- {3 - [(2,6-dimethylmorpholin-4-yl) sulfonyl] phenyl} -3- [4- (7 H -pyrrolo [2,3d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] propanonitrileEx 649
674 CH2CN4763- {3 - [(4-oxopiperedin1-yl) -sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazole-1il] trifluoroacetate propanonitrileEx 649
Ex. Nº R1R2M + 1NamePrep procedure
675 CH2CN image177 421 3- [3 (Isopropylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3d] -pyrimidin-4-yl) -1H-pyroxol-1-yl] propanonitrile ex. 516
676 CH2CN4753- {3 - [(cyclohexylmethyl) sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] -propanonitrile trifluoroacetateEx. 516
677 CH2CN5163- [3 (octahydroisoquinolin-2 (1H) -ylsulfonyl) phenyl] -3 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] propane-nitrile trifluoroacetateEx 649
678 CH2CN4833- {3 - [(2-Phenylethyl) sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx. 516
679 CH2CN image178 448 3- [3- (pyrrolidin-1-ylsulfonyl) -phenyl] -3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile Ex. 649
680 CH2CN498N-benzyl-3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -NmethylbenzenesulfonamideEx 649
681 CH2CN4943 - {[(3- {2-cyano-1- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) sulfonyl] methyl} - benzonitrileEx. 516
682 CH2CN5193- {3 - [(2-Naphthylmethyl) -sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx. 516
683 CH2CN4833- {3 - [(1-phenylethyl) sulfonyl] -phenyl} -3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx. 516
684 CH2CN image179 507 3- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin4-yl) -1H-pyrazol-1-yl] ethyl} -N- (2-morpholin-4-ethyl) -benzenesulfonamide Ex. 649
685 CH2CN494N- (2-aminoethyl) -2 - {[(3- {2-cyano-1- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) sulfonyl] -amino} acetamideEx 649
Ex. Nº R1R2M + 1NamePrep procedure
686 CH2CN image180 498 3- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N [(1S) -1 -phenylethyl] benzenesulfonamide Ex. 649
687 e.e. No. 1 CH2CN4343- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] ethyl} -N-phenyl-benzamide trifluoroacetateEx 472
687 e.e. No. 2 CH2CN image181 434 3- {2-Cyano-1- [4 (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1-Hirozol-1-yl] ethyl} -N-phenyl-benzamide trifluoroacetate Ex. 472
688 CH2CN image182 478 3- {2-cyano-1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N (tetrahydrofuran-2-ylmethyl ) benzenesulfonamide Ex. 472
689 CH2CN image183 433 3- {3 [(cyclopropylmethyl) sulfonyl] phenyl} -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-Hirozol-1-yl] propanonitrile ex. 516 trifluoroacetate
690 CH2CN4773- {3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} -3- [4- (7 H -pyrrolo [2,3d] pyrimidin-4-yl) -1 H -pyrazol-1-yl] propanonitrileEx 472
691 CH2CN5611 - [(3- {2-cyano-1- [4- (7H-pyrrolo- [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} phenyl) sulfonyl] -N, N-diethyl-piperidine-3carboxamideEx 472
692 CH2CN4963- {3 - [(1-oxidothiomorpholin-4-yl) sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 472
693 CH2CN4633- [3- (piperazin-1-ylsulfonyl) -phenyl] -3- [4 (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1-pyrazol-1-yl] propanonitrileEx 472
694 CH2CN4803- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) 1H-pyrazol-1-yl] -3- [3- (thiomorpholin-ylsulfonyl) phenyl] propanonitrileEx 472
695 CH2CN image184 478 3- {3 - [(4-Hydroxypiperidin-1-yl) -sulfonyl] phenyl} -3 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] trifluoroacetate propanonitrile Ex. 472
Ex. Nº R1R2M + 1NamePrep procedure
696 CH2CN4353- [3 (Isobutyl sulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propane-nitrile trifluoroacetateEx. 516
697 CH2CN4773- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] -3- {3 [(tetrahydro-2H-pyran-4-methyl) sulfonyl] -phenyl- trifluoroacetate propanonitrileEx. 516
698 CH2CN4373- {3 - [(2methoxyethyl) sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx. 516
699 CH2CN4593- {3 - [(3-Furylmethyl) sulfonyl] -phenyl} -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetateEx. 516
700 CH2CN5123- {3 - [(1,1-dioxidothiomorpholin-4-yl) sulfonyl] phenyl} -3- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 649
701 CH2CN5053- {3 - [(4-acetylpiperazin-1-yl) sulfonyl] phenyl} -3- [4 (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrileEx 649
702 CH2CN4703- {3 - [(pyridin-4-ylmethyl) -sulfonyl] phenyl} -3 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1Hpyrazol-1-yl] propanonitrileEx. 516
703 CH2C≡CHH3144- [1- (1-Phenylbut-3in-1-yl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3d] -pyrimidine trifluoroacetateEx 705
704 CH2C≡CH4634- (1- {1- [3- (morpholin-4-ylsulfonyl) phenyl] but-3-in-1-yl} -1 H -pyrazol 4-yl) -7 H -pyrrolo [2,3-d] pyrimidineEx 705
705 CH2C≡CHCN3393- {1- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] but-3-in-1-yl} benzonitrile trifluoroacetateEx 705
706 CH2C≡CHCH = O3423- {1- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] but-3-in-1-yl} benzaldehyde trifluoroacetateEx 706
707 CH2CO2CH3CN373methyl 3- (3-cyanophenyl) -3 [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] propanoate methyl trifluoroacetateEx 712
708 CH2C≡CH421N, N-dimethyl-3- {1- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] but-3-in-1-yl} benzenesulfonamide trifluoroacetateEx 705
Ex. Nº R1R2M + 1NamePrep procedure
709 CH2CN5133- {2-cyano-1- [4- (7H-pyrro lo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethyl} -N- [4- (dimethylamino) phenyl] benzenesulfonamideEx 649
710 CH2CH2-OCH34413- {3-Methoxy1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propyl} -N trifluoroacetate-N, N-dimethylbenzenesulfonamideEx 712
711 CH2C = CH image185 433 N-phenyl-3- {1 [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] but-3-in-1-yl} benzamide trifluoroacetate Ex 705
712 CH2CH2-OCH3H3344- [1- (3methoxy-1-phenyl-propyl) -1-pyrazol-4-yl] -7H-pyrrolo [2,3d] pyrimidine trifluoroacetateEx 712
713 CH2C≡CH476N- [4 (dimethylamino) phenyl] -3- {1- [4- (7 H -pyrrolo [2,3-d] -pyrimidin-4-yl) -1-pyrazol-1-yl] but-3-in-1-trifluoroacetate }benzamideEx 705
714 CH2CH2OH4273- {3-Hydroxy1- [4- (7H-pyrrolo- [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propyl-N trifluoroacetate, N-dimethylbenzenesulfonamideEx 712
715 CH2-CH = CH2CN3413- {1- [4-7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1-pyrazol-1-yl] but-3-en-1-yl} benzonitrile trifluoroacetateEx 715
716 CH2-CH = CH2Br394,3964- {1- [1- (3bromophenyl) but-3-en-1-yl) -1Hyrazzol-4-yl} -7H-pyrrolo [2,3d] pyrimidine trifluoroacetateEx 716
717 CH2CH = CF2CN3773- {4,4-difluoro-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-pyrazol-1-yl] but-3-en-1-yl} benzonitrileEx 717
718 CH2CH = CF25014- (1- {4,4-difluoro-1- [3- (morpholin-4-sulfonyl) -phenyl] but-3-en-1-yl} -1-pyrazol-4-yl) -7H-pyrrolo trifluoroacetate [2,3 -d] pyrimidineEx 717
719 CH2CH = CF2 image186 444 4- (1- {1- [3 (ethylsulfonyl) -phenyl] -4,4-difluorobut-3-en-1-yl} -1-Hpirazol-4-yl) -7H-pyrrolo [2,3d] pyrimidine Ex trifluoroacetate .717
720 CH2CH = CF24584- (1- {1- [3 (benzyloxy) phenyl] -4,4-difluorobut-3-en-1-yl} -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d] trifluoroacetate -pyrimidineEx 717
Ex. Nº R1R2M + 1NamePrep procedure
721 CH2OCH3H3204- [1- (2-Methoxy-1-phenylethyl) -1Hpyrazol-4-yl] -7H-pyrrolo- [2,3d] pyrimidineEx 712
722 CH2CH = CF2 image187 430 4- (1- {4,4difluoro-1- [3- (methylsulfonyl) phenyl] but-3-en-1-yl} -1-Hpirazol-4-yl) -7H-pyrrolo- [2,3d] trifluoroacetate [2,3d] pyrimidine Ex. 717
723 HCN3013 - {[4- (7H-pyrrolo [2,3-d] -pyrimidin-4il) -1H-pyrazol-1-yl] methyl} benzonitrileEx 250
724 CH2CH2CH3CN3433- {1- [4- (7H-pyrrolo [2,3-d] -pyrimidin4-yl) -1H-pyrazol-1-yl] butyl} benzonitrileEx 250
725 CH2CH2CH24464- (1- {1- [3 (ethylsulfonyl) -phenyl] -4,4-difluorobutyl} -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d] -pyrimidine trifluoroacetateEx 717
726 CH2CH = CF24744- [1- (4,4difluoro-1- {3 - [(2-methoxyethyl) sulfonyl] phenyl} -but-3-en1-yl) -1H-pyrazol-4-yl] -7H-pyrrolo [2, trifluoroacetate [2, 3d] pyrimidineEx 717
Example 649: 3- [3- (Morpholin-4-ylsulfonyl) phenyl] -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile
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Stage 1: 4 - [(3-Bromophenyl) sulfonyl] morpholine
Morpholine (0.19 ml, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (0.3 ml, 0.002 mol) and TEA (0.30 ml, 0, 0022 mol) in 4.0 ml of dry THF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and then partitioned between 0.05 N HCl and ethyl acetate. The organic layer was washed with water (2 x) and brine (1 x), then dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo, giving 4 - [(3-bromophenyl) sulfonyl] morpholine as of a white crystalline product (470 mg, 78%). LCMS (M + H) +: m / z = 306, 308.
Stage 2: (2E and Z) -3- [3- (Morpholin-4-ylsulfonyl) phenyl] acrylonitrile
The 4 - [(3-bromophenyl) sulfonyl] morpholine (0.250 g, 0.000816 mol) was dissolved in dry DMF (2.5 ml, 0.032 mol) and the mixture was degassed using a stream of nitrogen. To this mixture were added TEA (0.23 ml, 0.0016 mol), 2-propenonitrile (0.11 ml, 0.0016 mol), palladium acetate (0.011 g, 0.000049 mol) and triphenylphosphine (0 0.364 g, 0.000139 mol) and the mixture was degassed again with nitrogen. The reaction mixture in a sealed tube was heated at 110 ° C for 16 hours. The reaction mixture, after cooling to room temperature, was partitioned between 0.05 N HCl and ethyl acetate. The organic layer was washed with water (2 x) and brine (1 x), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, giving (2E and Z) -3- [3 (morpholin-4- il-sulfonyl) phenyl] acrylonitrile in the form of an oil (0.240 g, 85%) which was a mixture of cis and trans isomers. LCMS (M + H) +: m / z = 279.
Stage 3: 3- [3- (Morpholin-4-ylsulfonyl) phenyl] -3- [4- (7- [2- (trimethylsilyl) ethoxy] methyl-7H-pyrrolo- [2,3-d] pyrimidin-4 -il) -1H-pyrazol-1il] propanonitrile
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Table 14 (continued) (continued)
 image207
Ex. Nº R structureMS (M + H)NameEx Prep. No.
727 3084- [1- (1-Cyclopentylbut-3-en-1-yl) -1-pyrazol-4-yl] -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetate salt 727
728 2544- [1- (1-Methylbut-3-en-1-yl) -1-pyrazol-4-yl] -7H-pyrrolo [2,3-d] -pyrimidine trifluoroacetate salt727
729 4524- [1- (1-Cyclopentyl-2-cyclopropylethyl) 1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] -pyrimidine trifluoroacetate salt727
730 3064- [1- (1-Cyclopentylbut-3-in-1-yl) -1-pyrazol-4-yl] -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetate salt727
731 3104- [1- (1-Cyclopentylbutyl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] -pyrimidine trifluoroacetate salt729
732 3444- [1- (1-Cyclopentyl-4,4-difluorobut3-en-1-yl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] -pyrimidine trifluoroacetate salt727
733 3464-1- [4,4-difluoro-1- (tetrahydrofuran-3-yl) but-3-en-1-yl] -1H-pyrazol-4-yl-7H-pyrrolo [2,3- trifluoroacetate salt d] pyrimidine727 Stage 3 and 4, then 731, stage 1 *
734 2544- [1- (1-Methylbut-3-en-1-yl) -1-pyrazol-4-yl] -7H-pyrrolo [2,3-d] -pyrimidine trifluoroacetate salt727 Stage 3 and 4, then 731
735 3164- [1- (1-Cyclopropyl-4,4-difluoro-but3-en-1-yl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetate salt727 Stage 3 and 4, then 731
Ex. Nº R structureMS (M + H)NameEx Prep. No.
736 3464- [1- (1-Cyclopentyl-4,4-difluoro-butyl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3d] pyrimidine trifluoroacetate salt731
737 image208 321 3- (1-methylcyclopentyl) -3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetate salt 737
738 295(3R) -y (3S) -4,4-dimethyl-3 [4- (7- [2- (trimethylsilyl) ethoxy] -methyl-7H-pyrrolo [2,3-d] pyrimidin-4- trifluoroacetate salt il) -1H-pyrazol-1-yl] pentanonitrile737
739 3041-2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] ethylcyclopropanecarbonitrile trifluoroacetate salt 739
740 440N - [(1-2-cyano-1- [4- (7H-pyrrolo [2,3-d] pyrimidin-4il) -1H-pyrazol-1-yl] ethylcyclopentyl) methyl] benzamide 740
741 4273-1 - [(Benzyloxy) methyl] cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] -pyrimidin-4-yl) -1-pyrazol-1-yl] propanonitrile trifluoroacetate salt 741
742 3863- [1 (Methylsulfonyl) pyrrolidin-3-yl] -3- [4- (7H-pyrrolo [2,3d] -pyrimidin-4-yl) -1H-pyrazol-1-yl] propanonitrile trifluoroacetate salt 742
743 375N'-cyano-4- (cyanomethyl) -4- [4- (7H-pyrrolo [2,3d] pyrimidin-4-yl) -1H-pyrazol-1-yl] piperidine-1carboximidamide 743
744 image209 348 4-1- [2,2,2-trifluoro-1- (1 H -imidazol-2-ylmethyl) ethyl] 1 H -pyrazol-4-yl-7 H -pyrrolo [2,3-d] -pyrimidine 744
Ex. Nº R structureMS (M + H)NameEx Prep. No.
745 3794- (1- (1R) -2,2,2-Trifluoro-1 - [(4-methyl-1,3-thiazol-2yl) -methyl] ethyl-1H-pyrazol-4-yl) -7H-pyrrolo [2,3d] pyrimidine 745
746 3064-1- [1- (trifluoromethyl) but-3-in-1-yl] -1H-pyrazol-4yl-7H-pyrrolo [2,3-d] pyrimidine730
747 3084-1- [1- (trifluoromethyl) but-3-en-1-yl] -1H-pyrazol-4yl-7H-pyrrolo [2,3-d] pyrimidine727
748 3104-1- [1- (trifluoromethyl) butyl] -1H-pyrazol-4-yl-7Hpyrrolo- [2,3-d] pyrimidine731
749 image210 344 4-1- [4,4-difluoro-1- (trifluoro-methyl) but-3-en-1-yl] 1H-pyrazol-4-yl-7H-pyrrolo [2,3-d] -pyrimidine 732
750 image211 346 4-1- [4,4-difluoro-1- (trifluoro-methyl) butyl] -1Hpirazol-4-yl-7H-pyrrolo [2,3-d] pyrimidine 731
* Step 1 of Example 731 was modified as follows: Ph3P and CF2Br2 were combined in DMAC at 0 ° C and then allowed to warm to room temperature until the ilium formation was completed as determined by CLEM. Then, the ilium solution was cooled again to 0 ° C and the aldehyde and zinc were added to the ilium solution and the reaction was slowly heated to room temperature.
Example 727: 4- [1- (1-Cyclopentylbut-3-en-1-yl) -1H-pyrazol-4-yl] -7H-pyrrolo [2,3-d] pyrimidine trifluoroacetate salt
image212
Stage 1: (2E) -3-cyclopentyl acrylic acid
To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 ml) were added piperidine (0.15 ml) and cyclopentanecarbaldehyde (1.00 g, 10.2 mmol). The mixture was heated at 40 ° C for 2 hours followed by stirring at room temperature for 16 hours. Then, the mixture was cooled in an ice bath and 2 N HCl was added to acidify. The product was extracted with ether. The ether extract was washed with ac HCl. and brine, dried over sodium sulfate, filtered and the solvent removed in vacuo to provide the product (1.30 g, 77%), which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 7.06 (dd, 1H), 5.80 (dd, 1H), 2.70-2.54 (m, 1H), 1.93-1.32 (m , 8H); MS (ES): 141 (M + H).
Step 2. (2E) -3-Methyl cyclopentyl acrylate
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权利要求:
Claims (1)
[1]
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AU2006326548A1|2007-06-21|

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EP2348023A1|2011-07-27|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US74990505P| true| 2005-12-13|2005-12-13|

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US749905P|2005-12-13|

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US81023106P| true| 2006-06-02|2006-06-02|

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US810231P|2006-06-02|

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US85062506P| true| 2006-10-10|2006-10-10|

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US850625P|2006-10-10|

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US85687206P| true| 2006-11-03|2006-11-03|

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US856872P|2006-11-03|

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US85940406P| true| 2006-11-16|2006-11-16|

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US859404P|2006-11-16|

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