Pyrrolopyrimidine Compounds and Their Uses

• US 20090318441A1
• Filed: 05/24/2007
• Published: 12/24/2009
• Est. Priority Date: 05/26/2006
• Status: Active Grant

• Current Assignee: Novartis Pharmaceuticals Corporation (Novartis Ag), Astex Therapeutics Limited (Otsuka Holdings Company Limited)
• Original Assignee: Astex Therapeutics Limited (Otsuka Holdings Company Limited)
• Inventors: Sung, Moo Je, Brain, Christopher Thomas, Thoma, Gebhard
• Granted Patent: US 8,324,225 B2
• Time in Patent Office: Days
• US Class Current: 514/234.200
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases, particularly pyrrolopyrimidine compounds and derivatives are described which inhibit protein kinases. The organic compounds are useful in treating proliferative disease.

Claims

1. A method of regulating, modulating, or inhibiting protein kinase activity which comprises contacting a protein kinase with a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein;

the dashed line indicates a single or double bond;

A is N or CR⁵, wherein R⁵ is hydrogen or C₁-C₃-alkyl;

R² and R³ are each, independently, selected from the group consisting of hydrogen, hydroxyl, C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, substituted C₁-C₃-alkyl, substituted C₃-C₈-cycloalkyl, substituted heterocyclyl, substituted aryl and substituted heteroaryl;

R⁴ is selected from the group consisting of hydrogen, C₁-C₈-alkyl, substituted C₁-C₈-alkyl, C₃-C₈-cycloalkyl, substituted C₃-C₈-cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

when the bond between X and Y is a single bond, X is CR⁶R⁷, NR⁸ or C═

O, and Y is CR⁹R¹⁰ or C═

O;

when the bond between X and Y is a double bond, X is N or CR¹¹, and Y is CR¹²;

wherein R⁶ and R⁷ are each, independents selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydrogen, C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, substituted alkyl, substituted cycloalkyl, and substituted heterocyclyl;

R⁸ is hydrogen, C₁-C₃-alkyl, and C₃-C₈-cycloalkyl;

R⁹ and R¹⁰ are each, independently, hydrogen, C₁-C₃-alkyl, or C₃-C₈-cycloalkyl;

R¹¹ and R¹² are each, independently, selected from the group consisting of halo, hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, CN, C═

NOH, C═

NOCH₃, C(O)H, C(O)C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, substituted C₁-C₃-alkyl, substituted C₃-C₈-cycloalkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl, —

BNR¹³R¹⁴, —

BOR¹³, —

BC(O)R¹³, —

BC(O)OR¹³, —

BC(O)NR¹³R¹⁴;

wherein B is a bond, C₁-C₃-alkyl or branched C₁-C₃-alkyl;

wherein R¹³ and R¹⁴ are each, independently, selected from the group consisting of hydrogen, C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and substituted heteroaryl.

2. The method of claim 1, wherein R⁴ is branched or linear C₁-C₅-alkyl, wherein the branched C₁-C₅-alkyl group may be interrupted by one or more heteroatoms, and/or substituted with one or more heteroatoms, halogens, C₃-C₈ cycloalkyl groups, substituted C₃-C₈ cycloalkyl groups, C₃-C₈ heterocyclyl groups, aryl groups, heteroaryl groups, substituted aryl groups, or substituted heteroaryl groups.

3. The method of claim 1, wherein when R¹² is not hydrogen, R⁴ is selected from the group consisting of hydrogen, C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

4. The method of claim 3, wherein when R¹² is not hydrogen, R⁴ is branched or linear C₁-C₅-alkyl, wherein the branched C₁-C₅-alkyl group may be interrupted by one or more heteroatoms, and/or substituted with one or more heteroatoms, halogens, C₃-C₈ cycloalkyl groups, substituted C₃-C₈ cycloalkyl groups, C₃-C₈ heterocyclyl groups, aryl groups, heteroaryl groups, substituted aryl groups, or substituted heteroaryl groups.

5. The method of claim 1, wherein A is N.

6. The method of claim 1, wherein R⁴ is selected from the group consisting of hydrogen, branched C₁-C₅-alkyl, branched C₁-C₅-alkyl substituted by phenyl and C₃-C₆-cycloalkyl.

7. The method of claim 1, wherein R⁴ is C(H)(CH₂CH₃)₂, C(H)(CH₂CH₃)Ph, CH₂CH₃, cyclopropyl, cyclopentyl or cyclohexyl.

8. The method of claim 1, wherein the dashed line is a single bond, X is CH₂, C(C₁-C₃-alkyl)₂ or N(C₁-C₃-alkyl), and Y is C═

O.

9. The method of claim 8, wherein the dashed line is a single bond, X is CH₂ or C(CH₃)₂ and Y is C═

O.

10. The method of claim 1, wherein the dashed line is a double bond, X is CH, N, C—

C(O)C₁-C₃-alkyl or C—

(C₁-C₃-alkyl), and Y is CH, C—

CHO, C—

C₁-C₃-alkyl, C—

C₁-C₃alkoxy, C—

C(O)C₁-C₃-alkyl, C—

C═

NOH or C—

C═

NOCH₃.

11. The method of claim 1, wherein R² is H.

12. The method of claim 1, wherein R³ is an aryl group, which is further independently substituted one or more times by halogen, C₁-C₄-alkoxy, R¹⁵-amine, R¹⁵-heterocycle, or R¹⁵-heteroaryl, wherein R¹⁵ is a bond, C(O), N(H)C(O), N(H)SO₂, OC(O) or (CH₂)_1-4, wherein the (CH₂)_1-4 group may be interrupted by O, N(CH₃) or N(H).

13. The method of claim 12, wherein the aryl group is phenyl.

14. The method of claim 13, wherein the phenyl group is independently substituted one or more times with fluoro, methoxy, diethylamine, R¹⁵-piperazinyl, R¹⁵-morpholinyl, R¹⁵-piperidinyl, R¹⁵-triazolyl, R¹⁵-phenyl, R¹⁵-pyridinyl, R¹⁵-piperazinyl, R¹⁵-indazolyl, R¹⁵-pyrrolidinyl or R¹⁵-imidazolyl, wherein the piperazinyl, morpholinyl, piperidinyl, triazolyl, phenyl, pyridinyl, piperazinyl, indazolyl, pyrrolidinyl or imidazolyl groups may be further substituted with C₁-C₄-alkyl, C(O)C₁-C₄-alkyl, S(O)₂C₁-C₄-alkyl, OH, C(O)(CH₂)_1-3CN or N(H)C(O)C₁-C₄-alkyl.

15. The method of claim 13, wherein the phenyl group is substituted by N(H)C(O)aryl, C(O)N(H)C₁-C₄-alkyl, C(O)N(C₁-C₄-alkyl)₂ or C(O)N(H)C₃-C₈-cycloalkyl.

16. The method of claim 1, wherein the compound is selected from the group consisting of

17. The method of claim 1, wherein the protein kinase is a protein tyrosine kinase.

18. The method of claim 1, wherein the protein kinase is selected from the group consisting of abl, ATK, ber-abl, Blk, Brk, Btk, c-fms, e-kit, c-met, c-src, CDK, cRafl, CSFIR, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, 25 FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, fit-1, Fps, Frk, Fyn, GSK, Gst-Flkl, Hck, Her-2, Her-4, IGF-IR, INS-R, Jak, JNK, KDR, Lck, Lyn, MEK, p38, PANHER, PDGFR, PLK, PKC, PYK2, Raf, Rho, ros, SRC, t′

eII t′

e2, TRK, TYK2, UL97, VEGFR, Yes, and Zap70.

19. The method of claim 18, wherein the protein kinase is selected from the group consisting of CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9.

21. The method of claim 18, wherein the protein kinase is selected from the group consisting of Jak3 and CDK4.

20. (canceled)

22-23. -23. (canceled)

24. A method of treating a protein kinase-associated disorder comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the protein kinase-associated disorder is treated, wherein the compound is a compound of the Formula I.

25. The method of claim 24, wherein the protein kinase is selected from the group consisting of CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9.

28. The method of claim 24, wherein the protein kinase-associated disorder is selected from the group consisting of blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases and cancer.

29. The method of claim 24, wherein the protein kinase-associated disorder is cancer.

30. The method of claim 29, wherein the cancer is selected from the group consisting of breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, genitourinary tract, ovarian, gastric, bone, and pancreatic cancer.

26-27. -27. (canceled)

31-37. -37. (canceled)

38. A method of treating cancer comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the transplant rejection is treated, wherein the compound is a compound of the Formula I.

39. The method of claim 38, wherein the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer.

40-41. -41. (canceled)

42. A packaged protein kinase-associated disorder treatment, comprising a protein kinase-modulating compound of the Formula I, packaged with instructions for using an effective amount of the protein kinase-modulating compound to treat a protein kinase-associated disorder.

43. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein;

the dashed line indicates a single or double bond;

A is N or CR⁵, wherein R⁵ is hydrogen or C₁-C₃-alkyl;

R² and R³ are each, independently, selected from the group consisting of hydrogen, hydroxyl, C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, substituted C₁-C₃-alkyl, substituted C₃-C₈-cycloalkyl, substituted heterocyclyl, substituted aryl and substituted heteroaryl;

R⁴ is selected from the group consisting of hydrogen, C₁-C₈-alkyl, substituted C₁-C₈-alkyl, C₃-C₈-cycloalkyl, substituted C₃-C₈-cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

when the bond between X and Y is a single bond, X is CR⁶R⁷, NR⁸ or C═

O, and Y is CR⁹R¹⁰ or C═

O;

when the bond between X and Y is a double bond, X is N or CR¹¹, and Y is CR¹²;

wherein R⁶ and R⁷ are each, independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydrogen, C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, substituted alkyl, substituted cycloalkyl, and substituted heterocyclyl;

R⁸ is hydrogen, C₁-C₃-alkyl, and C₃-C₈-cycloalkyl;

R⁹ and R¹⁰ are each, independently, hydrogen, C₁-C₃-alkyl, or C₃-C₈-cycloalkyl;

R¹¹ and R¹² are each, independently, selected from the group consisting of halo, hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, CN, C═

NOH, C═

NOCH₃, C(O)H, C(O)C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, substituted C₁-C₃-alkyl, substituted C₃-C₈-cycloalkyl, substituted heterocyclyl, substituted aryl, substituted heteroaryl, —

BNR¹³R¹⁴, —

BOR¹³, —

BC(O)R¹³, —

BC(O)OR¹³, —

BC(O)NR¹³R¹⁴;

wherein B is a bond, C₁-C₃-alkyl or branched C₁-C₃-alkyl;

wherein R¹³ and R¹⁴ are each, independently, selected from the group consisting of hydrogen, C₁-C₃-alkyl, C₃-C₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and substituted heteroaryl.