Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of Their Use and Manufacture

• US 20100298290A1
• Filed: 05/20/2010
• Published: 11/25/2010
• Est. Priority Date: 05/22/2009
• Status: Active Grant

• Current Assignee: Exelixis Incorporated
• Original Assignee: Exelixis Incorporated
• Inventors: Zaharia, Cristiana A., Joshi, Anagha, Harris, Jason R., Jackson-Ugueto, Eileen E., Buhr, Chris Allen, Ng, Stephanie, Bowles, Owen Joseph, Kim, Angie Inyoung, Tsuhako, Amy Lew, Anand, Neel Kumar, Blazey, Charles M., Manalo, Jean-Claire Limun, Curtis, Jeffry Kimo, Bussenius, Joerg, Peto, Csaba J., Rice, Kenneth D., DeFina, Steven Charles, Tsang, Tsze H., Dubenko, Larisa, Ma, Sunghoon
• Granted Patent: US 8,648,066 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention is directed to Compounds of Formula I:

and pharmaceutically acceptable salts or solvates thereof, as well as methods of making and using the compounds.

Claims

1. A Compound of Formula I:

2. The Compound of claim 1 is according to Formula I(a)

3. The Compound of claim 1, or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, where

R¹ is phenyl optionally substituted with one, two, or three R⁶ groups;

or

R¹ is heteroaryl optionally substituted with one, two, or three R⁷;

R² is heteroaryl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

R³, R^3a, R^3b, R^3c, and R^3d are independently hydrogen;

cyano;

alkyl;

alkenyl;

halo;

haloalkyl;

hydroxyalkyl;

alkoxyalkyl;

cyanoalkyl;

—

SR¹²;

—

S(O)₂R²⁰;

carboxy;

alkoxycarbonyl;

halocarbonyl;

—

NR¹¹R^11a;

—

OR^11a;

phenyl optionally substituted with one or two groups which are independently alkyl or halo;

phenylalkyl optionally substituted with one or two R¹⁹;

cycloalkyl;

cycloalkylalkyl;

heterocycloalkyl optionally substituted with one or two groups which are independently alkyl, alkoxycarbonyl, or benzyloxycarbonyl;

heterocycloalkylalkyl optionally substituted with one or tow groups which are independently alkyl, alkoxycarbonyl, or benzyloxycarbonyl;

heteroaryl;

heteroarylalkyl;

or alkyl substituted with one or two R¹⁶;

or

two of R³, R^3a, R^3b, R^3c, and R^3d, when attached to the same carbon, form a cycloalkyl or a heterocycloalkyl; and

the other of R³, R^3a, R^3b, R^3c, and R^3d are hydrogen;

each R⁶, when R⁶ is present, is independently nitro;

cyano;

halo;

alkyl;

halo;

haloalkyl;

—

OR^8a;

—

NR⁸R^8a;

—

C(O)NR⁸R^8a;

—

S(O)₂R⁸;

—

NR⁸C(O)R⁹;

—

NR⁸S(O)₂R^8a;

—

NHC(O)NHR⁹;

carboxy, —

C(O)OR⁹;

or heteroaryl optionally substituted with 1, 2, or 3 R¹⁴;

each R⁷, when R⁷ is present, is independently oxo;

nitro;

cyano;

alkyl;

alkenyl;

halo;

haloalkyl;

hydroxyalkyl;

alkoxyalkyl;

—

OR^8a;

—

SR¹³;

—

S(O)R¹³;

—

S(O)₂R^13a;

—

NR⁸R^8a;

—

C(O)NR⁸R^8a;

—

NR⁸C(O)OR⁹;

—

NR⁸C(O)R⁹;

—

NR⁸S(O)₂R^8a;

—

NR⁸C(O)NR^8aR⁹;

—

C(O)OR⁹;

halocarbonyl;

—

S(O)₂NR⁸R⁹;

alkylsulfonylalkyl;

alkyl substituted with one or two —

NR⁸R^8a;

alkyl substituted with one or two —

NR⁸C(O)R^8a;

alkyl substituted with one or two —

NR⁸C(O)OR⁹;

alkyl substituted with one or two —

S(O)₂R^13a;

cycloalkyl;

cycloalkylalkyl;

heterocycloalkyl optionally substituted with one or two groups which are independently alkyl or amino;

phenyl;

phenylalkyl;

heterocycloalkylalkyl;

heteroaryl;

or heteroarylalkyl;

R⁸, R¹¹, R¹⁵, R¹⁷, and R¹⁸ are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, or haloalkyl;

R^8a;

R^11a; and

R^15a are independently hydrogen;

alkyl;

alkenyl;

alkynyl;

haloalkyl;

hydroxyalkyl;

cyanoalkyl;

aminoalkyl;

alkylaminoalkyl;

dialkylaminoalkyl;

alkoxyalkyl;

carboxyalkyl;

cycloalkyl;

cycloalkylalkyl;

heterocycloalkyl optionally substituted with one or two groups which are independently alkyl, alkoxycarbonyl, or benzyloxy;

heterocycloalkylalkyl optionally substituted with one or two groups which are independently alkyl, alkoxycarbonyl, or benzyloxy;

phenyl optionally substituted with one or two groups which are independently halo, alkyl, or alkoxy;

phenylalkyl;

heteroaryl;

or heteroarylalkyl;

R⁹ is hydrogen;

alkyl;

alkenyl;

alkynyl;

hydroxyalkyl;

alkoxyalkyl;

aminoalkyl;

alkylaminoalkyl;

dialkylaminoalkyl;

haloalkyl;

hydroxyalkyl substituted with one, two, or three groups which are independently halo, amino, alkylamino, or dialkylamino;

alkyl substituted with one or two aminocarbonyl;

phenyl;

phenylalkyl;

cycloalkyl;

cycloalkylalkyl optionally substituted with one or two groups which are independently amino or alkyl;

heterocycloalkyl optionally substituted with one or two groups which are independently alkyl, alkoxycarbonyl, or benzyloxy;

or heterocycloalkylalkyl optionally substituted with one or two groups which are independently alkyl, alkoxycarbonyl, or benzyloxy;

R¹² is alkyl or phenylalkyl;

R¹³ is alkyl, hydroxyalkyl, or haloalkyl; and

R^13a is hydroxy, alkyl, haloalkyl, hydroxyalkyl, or heterocycloalkyl optionally substituted with one or two groups which are independently halo, amino, alkylamino, dialkylamino, hydroxy, alkyl, or hydroxyalkyl;

each R¹⁴, when R¹⁴ is present, is independently amino, alkylamino, dialkylamino, acylamino, halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or phenyl;

each R¹⁶ is independently —

NR¹¹R^11a, —

NR¹⁵S(O)R^15a, —

OC(O)R¹⁷, or —

OR¹⁸;

each R¹⁹ is independently halo, alkyl, haloalkyl, amino, alkylamino, dialkylamino, or alkoxy; and

R²⁰ is amino, alkylamino, dialkylamino, or heterocycloalkyl.

4. The Compound of claim 2, or where R¹ is phenyl optionally substituted with one, two, or three R⁶ groups;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

5. The Compound of claim 4 where R¹ is phenyl substituted with one or two R⁶ groups independently nitro, halo, alkoxy, —

OR^8a, —

S(O)₂R⁸;

—

NR⁸R^8a, —

NR⁸S(O)₂R^8a, —

NR⁸C(O)R⁹, —

C(O)NR⁸R^8a, —

NR⁸C(O)NR^8aR⁹, carboxy, alkoxycarbonyl, or heteroaryl optionally substituted with one or two R¹⁴;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

6. The Compound of claim 5 where R¹ is phenyl substituted with one R⁶ where R⁶ is —

S(O)₂R⁸, —

C(O)NR⁸R^8a or heteroaryl optionally substituted with one or two R¹⁴;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

7. The Compound of claim 2 where R¹ is heteroaryl optionally substituted with one, two, or three R⁷;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

8. The Compound of claim 7 where R¹ is a 9-membered heteroaryl optionally substituted with one, two, or three R⁷;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

9. The Compound of claim 8 where R¹ is a 9-membered heteroaryl and the 9-membered heteroaryl is benzimidazolyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-c]pyridinyl, or thiazolo[5,4-b]pyridinyl where R¹ is optionally substituted with one, two, or three R⁷;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

10. The Compound of claim 7 where R¹ is a 5-membered heteroaryl optionally substituted with one, two, or three R⁷;

optionally where the 5-membered heteroaryl is thiazolyl or pyrazolyl and where the 5-membered is optionally substituted with one, two, or three R⁷;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

11. The Compound of claim 7 where R¹ is a 6-membered heteroaryl optionally substituted with one, two, or three R⁷;

optionally where the 6-membered heteroaryl is pyrimidinyl, pyridinyl, pyrazinyl, or pyridazinyl and where the 6-membered heteroaryl is optionally substituted with one, two, or three R⁷;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

12. The Compound of claim 11 where R¹ is pyridinyl optionally substituted with one, two, or three R⁷;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

13. The Compound of claim 7 where R¹ is optionally substituted with one or two R⁷ where each R⁷, when R⁷ is present, is independently halo, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, —

NR⁸R^8a, or —

NR⁸C(O)OR⁹;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

14. The Compound of claim 7 where R² is quinazolin-4-yl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

where R^3c and R^3d are hydrogen;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

15. The Compound of claim 7 where R² is quinolin-4-yl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

where R^3c and R^3d are hydrogen;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

16. The Compound of claim 7 where R² is isoquinolin-4-yl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

where R^3c and R^3d hydrogen;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

17. The Compound of claim 7 where R² is according to formula (a)

18. The Compound of claim 17 where R³ is hydrogen, halo, alkyl, cycloalkylalkyl, or phenylalkyl optionally substituted with one or two R¹⁹;

R^3a is hydrogen, alkyl, halo, optionally substituted heterocycloalkyl, or —

NR¹¹R^11a; and

R^3b is hydrogen, alkyl, hydroxyalkyl, or alkyl substituted with one or two R¹⁶;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

20. The Compound according to claim 7 where R² is according to formula (g)

21. The Compound according to claim 7 where R² is according to formula (d)

22. The Compound of claim 21 where R³ and R^3a together with the carbon to which they are attached form an optionally substituted cycloalkyl;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

23. The Compound of claim 21 where R³ and R^3a are halo or R³ and R^3a are alkyl;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

24. The Compound according to claim 20 where R^3b is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, or alkyl substituted with one R¹⁶;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

25. The Compound according to claim 7 where R² is according to formula (e)

26. A Compound according to claim 1 is

27. A pharmaceutical composition which comprises a compound, optionally as pharmaceutically acceptable salt thereof, of claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.

28. A method of making a Compound of Formula I, according to claim 1 which method comprises

(a) reacting the following, or a salt thereof:

29. A method for treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a Compound of claim 1, optionally as a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a Compound of claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.

30. The method of claim 29 where the disease is cancer.

31. The method of claim 30 where the cancer is breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NPM/ALK-transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, or head and neck cancer.

32. The Compound of claim 4 where R² is quinazolin-4-yl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

where R^3c and R^3d are hydrogen;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

33. The Compound of claim 4 where R² is quinolin-4-yl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

where R^3c and R^3d are hydrogen;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

34. The Compound of claim 4 where R² is isoquinolin-4-yl substituted with R³, R^3a, R^3b, R^3c, and R^3d;

where R^3c and R^3d hydrogen;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

35. The Compound of claim 4 where R² is according to formula (a)

36. The Compound according to claim 4 where R² is according to formula (g)

37. The Compound according to claim 4 where R² is according to formula (d)

38. The Compound according to claim 4 where R² is according to formula (e)

39. The Compound according to claim 21 where R^3b is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, or alkyl substituted with one R¹⁶;

or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

19. (canceled)