PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS

• US 20140179673A1
• Filed: 12/20/2013
• Published: 06/26/2014
• Est. Priority Date: 12/21/2012
• Status: Active Grant

• Current Assignee: Gilead Calistoga LLC (Gilead Sciences Inc.)
• Original Assignee: Gilead Calistoga LLC (Gilead Sciences Inc.)
• Inventors: EVARTS, Jerry, PATEL, Leena, TREIBERG, Jennifer A., PERREAULT, Stephane, YEUNG, Arthur, PURVIS, Lafe J. II, KIM, Musong
• Granted Patent: US 9,018,221 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/08 : Bridged systems

Abstract

The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I),

or pharmaceutically acceptable salts thereof, in which R¹, R², n, R³, R⁴, R⁵ and R⁶ are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

Claims

1. A compound having the structure of formula (I):

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is:

unsubstituted aryl;

unsubstituted heteroaryl;

unsubstituted cycloalkyl;

aryl, heteroaryl, or cycloalkyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, —

OR^1a, —

C(O)OR^1a, —

C(O)R^1a, NH₂, alkyl, and haloalkyl, wherein R^1a is alkyl or haloalkyl;

unsubstituted alkyl;

or

alkyl substituted with OH.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R² is independently halo or unsubstituted alkyl, alkyl substituted with cyano or haloalkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is:

unsubstituted C_6-12 aryl;

or

C_6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, —

C(O)NR^3aR^3b and —

SO₂NR^3aR^3b, wherein R^3a and R^3b are independently hydrogen or C_1-6 alkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is:

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen, C_1-6 alkyl, or NH₂.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is C_1-6 alkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is hydrogen.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ together with the carbon to which it is attached and R⁶ together with the nitrogen to which it is attached are taken together to form a five- or six-membered heterocycloalkyl.

11. The compound of claim 1, wherein the compound is the (S)-enantiomer.

12. The compound of claim 1, wherein the compound has the structure of formula (IA):

13. The compound of claim 1, wherein the compound has the structure of formula (IB):

14. The compound of claim 1, wherein the compound has the structure of formula (IC):

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5,8-difluoroquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one;

(S)-methyl 6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinate;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyridazin-3-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

2-((S)-1-((6-amino-5-((R)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

2-((S)-1-((6-amino-5-((S)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

2-((S)-1-((6-amino-5-((R)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

2-((S)-1-((6-amino-5-((S)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(cyclopropylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(cyclopropylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-5-chloro-2-(1-((2,6-diamino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)piperidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)pyrrolidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-3-(2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzamide;

(S)-3-(2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)-N-ethylbenzenesulfonamide;

(S)-3-(2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide;

(S)-2-(1-((6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((2-aminobenzo[d]thiazol-6-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((5-((1H-pyrazol-4-yl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one; and

(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one,

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising:

a compound of claim 1, or a pharmaceutically acceptable salt thereof; and

at least one pharmaceutically acceptable vehicle.

17. A method for treating a human, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of PI3Kδ

activity, comprising administering to the human a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the disease or condition is an inflammatory disorder, an autoimmune disease, or a cancer.

19. The method of claim 17, wherein the disease or condition is lymphoma, multiple myeloma, or leukemia.

20. The method of claim 17, wherein the disease or condition is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin'"'"'s lymphoma (NHL), indolent non-Hodgkin'"'"'s lymphoma (iNHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom'"'"'s macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer, colon cancer, systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren'"'"'s syndrome, autoimmune hemolytic anemia, asthma, rheumatoid arthritis, multiple sclerosis, or lupus.