# US 10,501,460 B2 · Heterocyclic compounds and uses thereof

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- Number: US 10,501,460 B2
- Document ID: US10501460B2
- Status: Granted
- Kind: B2
- Application number: 15/814,179
- Filed: 2017-11-15
- Published: 2018-03-15
- Granted: 2019-12-10
- Earliest claimed: 2013-03-15
- Assignees: Plexxikon Inc.
- Applicants: Plexxikon Inc.
- Inventors: Jiazhong Zhang; Wayne Spevak
- Web page: https://patentgrep.com/patent/US10501460B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/695: Silicon compounds
- A61P 35/00: Antineoplastic agents
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07F 7/0814: {said ring is substituted at a C ring atom by Si}
- C07F 7/10: containing nitrogen {having a Si-N linkage}
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions containing such a compound and their therapeutic uses.

## Claims

### Claim 1

A method for treating a subject suffering from a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of formula (III),
wherein the disease or condition is breast cancer, midline carcinomas, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma,
wherein the compound of formula (III) has the following structure:
or a pharmaceutically acceptable salt, solvate, a tautomer, a stereoisomer, or a deuterated analog thereof,
Y1 is N;
R1 is deuterated C1-6alkyl, C1-6alkyl, aryl, aryl-C1-4alkyl, C3-6-cycloalkyl, C3-6- cycloalkylakyl, heteroaryl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, C2-6alkenyl, or C2-6alkynyl, each of which is optionally substituted with from 1-3 Rjgroups,
R2 is H;
R3 is deuterated C1-6alkyl, aryl, aryl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, C3-8cycloalkyl, C3-8 cycloalkenyl, C3-8 cycloalkyl-C1-4alkyl, C2-6 alkynyl, heterocycloalkyl, or heterocycloalkyl-C1-4alkyl, wherein each R3 is optionally substituted with 1-3 substituents independently selected from CN, -OH, -NH2, -NO2, -C(O)OH, - C(S)OH,-C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)N H2, -CH═C(Rn)(Rn), -ORn, -SRn, -OC(O)Rn, -OC(S)Rn, -P(═O)HRn, -P(═O)RnRn, -PH(═O)ORn, - P(═O)(ORn)2, -OP(═O)(ORn)2 , -C(O)H, - O(CO)ORn, -C(O)Rn, -C(S)Rn, -C(O)ORn, -C(S)ORn, -S(O)Rn, -S(O)2Rn, -C(O)NHRn, -C(S)NHRn, -C(O)NRnRn, -C(S)NRnRn, -S(O)2NHRn, -S(O)2NRnRn, -C(NH)NHRn, -C(NH)NRnRn, -NHC(O)Rn, -NHC(S)Rn, -NRnC(O)Rn, -NRnC(S)Rn, -NHS(O)2Rn, -NRnS(O)2Rn, -NHC(O)NHRn, -NHC(S)NHRn, -NRn, -NRnC(O)NH2, -NRnC(S)NH2, -NRnC(O)NHRn, -NRnC(S)NHRn, -NHC(O)NRnRn, -NHC(S)NRnRn, -NRC(O)NRRn, -NRnC(S)NRnRn, -NHS(O)2NHRn, -NRnS(O)2NH2, -NRnS(O)2NHRn, -NHS(O)2NRnRn, -NRnS(O)2NRnRn, -NHRn, Rn, and -NRnRn, wherein each Rn is independently H, C1-6alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cyclaoalkylylalkyl; or two Rn groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8- membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N, and S, wherein the nitrogen or sulfur ring atoms are optionally oxidized, wherein the aliphatic or aromatic portion of Rn is further optionally substituted with from 1-3 Rh;
R4 is H;
R5 is:
each of which is optionally substituted with from 1-2 R11;
wherein the wavy line indicates the point of attachment to the rest of molecule and each R11 is independently D, halogen, C1-6alkyl, deuterated C1-6alkyl, C1-4haloalkyl, C1-4haloalkoxy, or CN;
L is —C(R6)(R7)—, —C(O)—, —S(O)—, —S—, —P(O)(Ra)—, —CH═C(Rb)—, or —Si(Rc)(Rc);
R6 is H or D;
R7 is H, D, halogen, —OH, C1-6alkyl, deuterated C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, aryl-C1-4 alkyl, C1-6alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, heteroaryl, heteroarylalkyl, C1-6haloalkyl, C1-6haloalkoxy, —ORd, —NRdRd, —C(O)ORd, —OC(O)Rd, —OC(O)ORd, —C(O)Rd, —NHC(O)Rd, —C(O)NRdRd, —SO2Rd, —NHSO2Rd, or —SO2NRdRd,
wherein R7 is further optionally substituted with from 1-3 Rh groups;
Ra is optionally substituted C1-6alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rb is H or C1-6alkyl;
each Rc is independently C1-6alkyl or C1-6alkoxy;
each Rd is independently H, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, or aryl;
each Rh is independently halogen, —CN, —OH, —NH2, —NO2, —CH═C(Rk)(Rk), —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NH2, —NHC(O)NH2, —NHC(S)NH2, —NHS(O)2NH2, —C(NH)NH2, —ORi, —SRi, —OC(O)Ri, —OC(S)Ri, —P(═O)HRi, —P(═O)RiRi, —PH(═O)ORi, —P(═O)(ORi)2, —OP(═O)(ORi)2, —C(O)H, —O(CO)ORi, —C(O)Ri, —C(S)Ri, —C(O)ORi, —C(S)OR1, —S(O)Ri, —S(O)2Ri, —C(O)NHRi, —C(S)NHRi, —C(O)NRiRi, —C(S)NRiRi, —S(O)2NHRi, —S(O)2NRiRi, —C(NH)NHRi, —C(NH)NRiRi, —NHC(O)Ri, —NHC(S)Ri, —NRiC(O)Ri, —NRiC(S)Ri, —NHS(O)2Ri, —NRiS(O)2Ri, —NHC(O)NHRi, —NHC(S)NHRi, —NRiC(O)NH2, —NRiC(S)NH2, —NRiC(O)NHRi, —NRiC(S)NHRi, —NHC(O)NRiRi, —NHC(S)NRiRi, —NRiC(O)NRiRi, —NRiC(S)NRiRi, —NHS(O)2NHRi, —NRiS(O)2NH2, —NRiS(O)2NHRi, —NHS(O)2NRiRi, —NRiS(O)2NRiRi, Ri, —NHRi, or —NRiRi,
each Ri is independently C1-6alkyl, aryl, aryl-C1-2alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocycloalkyl, or heterocycloalkyl-C1-4alkyl;
Rj is halogen, —CN, —OH, —NH2, —NO2, —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NH2, —NHC(O)NH2, —NHC(S)NH2, —NHS(O)2NH2, —C(NH)NH2, —CH═C(Rk)(Rk), —ORk, —SRk, —OC(O)Rk, —OC(S)Rk, —P(═O)HRk, —P(═O)RkRk, —PH(═O)ORk, —P(═O)(ORk)2, —OP(═O)(ORk)2, —C(O)H, —O(CO)ORk, —C(O)Rk, —C(S)Rk, —C(O)ORk, —C(S)ORk, —S(O)Rk, —S(O)2Rk, —C(O)NHRk, —C(S)NHRk, —C(O)NRkRk, —C(S)NRkRk, —S(O)2NHRk, —S(O)2NRkRk, —C(NH)NHRk, —C(NH)NRkRk, —NHC(O)Rk, —NHC(S)Rk, —NRkC(O)Rk, —NRkC(S)Rk, —NHS(O)2Rk, —NRkS(O)2Rk, —NHC(O)NHRk, —NHC(S)NHRk, —NRkC(O)NH2, —NRkC(S)NH2, —NRkC(O)NHRk, —NRkC(S)NHRk, —NHC(O)NRkRk, —NHC(S)NRkRk, —NRkC(O)NRkRk, —NRkC(S)NRkRk, —NHS(O)2NHRk, —NRkS(O)2NH2, —NRkS(O)2NHRk, —NHS(O)2NRkRk, —NRkS(O)2NRkRk, —NHRk, or —NRkRk; and
each Rk is independently H, C1-6alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl; or two Rk groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N, and S, wherein the nitrogen or sulfur ring atoms are optionally oxidized, and wherein Rk is optionally substituted with from 1-3 Rh.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the disease or condition mediated by a bromodomain is non-small cell lung cancer, midline carcinomas, or breast cancer.

### Claim 3 (depends on 1)

The method of claim 1, having formula (V):

### Claim 4 (depends on 1)

The method of claim 1, wherein
R7 is D, halogen, —OH, C1-6alkyl, deuterated C1-6alkyl, aryl, aryl-C1-4 alkyl, C1-6alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, heteroaryl, heteroarylalkyl, C1-6haloalkyl, C1-6haloalkoxy, —ORd, —NRdRd, —C(O)ORd, —OC(O)Rd, —OC(O)ORd, —C(O)Rd, —NHC(O)Rd, —C(O)NRdRd, —SO2Rd, —NHSO2Rd, or —SO2NRdRd.

### Claim 5 (depends on 1)

The method of claim 1, wherein L is a —C(O)—, —S—, —P(O)(C1-6alkyl)-, —P(O)(aryl)-, —CH(OH)—, —CHF—, —CH(C1-6alkyl)-, —CH(C3-6cycloalkyl)-, or —CH(C1-6haloalkyl)-.

### Claim 6 (depends on 1)

The method of claim 1, wherein:
L is —C(R6)(R7)—;
R6 is H; and
R7 is —OH, C1-6alkyl, aryl, C3-6cycloalkyl, heterocycloalkyl, heteroaryl, C1-6haloalkyl, —ORd, —C(O)NRdRd, or —SO2Rd.

### Claim 7 (depends on 1)

The method of claim 1, wherein R5 is 4-isoxazolyl, and R11 is C1-6alkyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R5 is 4-isoxazolyl, and R11 is D, CH3, or CD3.

### Claim 9 (depends on 1)

The method of claim 1, wherein R1 is deuterated C1-6alkyl, C1-6alkyl, aryl, aryl-C1-4alkyl, C3-6-cycloalkyl, C3-6-cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, C2-6alkenyl, or C2-6alkynyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein R3 is C1-6alkyl, aryl, aryl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-4alkyl, heterocycloalkyl, or heterocycloalkyl-C1-4alkyl, wherein each R3 is optionally substituted with 1-3 substituents independently selected from CN, —OH, —NH2, —NO2, —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NH2, —NHC(O)NH2, —NHC(S)NH2, —NHS(O)2NH2, —C(NH)NH2, —CH═C(Rn) (Rn), —ORn, —SRn, —OC(O)Rn, —OC(S)Rn, —P(═O)HRn, —P(═O)RnRn, —PH(═O)ORn, —P(═O)(ORn)2, —OP(═O)(ORn)2, —C(O)H, —O(CO)ORn, —C(O)Rn, —C(S)Rn, —C(O)ORn, —C(S)ORn, —S(O)Rn, —S(O)2Rn, —C(O)NHRn, —C(S)NHRn, —C(O)NRnRn, —C(S)NRnRn, —S(O)2NHRn, —S(O)2NRnRn, —C(NH)NHRn, —C(NH)NRnRn, —NHC(O)Rn, —NHC(S)Rn, —NRnC(O)Rn, —NRnC(S)Rn, —NHS(O)2Rn, —NRnS(O)2Rn, —NHC(O)NHRn, —NHC(S)NHRn, —NRnC(O)NH2, —NRnC(S)NH2, —NRnC(O)NHRn, —NRnC(S)NHRn, —NHC(O)NRnRn, —NHC(S)NRnRn, —NRnC(O)NRnRn, —NRnC(S)NRnRn, —NHS(O)2NHRn, —NRnS(O)2NH2, —NRnS(O)2NHRn, —NHS(O)2NRnRn, —NRnS(O)2NRnRn, —NHRn, Rn, and —NRnRn.

### Claim 11

A method for treating a subject suffering from a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound,
wherein the disease or condition is breast cancer, midline carcinomas, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma,
wherein the compound has one of the following structures:
or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the disease or condition mediated by a bromodomain is non-small cell lung cancer, midline carcinomas, acute myelogenous leukemia, or breast cancer.

### Claim 13 (depends on 1)

The method of claim 1, wherein the disease or condition mediated by a bromodomain is acute myelogenous leukemia.

### Claim 14 (depends on 1)

The method of claim 1, wherein the disease or condition mediated by a bromodomain is chronic lymphocytic leukemia.

### Claim 15 (depends on 13)

The method according to claim 13, further comprising administering a chemotherapeutic agent.

### Claim 16 (depends on 13)

The method according to claim 13, further comprising administering azacitidine.