# US 8,785,632 B2 · Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors

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- Number: US 8,785,632 B2
- Document ID: US8785632B2
- Status: Granted
- Kind: B2
- Application number: 13/537,759
- Filed: 2012-06-29
- Published: 2012-10-18
- Granted: 2014-07-22
- Earliest claimed: 2004-08-26
- Assignees: Agouron Pharmaceuticals, Inc.; Pfizer Inc.
- Applicants: Jingrong Jean Cui; Lee Andrew Funk; Lei Jia; Pei-Pei Kung; Jerry Jialun Meng; Mitchell David Nambu; Mason Alan Pairish; Hong Shen; Michelle Tran-Dube
- Inventors: Jingrong Jean Cui; Lee Andrew Funk; Lei Jia; Pei-Pei Kung; Jerry Jialun Meng; Mitchell David Nambu; Mason Alan Pairish; Hong Shen; Michelle Tran-Dube
- Web page: https://patentgrep.com/patent/US8785632B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/4418: having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 213/76: to which a second hetero atom is attached (nitro radicals C07D213/61)
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more 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

## Abstract

Enantiomerically pure compound of formula 1 are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.

## Claims

### Claim 1

An enantiomerically pure compound of formula 1
wherein:
Y is CR12;
R1 is 5-12 membered heteroaryl; and each hydrogen in R1 is optionally replaced by one or more R3 groups;
R2 is hydrogen;
each R3 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O)mR4, —SO2NR4R5, —S(O)2OR4, —NO2, —NR4R5, —(CR6R7)nOR4, —CN, —C(O)R4, —OC(O)R4, —O(CR6R7)nR4, —NR4C(O)R5, —(CR6R7)nC(O)OR4, —(CR6R7)nC(O)NR4R5, —(CR6R7)nNCR4R5, —C(═NR6)NR4R5, —NR4C(O)NR5R6, or —NR4S(O)pR5, each hydrogen in R3 is optionally replaced by R8, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally replaced by R8;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —NH2, —CN, —OH, —O—C1-12 alkyl, —O—(CH2)nC3-12 cycloalkyl, —O—(CH2)nC6-12 aryl, —O—(CH2)n(3-12 membered heteroalicyclic) or —O—(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally replaced by R11;
each R11 is independently halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —O—C1-12 alkyl, —O—(CH2)nC3-12 cycloalkyl, —O—(CH2)nC6-12 aryl, —O—(CH2)n(3-12 membered heteroalicyclic), —O—(CH2)n(5-12 membered heteroaryl) or —CN, and each hydrogen in R11 is optionally substituted by halogen, —OH, —CN, —C1-12 alkyl which may be partially or fully halogenated, or —O—C1-12 alkyl which may be partially or fully halogenated;
R12 is hydrogen;
each m is independently 0, 1 or 2;
each n is independently 0, 1, 2, 3 or 4; and
each p is independently 1 or 2;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is a furan, thiophene, pyrrole, thiazole, imidazole pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, and each hydrogen in R1 is optionally replaced by R3.

### Claim 3

An enantiomerically pure compound of formula 1a
wherein:
Y is CH;
R1 is pyrazole; and each hydrogen in R1 is optionally replaced by R3;
each R3 is independently 3-12 membered heteroalicyclic, and each hydrogen in R3 is optionally replaced by R8;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —NH2, —CN, —OH, —O—C1-12 alkyl, —O—(CH2)nC3-12 cycloalkyl, —O—(CH2)nC6-12 aryl, —O—(CH2)n(3-12 membered heteroalicyclic) or —O—(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally replaced by R11;
each R11 is independently halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —O—C1-12 alkyl, —O—(CH2)nC3-12 cycloalkyl, —O—(CH2)nC6-12 aryl, —O—(CH2)n(3-12 membered heteroalicyclic), —O—(CH2)n(5-12 membered heteroaryl) or —CN, and each hydrogen in R11 is optionally substituted by halogen, —OH, —CN, —C1-12 alkyl which may be partially or fully halogenated, or —O—C1-12 alkyl which may be partially or fully halogenated; and
each n is independently 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.

### Claim 4

An enantiomerically pure compound selected from the group consisting of 3[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine; 1-[4-(4-{6-Amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl]-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone; and 3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine; or a pharmaceutically acceptable salt thereof.