# US 2013/0158020 A1 · Indazole derivatives useful as erk inhibitors

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- Number: US 2013/0158020 A1
- Document ID: US20130158020A1
- Status: Published application
- Kind: A1
- Application number: 13/819,366
- Filed: 2011-08-29
- Published: 2013-06-20
- Earliest claimed: 2010-09-01
- Assignees: Merck Sharp & Dohme Corp.
- Inventors: Yongqi Deng; Gerald W. Shipps, JR.; Sie-Mun Lo; Liang Zhu; Alan B. Cooper; Kiran Muppalla
- Web page: https://patentgrep.com/patent/US20130158020A1

## CPC

- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- 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 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 491/113: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides a compound of the Formula I: Formula I or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R, R1, R2, R3, R4, X, m and n are as defined herein. The compounds are ERK inhibitors. Also disclosed are pharmaceutical compositions comprising the above compounds and methods of treating cancer using the same.

## Claims

### Claim 1

A compound of Formula I
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
R is H;
R1 is selected from the group consisting of aryl, heterocyclyl and —C(═O)—NR5R6;
R2 is H or alkyl;
X is selected from the group consisting of —NR7, —C(R8)(R9)—, —O—, —S—, —S(═O)—, and —S(═O)2;
each R3 independently is selected from the group consisting of alkyl, aryl, hydroxyl, and —S-alkyl, or wherein two R3 groups together with the same carbon atom to which both are attached form —C(═O)—;
m is 0, 1, or 2;
n is 0 or 1;
R4 is selected from the group consisting of H, alkyl, aryl, —C(═O)-aryl, and —C(═O)—O-alkyl;
R5, R6, and R7 independently are H or alkyl;
R8 and R9 independently are H, alkyl or aryl; or —C(R8)(R9)— together is heterocyclyl.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R1 is heterocyclyl which is pyridyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is —C(═O)—NR5R6 wherein R5 is H and R6 is alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein said R6 alkyl is unsubstituted or substituted with an aryl substituent.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 is H.

### Claim 6 (depends on 1)

The compound of claim 1, wherein m is 0.

### Claim 7 (depends on 1)

The compound of claim 1, wherein m is 1, and R3 is selected from the group consisting of alkyl, aryl, hydroxyl, and —S-alkyl; wherein said R3 alkyl is hydroxymethyl and said R3 aryl is phenyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein m is 2, and the two R3 groups together with the carbon atom to which both are attached form —C(═O)—.

### Claim 9 (depends on 1)

The compound of claim 1, wherein
is selected from the group consisting of:

### Claim 10 (depends on 1)

The compound of claim 1, wherein R4 is alkyl, which is unsubstituted or substituted with at least one substituent selected from the group consisting of aryl and heteroaryl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein said R4 is alkyl which is substituted with a heteroaryl selected from the group consisting of pyridyl, thiazolyl, and thiophenyl.

### Claim 12 (depends on 1)

The compound of claim 1, selected from the group consisting of:
N-[3-[6-(1-METHYLETHOXY)-3-PYRIDINYL]-1H-INDAZOL-5-YL]-4-(PHENYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
N-[3-[6-(1-METHYLETHOXY)-3-PYRIDINYL]-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(4-THIAZOLYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(3-THIENYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(2-PYRIDINYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(2-PYRIDINYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
4-[(2-BROMOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
4-[(2-BROMOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(3-PYRIDINYLMETHYL)-2-THIOMORPHOLINECARBOXAMIDE;
4-[(2-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
4-[(2-METHYL-4-THIAZOLYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(2-PYRIDINYLMETHYL)-2-THIOMORPHOLINECARBOXAMIDE;
4-(4-FLUOROPHENYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(4-THIAZOLYLMETHYL)-2-THIOMORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(3-THIENYLMETHYL)-2-THIOMORPHOLINECARBOXAMIDE;
4-[(2-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
PHENYLMETHYL 3-[[[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]AMINO]CARBONYL]-1-PIPERAZINECARBOXYLATE;
4-[(2-METHYL-4-THIAZOLYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(3-PYRIDINYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
4-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
1-[(2-BROMOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
1-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
1-[(2-CHLOROPHENYL)METHYL]-N-[3-[-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
1-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
1-METHYL-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
4-[(4-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-CYANOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CYANOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-CYANOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[4-(METHYLTHIO)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
4-[(2-CHLORO-6-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUORO-4-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[2-FLUORO-6-(TRIFLUOROMETHYL)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUORO-4,5-DIMETHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-CHLORO-2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[2-FLUORO-3-(TRIFLUOROMETHYL)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[2-FLUORO-5-(TRIFLUOROMETHYL)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,3-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,6-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,4-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUORO-5-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CHLORO-2,6-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-CHLORO-3,6-DIFLUOROPHENYL)METHYL]-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CHLORO-4-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3,5-DICHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,5-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-PHENYL-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
1-PHENYL-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-PIPERAZINECARBOXAMIDE;
5-[[[4-[(2-FLUOROPHENYL)METHYL]-2-THIOMORPHOLINYL]CARBONYL]AMINO]-N-METHYL-1H-INDAZOLE-3-CARBOXAMIDE;
N-BUTYL-5-[[[4-[(2-FLUOROPHENYL)METHYL]-2-THIOMORPHOLINYL]CARBONYL]AMINO]-1H-INDAZOLE-3-CARBOXAMIDE;
5-[[[4-[(2-FLUOROPHENYL)METHYL]-2-THIOMORPHOLINYL]CARBONYL]AMINO]-N-(PHENYLMETHYL)-1H-INDAZOLE-3-CARBOXAMIDE;
1-(2-CYANOPHENYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
1-BENZOYL-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
4-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2(S)-PIPERAZINECARBOXAMIDE;
4-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2(R)-PIPERAZINECARBOXAMIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2(S)-THIOMORPHOLINECARBOXAMIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2(R)-THIOMORPHOLINECARBOXAMIDE;
5-PHENYL-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE, 1-OXIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE, 1,1-DIOXIDE;
4-HYDROXY-1-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
8-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-1,4-DIOXA-8-AZASPIRO[4,5]DECANE-6-CARBOXAMIDE;
1-(1-PHENYLETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3(S)-PIPERIDINECARBOXAMIDE;
1-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3(R)-PYRROLIDINECARBOXAMIDE;
1-[(2-FLUOROPHENYL)METHYL]-3-(METHYLTHIO)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PYRROLIDINECARBOXAMIDE;
1-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PYRROLIDINECARBOXAMIDE;
1-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PYRROLIDINECARBOXAMIDE;
3-(HYDROXYMETHYL)-1-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
4-(3-PHENYLPROPYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE;
4-(2-PHENYLETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-THIOMORPHOLINECARBOXAMIDE; and
1-METHYL-5-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-3-PIPERIDINECARBOXAMIDE;
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 1)

A method of inhibiting ERK in a patient in need of such treatment, said method comprising administering an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 15 (depends on 1)

A method of treating cancer in a patient in need of such treatment, said method comprising administering an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 16 (depends on 1, 15)

The method of claim 15, further comprising administering an effective amount of at least one chemotherapeutic agent distinct from the compound of claim 1.

### Claim 17 (depends on 16)

The method of claim 16, wherein the chemotherapeutic agent is selected from the group consisting of: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, y-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.

### Claim 18 (depends on 16)

The method of claim 16, wherein the chemotherapeutic agent is selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) vinca alkaloids, (12) antibodies that are inhibitors of αVβ3 integrins, (13) folate antagonists, (14) ribonucleotide reductase inhibitors, (15) anthracyclines, (16) biologics; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha) such as thalidomide (or related imid), (18) Bcr/abl kinase inhibitors, (19) MEK1 and/or MEK 2 inhibitors that are small molecules, (20) IGF-1 and IGF-2 inhibitors that are small molecules, (21) small molecule inhibitors of RAF and BRAF kinases, (22) small molecule inhibitors of cell cycle dependent kinases such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) farnesyl protein transferase inhibitors.

### Claim 19 (depends on 25)

The method of claim 25, wherein said cancer is selected from the group consisting of: lung cancer, pancreatic cancer, colon cancer, colorectal cancer, myeloid leukemias, acute myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, thyroid cancer, myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers, ovarian cancer, brain cancers, cancers of mesenchymal origin, sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroid carcinoma.