# US 9,434,725 B2 · 5-azaindazole compounds and methods of use

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- Number: US 9,434,725 B2
- Document ID: US9434725B2
- Status: Granted
- Kind: B2
- Application number: 13/927,278
- Filed: 2013-06-26
- Published: 2014-01-02
- Granted: 2016-09-06
- Earliest claimed: 2012-06-27
- Assignees: F. Hoffmann-La Roche AG
- Applicants: Genentech, Inc.
- Inventors: Steven Do; Huiyong Hu; Aleksandr Kolesnikov; Vickie H. Tsui; Xiaojing Wang
- Web page: https://patentgrep.com/patent/US9434725B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- 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 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/10: Spiro-condensed systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/052: the oxygen-containing ring being six-membered
- 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

5-Azaindazole compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

## Claims

### Claim 1

A compound selected from Formula I:
and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R1 is a five-membered or six-membered heteroaryl selected from the group consisting of:
where the wavy line indicates the point of attachment
R3 is selected from H, —CH3, —CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2CH(CH3)2, —CH2NH2, —CH2NHCH3, —CH2CH2NH2, —CH2CH2CH2NH2, —CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CF3, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and oxetanyl;
R4 is independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2CH(CH3)2, —CH2NH2, —CH2NHCH3, —CH2CH2NH2, —CH2CH2CH2NH2,—CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CHF2, —CF3, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CHF2, —NHCH2CF3, —NHCOCH3, —N(CH3)COCH3, —NHC(O)OCH2CH3, —NHC(O)OCH2Cl3, —NHC(O)OC6H5, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —OCH2CH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and
n is 0, 1, 2, or 3;
R2 is a six-membered heteroaryl, having the structure:
where the wavy line indicates the point of attachment;
Xa is N or CRa;
Xb is N or CRb;
Xc is N or CRc;
Xd is N or CRd;
where 0 or 1 of Xa, Xb, Xc, and Xd is N;
Ra, Rb, Rc and Rd are independently selected from H, F, Cl, Br, I, —CH3, —CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2CH(CH3)2, —CH2NH2, —CH2NHCH3, —CH2CH2NH2, —CH2CH2CH2NH2, —CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CHF2, —CF3, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CHF2, —NHCH2F3, —NHCOCH3, —N(CH3)COCH3, —NHCH(O)OCH2CH3, —NHC(O)OCH2Cl3, —NHC(O)(OC6H5, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —OCH2CH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholine;
and, wherein at least one of Ra, Rb, Rc and Rd is independently selected from a 3-7 member monocyclic heterocyclyl, having 1 or 2 N, and a 7-10 member bicyclic heterocyclyl, having 1 or 2 N, the other of Ra, Rb, Rc and Rd are as described above, wherein said heterocyclyl is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2CH(CH3)2, —CH2NH2, —CH2NHCH3, —CH2CH2NH2, —CH2CH2CH2NH2, —CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —C(CH3)20H, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CHF2, —CF3, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CHF2, —NHCH2F3, —NHCOCH3, —N(CH3)COCH3, —NHCH(O)OCH2CH3, —NHC(O)OCH2Cl3, —NHC(O)OC6H5, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —OCH2CH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholine.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R2 is selected from the structures:

### Claim 3 (depends on 1)

The compound of claim 1 wherein R2 is selected from the structures:
where Re is selected from H, —CH3, —CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2CH(CH3)2, —CH2NH2, —CH2NHCH3, —CH2CH2NH2, —CH2CH2CH2NH2, —CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CF3, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and oxetanyl.

### Claim 4 (depends on 1)

The compound of claim 1 wherein Ra is a heterocyclyl selected from the structures:
wherein the heterocyclyl is optionally substituted with one or more groups independently selected from F, —OH, —OCH3, ═O, —NH2, —CH3, —CH2CH3, and oxetan-3-yl.

### Claim 5 (depends on 1)

The compound of claim 1 having the structure of Formula Ia:

### Claim 6 (depends on 1)

The compound of claim 1 having the structure of Formula Ib:

### Claim 7 (depends on 1)

The compound of claim 1 having the structure of Formula Ic:

### Claim 8 (depends on 1)

The compound of claim 1 having the structure of Formula Id:

### Claim 9

A compound selected from Table 1, excluding:
(S)-2-((6-(1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)oxy)-1-phenylethanamine; and
(R)-2-((6-(1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)oxy)-1-phenylethanamine.

### Claim 10

A compound selected from Table 2, excluding:
6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine;
1-(2-fluorophenyl)-6-(1-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine; and
1-(4-(1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)piperidin-4-amine.

### Claim 11 (depends on 1, 9, 10)

A pharmaceutical composition comprised of a compound of claim 1, 9 or 10 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 12 (depends on 11)

The pharmaceutical composition according to claim 11, further comprising a chemotherapeutic agent.

### Claim 13 (depends on 11)

A method of treating a disease or disorder which method comprises administering a therapeutically effective amount of a pharmaceutical composition of claim 11 to a patient with a disease or disorder selected from a hematopoietic cancer and prostate cancer.

### Claim 14 (depends on 13)

The method of claim 13 wherein the hematopoietic cancer is selected from the group consisting of multiple myeloma, myeloid disorders, Hodgkin's, leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, and non-Hodgkin lymphoma.

### Claim 15 (depends on 13)

The method of claim 13 further comprising administering an additional therapeutic agent selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

### Claim 16 (depends on 11)

A kit for treating a condition mediated by Pim kinase, comprising:
a) a pharmaceutical composition of claim 11; and
b) instructions for use.

### Claim 17 (depends on 1, 9, 10)

A method of inhibiting a PIM kinase comprising contacting a PIM kinase with a compound of claim 1, 9 or 10.