# US 2019/0169198 A1 · New pyrazolopyrimidine derivatives as nik inhibitors

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- Number: US 2019/0169198 A1
- Document ID: US20190169198A1
- Status: Published application
- Kind: A1
- Application number: 16/265,679
- Filed: 2019-02-01
- Published: 2019-06-06
- Earliest claimed: 2014-10-23
- Assignees: Janssen Pharmaceutical N.V.
- Applicants: Janssen Pharmaceutical NV
- Inventors: George HYND; Patrizia Tisselli; Calum Macleod; Samuel Edward Mann; Terry Aaron Panchal; John Gary Montana; Stephen Colin Price
- Web page: https://patentgrep.com/patent/US20190169198A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

## Claims

### Claim at position 1

1-14. (canceled)

### Claim 15

A method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I):
or a tautomer or a stereoisomeric form thereof, wherein
R1 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl; and Het1;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
Het1 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkyloxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
X is N or CR9;
R9 is selected from hydrogen and halogen;
R3 is selected from the group of hydrogen; halogen; cyano; C3-6cycloalkyl; C1-6alkyl; Het4;
C1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl;
—OC1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from —NR3aR3b and —OC1-4alkyl;
Het4 is a heteroaryl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, piperazinyl, morpholinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C3-6cycloalkyl and C1-4alkyl substituted with one or more fluoro substituents;
R3a and R3b are each independently selected from hydrogen and C1-4alkyl;
R4 is hydrogen;
R5 is selected from the group of hydrogen; cyano; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one substituent selected from the group of —NR5aR5b, —OC1-4alkyl, and Het5;
R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl;
Het5 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C3-6cycloalkyl and C1-4alkyl substituted with one or more fluoro substituents;
R6 is selected from the group of hydrogen; Het2; R8; C1-6alkyl optionally substituted with one Het3; and C2-6alkyl substituted with one or more substituents independently selected from the group of fluoro, —NR6aR6b, and —OR6c;
R6a, R6b and R6c are each independently selected from hydrogen and C1-6alkyl;
Het2 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one —OC1-4alkyl, C1-4alkyl substituted with one C3-6cycloalkyl,
and C1-4alkyl substituted with one or more fluoro substituents;
Het3 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C3-6cycloalkyl,
C1-4alkyl substituted with one —OC1-4alkyl,
C1-4alkyl substituted with one C3-6cycloalkyl,
and C1-4alkyl substituted with one or more fluoro substituents;
R8 is C3-6cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C1-4alkyl substituted with one —OC1-4alkyl, and C1-4alkyl substituted with one or more fluoro substituents;
R7 is selected from the group of hydrogen, C1-6alkyl, C3-6cycloalkyl and
C1-4alkyl substituted with one —OC1-4alkyl;
or a pharmaceutically acceptable addition salt, or a solvate thereof.

### Claim 16 (depends on 15)

The method according to claim 15, wherein
R1 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl; and Het1;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
Het1 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkyloxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
X is N or CR9;
R9 is selected from hydrogen and halogen;
R3 is selected from the group of hydrogen; halogen; cyano; C3-6cycloalkyl; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from —NR3aR3b and —OC1-4alkyl;
R3a and R3b are each independently selected from hydrogen and C1-4alkyl;
R4 is hydrogen;
R5 is selected from the group of hydrogen; cyano; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one substituent selected from the group of —NR5aR5b, and —OC1-4alkyl;
R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl;
R6 is selected from the group of hydrogen; Het2; R8; C1-6alkyl optionally substituted with one Het3; and C2-6alkyl substituted with one or more substituents independently selected from the group of fluoro, —NR6aR6b, and —OR6c;
R6a, R6b and R6c are each independently selected from hydrogen and C1-6alkyl;
Het2 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one —OC1-4alkyl, C1-4alkyl substituted with one C3-6cycloalkyl,
and C1-4alkyl substituted with one or more fluoro substituents;
Het3 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C3-6cycloalkyl,
C1-4alkyl substituted with one —OC1-4alkyl,
C1-4alkyl substituted with one C3-6cycloalkyl,
and C1-4alkyl substituted with one or more fluoro substituents;
R8 is C3-6cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C1-4alkyl substituted with one —OC1-4alkyl, and C1-4alkyl substituted with one or more fluoro substituents;
R7 is selected from the group of hydrogen, C1-6alkyl, C3-6cycloalkyl and C1-4alkyl substituted with one —OC1-4alkyl.

### Claim 17 (depends on 15)

The method according to claim 15, wherein
R1 is C1-4alkyl;
R2 is selected from the group of C1-4alkyl; and C3-6cycloalkyl;
X is N or CR9;
R9 is halogen; in particular fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of Het2; and C2-6alkyl substituted with one —OR6c;
R6c is C1-6alkyl;
Het2 is a heterocyclyl, bound through any available carbon atom, selected from the group of pyrrolidinyl, and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from C1-4alkyl, C3-6cycloalkyl, and
C1-4alkyl substituted with one C3-6cycloalkyl;
R7 is selected from the group of C1-6alkyl, and C3-6cycloalkyl.

### Claim 18 (depends on 15)

The method according to claim 15, wherein
R3 is hydrogen; and R5 is hydrogen.

### Claim 19 (depends on 15)

The method according to claim 15,
R6 is selected from the group of Het2; and C2-6alkyl substituted with one —OR6c.

### Claim 20 (depends on 19)

The compound according to claim 19, wherein R6 is selected from the group of

### Claim 21 (depends on 15, 16, 17, 18, 19, 20)

The method according to claims 15 to 20,
R1 is selected from the group of C1-4alkyl;
R2 is selected from the group of C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents C3-6cycloalkyl; and Het1;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.

### Claim 22 (depends on 15, 16, 17, 18, 19, 20)

The method according to claims 15 to 20, wherein X is N.

### Claim 23 (depends on 15, 16, 17, 18, 19, 20)

The method according to claims 15 to 20, wherein X is CR9.

### Claim 24 (depends on 15)

The method according to claim 15, wherein the compound is selected from
tautomers and stereoisomeric forms thereof,
and the pharmaceutically acceptable addition salts, and the solvates thereof.

### Claim 25 (depends on 15, 16, 17, 18, 19, 20)

The method according to claims 15 to 20, wherein the compound is in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier or diluent.

### Claim 26 (depends on 24)

The method according to claim 24, wherein the compound is in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier or diluent.