# US 2019/0169189 A1 · Triaza-spirodecanones as ddr1 inhibitors

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- Number: US 2019/0169189 A1
- Document ID: US20190169189A1
- Status: Published application
- Kind: A1
- Application number: 16/266,782
- Filed: 2019-02-04
- Published: 2019-06-06
- Earliest claimed: 2015-07-03
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: BERND BUETTELMANN; BUELENT KOCER; BERND KUHN; MARCO PRUNOTTO; HANS RICHTER; MARTIN RITTER; MARKUS RUDOLPH; ALEXANDER LEE SATZ
- Web page: https://patentgrep.com/patent/US20190169189A1

## CPC

- C07D 471/10: Spiro-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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 compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein L and R1 to R5 are as described herein, as well as processes for their manufacture, pharmaceutical compositions comprising them, and their use as medicaments.

## Claims

### Claim 1

A compound of formula (I)
wherein
L is —(CHR8)m—(CHR9)n—(CO)q—
R1 is —NR6R7, aryl or C3-7 cycloalkyl, wherein each aryl and C3-7 cycloalkyl is optionally substituted with one or more R1′;
each R1′ is independently selected from halogen, cyano, C1-7 alkyl, halo-C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, phenyl, benzyl, amino, hydroxy, C1-7 alkoxy, halo-C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, oxo, —CH2—OR16, —C(O)—OR16, —CH2—NHR16, —CH2—CH2—NR17R18, —CH2—C(O)—NHR16 and —C(O)—NHR16;
or two R1′ together are —(CR12R13)s—;
R2 is hydrogen, fluorine, C1-7 alkyl, or halo-C1-7 alkyl;
R3 is hydrogen or C1-7 alkyl;
R4 is aryl optionally substituted by one or more R4′;
each R4′ is independently selected from halogen, cyano, C1-7 alkyl, halo-C1-7 alkyl, C3-7 cycloalkyl, amino, hydroxy, C1-7 alkoxy and halo-C1-7 alkoxy;
R5 is 1H-pyrazolo[3,4-b]pyridine which is optionally substituted with one or more R5′;
each R5′ is independently selected from halogen, cyano, C1-7 alkyl, halo-C1-7 alkyl, C3-7 cycloalkyl, amino, hydroxy, C1-7 alkoxy and —C(O)NH2;
R6 is C1-7 alkyl, halo-C1-7 alkyl, hydroxy-C1-7 alkyl, C1-7 alkoxy-C1-7 alkyl, C3-7 cycloalkyl, aryl, —CH2—CH2—NR17R18, wherein C1-7 alkyl, C3-7 cycloalkyl, aryl or benzyl are optionally substituted with one or more R6′;
each R6′ is independently selected from halogen, cyano, C1-7 alkyl, halo-C1-7 alkyl, C3-7 cycloalkyl, amino, hydroxy, C1-7 alkoxy, halo-C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, oxo, —CH2—C(O)—NHR16, phenyl or benzyl said phenyl optionally substituted with C1-7 alkyl;
R7 is hydrogen, C1-7 alkyl, C3-7 cycloalkyl or halo-C1-7 alkyl;
R8 is hydrogen, C1-7 alkyl, hydroxy-C1-7 alkyl, C1-7 alkoxy-C1-7 alkyl, halo-C1-7 alkoxy-C1-7 alkyl, —(CH2)r-phenyl, or —(CH2)rNR10R11;
R9 is hydrogen, C1-7 alkyl, or halo-C1-7 alkyl;
R10 and R11 are independently selected from hydrogen and C1-7 alkyl;
R12, R13, R14 and R15 are each independently selected from hydrogen, halogen and C1-7 alkyl;
R16 is hydrogen, C1-7alkyl, halo-C1-7 alkyl or C3-7 cycloalkyl;
R17 and R18 are independently selected from hydrogen and C1-7 alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
q is 0 or 1;
r is 0, 1 or 2;
s is 2, 3 or 4;
or a pharmaceutically acceptable salt thereof;
with the proviso that if R1 is —NR6R7 then:
if q=0 then m+n≥2, or
if q=1 then m+n≥1.

### Claim 2 (depends on 1)

The compound of formula (I) according to claim 1, wherein m, n and q are each 0, m and q are both 0, n is 1 and R9 is hydrogen- or m is 0, n and q are 1 and R9 is hydrogen.

### Claim 3 (depends on 1)

The compound of formula (I) according to claim 1 wherein m is 0, n and q are 1 and R9 is hydrogen.

### Claim 4 (depends on 1)

The compound of formula (I) according to claim 1 wherein R1 is NR6R7 or aryl said aryl optionally substituted with one or more R1′.

### Claim 5 (depends on 4)

The compound of formula (I) according to claim 4, wherein R1 is —NR6R7 or phenyl said phenyl optionally substituted with one, two or three R1′.

### Claim 6 (depends on 1)

The compound of formula (I) according to claim 1 wherein each R1′ is independently selected from the group consisting of halogen, cyano, C1-7 alkyl, halo-C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, amino, hydroxy, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, oxo, phenyl and benzyl.

### Claim 7 (depends on 6)

The compound of formula (I) according to claim 6 wherein each R1′ is independently selected from the group consisting of fluoro, chloro, cyano, methyl, ethyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclopropyl-methyl, dimethylamino, hydroxy, methoxy, methoxymethyl, oxo, phenyl and benzyl.

### Claim 8 (depends on 1)

The compound of formula (I) according to claim 1 wherein R2 is hydrogen.

### Claim 9 (depends on 1)

The compound of formula (I) according to claim 1 wherein R3 is hydrogen.

### Claim 10 (depends on 1)

The compound of formula (I) according to claim 1 wherein R4 is aryl optionally substituted by one or more R4′.

### Claim 11 (depends on 1)

The compound of formula (I) according to claim 1 wherein R4 is phenyl optionally substituted with one or two halogen independently selected from fluoro and chloro.

### Claim 12 (depends on 11)

The compound of formula (I) according to claim 11, wherein R4 is phenyl.

### Claim 13 (depends on 1)

The compound of formula (I) according to claim 1 wherein each R4 is independently selected from fluoro and chloro.

### Claim 14 (depends on 1)

The compound of formula (I) according to claim 1 wherein R6 is C1-7 alkyl, halo-C1-7 alkyl, C3-7 cycloalkyl or aryl, each optionally substituted with one R6′.

### Claim 15 (depends on 14)

The compound of formula (I) according to claim 14, wherein R6 is methyl, ethyl, trifluoroethyl, cyclopropyl, adamantyl, or phenyl, each optionally substituted with one R6′.

### Claim 16 (depends on 15)

The compound of formula (I) according to claim 15, wherein R6 is trifluoroethyl.

### Claim 17 (depends on 1)

The compound of formula (I) according to claim 1, wherein each R6′ is independently selected from halo-C1-7 alkoxy or phenyl.

### Claim 18 (depends on 17)

The compound of formula (I) according to claim 17, wherein each R6′ is independently selected from trifluoromethoxy or phenyl.

### Claim 19 (depends on 1)

The compound of formula (I) according to claim 1, wherein R7 is hydrogen or C1-7 alkyl.

### Claim 20 (depends on 19)

The compound of formula (I) according to claim 19, wherein R7 is hydrogen, methyl or isopropyl.

### Claim 21 (depends on 1)

The compound of formula (I) according to claim 1 which compound is selected from the group consisting of:
2-[1-(4-Fluorophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[1-(3-Fluorophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[1-(2-Fluorophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-(4-Oxo-1-phenyl-8-(1H-pyrazolo [3,4-b] pyridine -5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;
2-(4-Oxo-1-phenyl-8-(1H-pyrazolo [3,4-b] pyridine -5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)-N-phenylacetamide;
N-Methyl-2-(4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine -5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;
N-(Adamantan-1-yl)-2-(4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)acetamide;
(RS)-3-(2-Oxo-1-phenylpyrrolidin-3-yl)-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-4-one;
2-[4-Oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-propan-2-yl-N-(2,2,2-trifluoroethyl)acetamide;
N,N-Dimethyl-2-[4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide;
1-Phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4.5]decan-4-one;
3-[2-Fluoro-4-(trifluoromethyl)phenyl]-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-4-one;
3-(2-Fluoro-4-methylphenyl)-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-4-one;
4-[4-Oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]benzonitrile;
3-(3-Chlorophenyl)-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-4-one;
3-(4-Chloro-2-fluorophenyl)-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-4-one;
3-(5-Chloro-2-fluoro-4-methyl-phenyl)-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-4-one;
N-(2-fluoroethyl)-2-[4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide;
N-(2,2-difluoroethyl)-2-[4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide;
2-(1-(3-Chlorophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;
N-[2-(dimethylamino)ethyl]-2-[4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide;
N-[2-(dimethylamino)ethyl]-2-[4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
N-(1-hydroxy-2-methylpropan-2-yl)-2-[4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide;
2-[1-(3-Bromophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[4-Oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1-[3-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[1-(3-Chloro-5-fluorophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[1-(3-Cyanophenyl)-4-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide; or,
a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The compound of claim 21 which compound is
2-(4-Oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide; or
N-Methyl-2-(4-oxo-1-phenyl-8-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide; or,
a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A process for the manufacture of a compound of formula (I) according to claim 1, the process comprising coupling of a compound of formula (III) with an optionally protected carboxylic acid of formula R5COOH.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and at least one pharmaceutically acceptable excipient.

### Claim 25 (depends on 1)

A method for the treatment or prevention of renal conditions, liver conditions, inflammatory conditions, vascular conditions, cardiovascular conditions, fibrotic diseases, cancer and acute and chronic organ transplant rejection, which method comprises administering a therapeutically effective amount of a compound of formula (I) according to claim 1 to a human being or animal in need thereof.