Granted Patent B2

US 12,252,484 · App. 17/274,035 · Granted Mar 18, 2025

Inventors: Fabian Dey (Basel, CH); Taishan Hu (Shanghai, CN); Haixia Liu (Shanghai, CN); Hong Shen (Shanghai, CN); Zhiwei Zhang (Shanghai, CN); Wei Zhu (Shanghai, CN)

Assignee: Hoffmann-La Roche Inc.

C07D471/04C07D471/08C07D471/18C07D498/18C07D519/00

Abstract

Claims (104)

1. A compound of formula (I),

wherein:

R 1 is cyano, C 1-6 alkyl, halogen, haloC 1-6 alkyl or nitro;

R 2 is C 1-6 alkyl or haloC 1-6 alkyl;

R 3 is —NHR 3a or —COR 3b , wherein:

R 3a is H, aminoC 1-6 alkylcarbonyl, (C 1-6 alkyl) 2 aminoC 1-6 alkylcarbonyl or cyanoC 1-6 alkyl;

R 3b is (heterocyclylcarbonyl)phenylamino, (hydroxyC 1-6 alkoxy)C 1-6 alkylamino, adamantylamino, aminoC 1-6 alkylamino, C 1-6 alkoxyC 1-6 alkylamino, C 1-6 alkylamino, C 1-6 alkylpyrazolylamino, cyanoC 3-7 cycloalkylamino, heterocyclyl, heterocyclylamino, heterocyclylC 1-6 alkylamino, hydroxyC 1-6 alkylamino, hydroxyC 1-6 alkylC 3-7 cycloalkylamino, hydroxyC 3-7 cycloalkylamino or pyridylamino;

R 4 is H or halogen; and

X is O or CH 2 ;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

2. A compound according to claim 1 , wherein R 1 is cyano or halogen.

3. A compound according to claim 2 , wherein:

R 1 is cyano or halogen;

R 2 is C 1-6 alkyl;

R 3 is —NHR 3a or —COR 3b , wherein:

R 3a is H, aminoC 1-6 alkylcarbonyl, (C 1-6 alkyl) 2 aminoC 1-6 alkylcarbonyl or cyanoC 1-6 alkyl;

R 3b is (C 1-6 alkylmorpholinyl)C 1-6 alkylamino, (hydroxyC 1-6 alkoxy)C 1-6 alkylamino, (piperazinylcarbonyl)phenylamino, adamantylamino, aminoazetidinyl, aminoC 1-6 alkylamino, azabicyclo[2.2.1]heptanylamino, azabicyclo[3.1.0]hexanylamino, azabicyclo[3.2.1]octanylamino, azabicyclo[3.3.1]nonanylamino, azaspiro[3.3]heptanylamino, azepanylamino, C 1-6 alkoxyC 1-6 alkylamino, C 1-6 alkylamino, C 1-6 alkylazabicyclo[2.2.2]octanylamino, C 1-6 alkylazabicyclo[3.2.1]octanylamino, C 1-6 alkylazabicyclo[3.3.1]nonanylamino, C 1-6 alkylazaspiro[2.4]heptanylamino, C 1-6 alkylpiperidylamino, C 1-6 alkylpyrazolylamino, cyanoC 3-7 cycloalkylamino, diazaspiro[5.5]undecanyl, halopyrrolidinylamino, halopyrrolidinylC 1-6 alkylamino, hydroxyC 1-6 alkylamino, hydroxyC 1-6 alkylC 3-7 cycloalkylamino, hydroxyC 3-7 cycloalkylamino, oxaazabicyclo[3.3.1]nonanylamino, piperidylamino, pyridylamino, pyrrolidinylamino, pyrrolidinylC 1-6 alkylamino or tetrahydropyranylamino;

R 4 is H or halogen; and

X is O or CH 2 ;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

4. A compound according to claim 3 , wherein R 1 is cyano or chloro.

5. A compound according to claim 4 , wherein R 1 is cyano.

6. A compound according to claim 4 , wherein R 2 is methyl.

7. A compound according to claim 3 , wherein:

R 3 is —NHR 3a or —COR 3b , wherein R 3a is H, aminoethylcarbonyl, (dimethylamino)methylcarbonyl or cyanomethyl; R 3b is (hydroxyethoxy)ethylamino, (hydroxymethyl)bicyclo[1.1.1]pentanylamino, (methylmorpholinyl)methylamino, (piperazinylcarbonyl)phenylamino, 2-azabicyclo[2.2.1]heptan-5-ylamino, 2-azaspiro[3.3]heptan-6-ylamino, 2-methyl-2-azabicyclo[2.2.2]octan-5-ylamino, 3,9-diazaspiro[5.5]undecanyl, 3-azabicyclo[3.1.0]hexan-6-ylamino, 3-azabicyclo[3.2.1]octan-8-ylamino, 3-azabicyclo[3.3.1]nonan-9-ylamino, 3-oxa-7-azabicyclo[3.3.1]nonan-9-ylamino, 3-oxa-9-azabicyclo[3.3.1]nonan-7-ylamino, 5-methyl-5-azaspiro[2.4]heptan-7-ylamino, 8-azabicyclo[3.2.1]octan-3-ylamino, 8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino, 9-azabicyclo[3.3.1]nonan-3-ylamino, 9-methyl-9-azabicyclo[3.3.1]nonan-3-ylamino, adamantylamino, aminoazetidinyl, aminodimethylethylamino, aminodimethylpropylamino, azepan-4-ylamino, cyanocyclopropylamino, difluoropyrrolidinylmethylamino, dimethylpropylamino, fluoropyrrolidinylamino, hydroxybutylamino, hydroxycyclohexylamino, hydroxydimethylethylamino, methoxyethylamino, methylpiperidylamino, methylpyrazolylamino, piperidylamino, pyridylamino, pyrrolidinylamino, pyrrolidinylmethylamino or tetrahydropyranylamino.

8. A compound according to claim 7 , wherein R 3 is —COR 3b , wherein R 3b is methylpiperidylamino, azepanylamino or 3-azabicyclo[3.3.1]nonan-9-ylamino.

9. A compound according to claim 8 , wherein R 4 is H or fluoro.

10. A compound according to claim 9 , wherein X is O.

11. A compound according to claim 2 , selected from:

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(1-methyl-4-piperidyl)morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-6-methyl-morpholine-2-carboxamide;

(2R,6R)-N-(2-azaspiro[3.3]heptan-6-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-tetrahydropyran-4-yl-morpholine-2-carboxamide;

Cis-(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(4-fluoropyrrolidin-3-yl) morpholine-2-carboxamide;

(2R,6R)-N-(azepan-4-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-[(4-methylmorpholin-2-yl)methyl]morpholine-2-carboxamide;

4-[(2R,6R)-2-(3-aminoazetidine-1-carbonyl)-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-(2-methoxyethyl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-[2-(2-hydroxyethoxy)ethyl]-6-methyl-morpholine-2-carboxamide;

(2R,6R)-N-(1-cyanocyclopropyl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-N-(1-adamantyl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-(2-hydroxybutyl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-N-(9-azabicyclo[3.3.1]nonan-3-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-[3-(hydroxymethyl)-1-bicyclo[1.1.1]pentanyl]-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-(2-hydroxy-1,1-dimethyl-ethyl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-(1,1-dimethylpropyl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-[(4,4-difluoropyrrolidin-3-yl)methyl]-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(4-methyl-4-piperidyl)morpholine-2-carboxamide;

Cis-(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-(4-hydroxycyclohexyl)-6-methyl-morpholine-2-carboxamide;

Trans-(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-N-(4-hydroxycyclohexyl)-6-methyl-morpholine-2-carboxamide;

Endo-(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-[3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]morpholine-2-carboxamide;

Exo-(2R,6R)-N-[8-azabicyclo[3.2.1]octan-3-yl]-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(4-piperidyl)morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-pyrrolidin-3-yl-morpholine-2-carboxamide;

(2R,6R)-N-(3-azabicyclo[3.2.1]octan-8-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)morpholine-2-carboxamide;

4-[(2R,6R)-2-(3,9-diazaspiro[5.5]undecane-3-carbonyl)-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(4-pyridyl)morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(1-methylpyrazol-3-yl)morpholine-2-carboxamide;

Trans-(2R,6R)-N-(3-azabicyclo[3.1.0]hexan-6-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(2-methyl-2-azabicyclo[2.2.2]octan-5-yl)morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)morpholine-2-carboxamide;

(2R,6R)-N-(2-azabicyclo[2.2.1]heptan-5-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-N-(3-azabicyclo[3.3.1]nonan-9-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(1-methyl-4-piperidyl)morpholine-2-carboxamide;

(2R,6R)-N-(3-amino-2,2-dimethyl-propyl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(pyrrolidin-3-ylmethyl)morpholine-2-carboxamide;

(2R,6R)-N-(2-amino-1,1-dimethyl-ethyl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-[4-(piperazine-1-carbonyl)phenyl]morpholine-2-carboxamide;

4-[(3R,5S)-3-amino-5-methyl-1-piperidyl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

(2S)-2-amino-N-[(3R,5S)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-methyl-3-piperidyl]propanamide;

N-[(3R,5S)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-methyl-3-piperidyl]-2-(dimethylamino)acetamide;

4-[(3R,5S)-3-(cyanomethylamino)-5-methyl-1-piperidyl]pyrazolo[1,5-a]pyridine-7-carbonitrile; and

(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(1-methyl-4-piperidyl)morpholine-2-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

12. A compound according to claim 11 , selected from:

(2R,6R)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(1-methyl-4-piperidyl)morpholine-2-carboxamide;

(2R,6R)-N-(azepan-4-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide;

(2R,6R)-N-(3-azabicyclo[3.3.1]nonan-9-yl)-4-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-6-methyl-morpholine-2-carboxamide; and

(2R,6R)-4-(7-cyano-3-fluoro-pyrazolo[1,5-a]pyridin-4-yl)-6-methyl-N-(1-methyl-4-piperidyl)morpholine-2-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

13. A process for preparing a compound according to claim 1 comprising any of the following steps:

a) reacting a compound of formula (IX),

with R 5 R 6 NH in the presence of a coupling reagent;

b) reacting a compound of formula (XII),

with compound of formula (VII),

in the presence of a catalyst and a base;

c) reacting a compound of formula (XV),

in the presence of an acid;

d) reacting a compound of formula (III),

with an acid (XVI),

in the presence of a coupling reagent;

wherein:

the coupling reagent is HATU; the catalyst is Ruphos Pd-G2 and the base is Cs 2 CO 3 ;

the acid is TFA/CH 2 Cl 2 or HCl in dioxane;

R 5 and R 6 are independently selected from H, (hydroxyC 1-6 alkoxy)C 1-6 alkyl, adamantyl, aminoC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkylpyrazolyl, cyanoC 3-7 cycloalkyl, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkylC 3-7 cycloalkyl, pyridyl, hydroxyC 3-7 cycloalkyl, heterocyclylC 1-6 alkyl, (heterocyclylcarbonyl)phenyl or heterocyclyl; or

R 5 and R 6 together with the nitrogen they are attached to form a heterocyclyl; and

R 7 is H, C 1-6 alkyl, aminoC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkyl) 2 aminoC 1-6 alkyl or heterocyclyl.

14. A pharmaceutical composition comprising a compound in accordance with claim 1 and a therapeutically inert carrier.

15. A method for treating systemic lupus erythematosus or lupus nephritis, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claim 1 .

16. A method for treating systemic lupus erythematosus or lupus nephritis, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claim 12 .

17. A pharmaceutical composition comprising a compound in accordance with claim 12 and a therapeutically inert carrier.

Assignments (4)

Continuity (1)

References Cited (65)