IP Library › Patent Application 16287871

Patent Application

App. No. 16/287,871

SATURATED-RING-FUSED DIHYDROPYRIMIDINONE OR DIHYDROTRIAZINONE COMPOUNDS AND PHARMACEUTICAL USE THEREOF

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Patent No.: US None
App. No.: 16/287,871

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Abstract

The present invention relates to saturated-ring-fused dihydropyrimidinone or dihydrotriazinone compounds, or pharmaceutically acceptable salts thereof, having RORγ antagonist activity, pharmaceutical compositions comprising the same, and pharmaceutical use thereof. A compound of Formula [I] or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and pharmaceutical use thereof are provided: wherein each substituent is defined as defined in the description.

Claims (129)

1 : A compound of Formula [I]:

wherein R 1 is

(1) C 1-8 alkyl,

(2) halo-C 1-8 alkyl,

(3) C 3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from Group A 1 , or

(4) C 3-8 cycloalkyl-C-4 alkyl wherein the C 3-8 cycloalkyl moiety may be optionally substituted with the same or different 1 to 3 substituents selected from Group A 1 ,

Group A 1 is

(1) halogen,

(2) C 1-4 alkyl, or

(3) halo-C 1-4 alkyl,

X 1 is

(1) a bond, or

(2) —O—,

R 2 is

(1) hydrogen, or

(2) halogen,

R 3 is

(1) hydrogen, or

(2) —Y 3 —COO—R 30 ,

Y 3 is

(1) C 1-8 alkylene,

(2) C 5-8 cycloalkylene,

(3) bridged C 5-8 cycloalkylene, or

(4) C 6-14 arylene,

R 30 is

(1) hydrogen, or

(2) C 1-4 alkyl,

X 2 is

(1) ═C(R 4 )—, or

(2) ═N—,

R 4 is

(1) hydrogen, or

(2) C 1-4 alkyl,

X 3 is

(1) —C(R 5 )(R 6 )—,

X 4 is

(1) a bond, or

(2) —C(R 7 )(R 8 )—,

X 5 is

(1) —C(R 9 )(R 10 )—

(2) —N(R 11 )—, or

(3) —O—,

R 5 and R 6 are each independently

(1) hydrogen,

(2) C 1-4 alkyl,

(3) halo-C 1-4 alkyl,

(4) cyano-C 1-4 alkyl, or

(5) C 1-4 alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —CO—R 61 , —COO—R 52 , —N(R 71 )(R 72 ), —CO—N(R 73 )(R 74 ), —N(R 75 )—CO—R 62 , —N(R 76 )—COO—R 53 , and —O—S(O) 2 —R 63 ,

R 7 , R 8 , R 9 and R 10 are each independently

(1) hydrogen,

(2) halogen,

(3) cyano,

(4) hydroxy,

(5) C 1-4 alkyl,

(6) halo-C 1-4 alkyl,

(7) cyano-C 1-4 alkyl,

(8) C 1-4 alkoxy, or

(9) C 1-4 alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —CO—R 61 , —COO—R 52 , —N(R 71 )(R 72 ), —CO—N(R 73 )(R 74 ), —N(R 75 )—CO—R 62 , —N(R 76 )—COO—R 53 , and —O—S(O) 2 —R 3 ,

R 51 , R 52 , and R 53 are each independently

(1) hydrogen,

(2) C 1-4 alkyl, or

(3) C 6-14 aryl-C 1-4 alkyl,

R 61 , R 62 , and R 63 are each independently

(1) C 1-4 alkyl,

R 71 , R 72 , R 73 , R 74 , R 75 , and R 76 are each independently

(1) hydrogen, or

(2) C 1-4 alkyl,

R 11 is

(1) —CO—R 111 , or

(2) —COO—R 112 ,

R 111 is

(1) C 1-4 alkyl, and

R 112 is

(1) C 1 -4 alkyl, or a pharmaceutically acceptable salt thereof.

2 : The compound according to claim 1 , having a structure of Formula [II]:

wherein each variable is defined as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

3 : The compound according to claim 1 , wherein X 2 is ═N—, or a pharmaceutically acceptable salt thereof.

4 : The compound according to claim 1 , wherein X 2 is —C(R 4 )— and R 4 is hydrogen, or a pharmaceutically acceptable salt thereof.

5 : The compound according to claim 1 , wherein R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

6 : The compound according to claim 1 , wherein R 3 is —Y 3 —COO—R 3 ,

Y 3 is

(1) C 1-8 alkylene,

(2) Cm cycloalkylene, or

(3) bridged C 5-8 cycloalkylene, and

R 30 is hydrogen or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

7 : The compound according to claim 1 , wherein R 2 is halogen, or a pharmaceutically acceptable salt thereof.

8 : The compound according to claim 1 , wherein R 1 is C 1-8 alkyl and X 1 is a bond, or a pharmaceutically acceptable salt thereof.

9 : The compound according to claim 1 , wherein R 5 and R 6 are each independently hydrogen or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

10 : The compound according to claim 1 , wherein X 4 is a bond or —C(R 7 )(R 8 )— and both of R 7 and R 8 are hydrogen, or a pharmaceutically acceptable salt thereof.

11 : The compound according to claim 1 , wherein X 5 is —C(R 9 )(R 10 )— or —O— and both of R 9 and R 10 are hydrogen, or a pharmaceutically acceptable salt thereof.

12 . (canceled)

13 : A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14 : An RORγ antagonist comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15 . (canceled)

16 : A method of antagonizing RORγ, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a mammal.

17 : A method of treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a mammal.

18 - 21 . (canceled)

22 : The compound according to claim 1 , having a structure: