JPWO2020154492A5

JPWO2020154492A5 -

Info

Publication number: JPWO2020154492A5
Application number: JP2021543122A
Authority: JP
Publication date: 2023-02-07

Claims

A compound having the structure of Formula (I''), or a pharmaceutically acceptable salt or solvate thereof,

During the ceremony,
R ¹ is —CH ₂ R ⁴ , —CN, —B(OH) ₂ , —N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O)R ⁹ , —C(O)OH, —CH ₂ C( O)OH, —C(O)N(R ¹⁰ ) ₂ , —C(O)NHS(O) ₂ N(R ¹⁰ ) ₂ , —C _1-6 alkyl-OH, C _3-8 cycloalkyl,

or 5- or 6-membered heteroaryl optionally substituted with 1, ² , or 3 R8 groups;
R ² is H, —OH, —N(R ¹⁰ ) ₂ , —NHS(O) ₂ R ⁹ , —S(O) ₂ N(R ¹⁰ ) ₂ , —C(O)N(R ¹⁰ ) ₂ , —OC(O)N(R ¹⁰ ) ₂ , —O—C _1-6 alkyl, —C _1-6 alkyl-OH, —C _1-6 alkyl-OR ⁹ , —C _1-6 alkyl-N( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
each R ³ is independently halogen, —CN, —OH, —OR ⁹ , —SR ⁹ , —N(R ¹⁰ ) ₂ , —NO ₂ , —S(O)R ⁹ , —S(O) ₂ R ⁹ , —NHS(O) ₂ R ⁹ , —S(O) ₂ N(R ¹⁰ ) ₂ , —C(O)R ⁹ , —C(O)OR ¹⁰ , —OC(O)R ⁹ , — C(O)N(R ¹⁰ ) ₂ , —OC(O)N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O)N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O)R ⁹ , —NR ¹⁰ C(O)OR ⁹ , C _1-6 alkyl, —C _1-6 alkyl-OH, —C _1-6 alkyl-OR ⁹ , —C _1-6 alkyl-N(R ¹⁰ ) ₂ , C _2-6 selected from alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and —C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

and
Each R ⁵ is independently halogen, —CN, —OH, —OR ⁹ , —SR ⁹ , —N(R ¹⁰ ) ₂ , —S(O)R ⁹ , —S(O) ₂ R ⁹ , — NHS(O) ₂ R ⁹ , —S(O) ₂ N(R ¹⁰ ) ₂ , —C(O)NHS(O) ₂ N(R ¹⁰ ) ₂ , —C(O)R ⁹ , —C(O ) OR ¹⁰ , —OC(O)R ⁹ , —C(O)N(R ¹⁰ ) ₂ , —OC(O)N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O)N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O)R ⁹ , —NR ¹⁰ C(O)OR ⁹ , C _1-6 alkyl, —C _1-6 alkyl-R ⁹ , —C _1-6 alkyl-OH, —C _1-6 alkyl-OR ⁹ , —C _1-6 alkyl-N(R ¹⁰ ) ₂ , —C _1-6 alkyl-C(O)OR ¹⁰ , C _2-6 alkenyl, —C _2-6 alkenyl-C(O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, —C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, —C _{1- 6} alkyl-phenyl, C _2-9 heterocycloalkyl, —C _1-6 alkyl-C _2-9 heterocycloalkyl, and C _1-9 heteroaryl , wherein C _3-8 cycloalkyl, — C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, —C _1-6 alkyl-phenyl and C _1-9 heteroaryl are halogen, —C(O)OR ¹⁰ , C _1-6 alkyl, C optionally substituted with 1, 2, or 3 groups independently selected from _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl , and wherein C _{2- 9heterocycloalkyl} and —C _1-6alkyl -C _{2-9heterocycloalkyl} are independently selected from halogen, —C(O)OR ¹⁰ , C _1-6alkyl , C _1-6haloalkyl , and oxo optionally substituted with 1, 2, or 3 groups
R ⁶ is —C(O)OR ⁷ , —C(O)NHS(O) ₂ N(R ¹⁰ ) ₂ ,

and
R ⁷ is independently selected from H and C _1-6 alkyl;
each R ⁸ is independently halogen, —OH, —OR ⁹ , —N(R ¹⁰ ) ₂ , —S(O)R ⁹ , —S(O) ₂ R ⁹ , —NHS(O) ₂ R ⁹ , —S(O) ₂ N(R ¹⁰ ) ₂ , —C(O)NHS(O) ₂ N(R ¹⁰ ) ₂ , —C(O)R ⁹ , —C(O)OR ¹⁰ , —OC( O)R ⁹ , —C(O)N(R ¹⁰ ) ₂ , —OC(O)N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O)N(R ¹⁰ ) ₂ , —NR ¹⁰ C(O) R ⁹ , —NR ¹⁰ C(O)OR ⁹ , C _1-6 alkyl, —C _1-6 alkyl-OH, —C _1-6 alkyl-OR ⁹ , —C _1-6 alkyl-N(R ¹⁰ ) ₂ , —C _1-6 alkyl-C(O)OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, —C _1-6 alkyl-C _3-8 cycloalkyl , phenyl, —C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl , wherein phenyl, —C _1-6 alkyl-phenyl, and C _1-9 heteroaryl is 1, 2 or 3 groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl and C _2-9 heterocycloalkyl and wherein C _2-9 heterocycloalkyl is 1, 2, or 3 independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo optionally substituted with one group,
Each R ⁹ is independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, —C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, —C _1-6 alkyl- selected from phenyl, C _2-9 heterocycloalkyl, —C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and —C _1-6 alkyl-C _2-9 heteroaryl; wherein C _1-6 alkyl, phenyl, —C _1-6 alkyl-phenyl, —C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and —C _1-6 alkyl- C _2-9 heteroaryl is C _1-6 alkyl, —OR ¹¹ , —N(R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, —N(R ¹¹ )C(O)R ¹² , —C(O)R ¹² , and —C(O)OR ¹² , optionally substituted with one or two groups independently selected from;
Each R ¹⁰ is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, —C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, —C _1-6 alkyl-phenyl, and C _2-9 heteroaryl, wherein C _1-6 alkyl, phenyl, —C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 optionally substituted with one or two groups independently selected from alkyl, —N(R ¹¹ ) ₂ , and —C(O)OR ¹² , or two R ¹⁰ , and they are linked _nitrogen atoms together are 5-membered or forming a 6-membered heterocycloalkyl ring,
each R ¹¹ is independently selected from H and C _1-6 alkyl;
each R ¹² is independently selected from H and C _1-6 alkyl;
each R ¹³ is independently selected from C _1-6 alkyl;
m is 1, 2, 3, or 4;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, or 4;
A compound, or a pharmaceutically acceptable salt or solvate thereof.

R. ^１1 teeth

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2.

(i) R ^５5 are each independently halogen, —OH, —OR ^９9 , -N(R ^１０10 ) _２2 , -S(O) _２2 R. ^９9 , -NHS(O) _２2 R. ^９9 , -S(O) _２2 N(R ^１０10 ) _２2 , —C(O)NHS(O) _２2 N(R ^１０10 ) _２2 , -C(O)R ^９9 , -C(O)OR ^１０10 , -OC(O)R ^９9 , -C(O)N(R ^１０10 ) _２2 , -OC(O)N(R ^１０10 ) _２2 , -NR ^１０10 C(O)N(R ^１０10 ) _２2 , -NR ^１０10 C(O)R ^９9 , C _１－６1-6 alkyl, -C _１－６1-6 Alkyl-OH, —C _１－６1-6 alkyl-OR ^９9 , -C _１－６1-6 Alkyl-N(R ^１０10 ) _２2 , -C _１－６1-6 Alkyl-C(O)OR ^１０10 , C _１－６1-6 haloalkyl, C _１－６1-6 haloalkyl-OH, C _３－８3-8 cycloalkyl, C _２－９2-9 heterocycloalkyl, and C _１－９1-9 selected from heteroaryl;
(ii) R ^５5 are each independently halogen, —OH, —OR ^９9 , -N(R ^１０10 ) _２2 , —C(O)NHS(O) _２2 N(R ^１０10 ) _２2 , -C(O)OR ^１０10 , -C(O)N(R ^１０10 ) _２2 , -NR ^１０10 C(O)R ^９9 , C _１－６1-6 alkyl, -C _１－６1-6 Alkyl-C(O)OR ^１０10 , and C _１－９1-9 selected from heteroaryl;
(iii) R ^５5 are each independently halogen, —OH, —OR ^９9 , -C(O)OR ^１０10 , -C(O)N(R ^１０10 ) _２2 , C _１－６1-6 alkyl, -C _１－６1-6 Alkyl-C(O)OR ^１０10 ,and,

is selected from
(iv) R ^５5 are each independently halogen, —OH, and —C(O)OR ^１０10 is selected from or
(v) R ^５5 are each independently halogen, —OH, —OR ^９9 , and -C _１－６1-6 Alkyl-C(O)OR ^１０10 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, selected from:

R. ^９9 is -C(O)OR ^１２12 C optionally substituted with _１－６1-6 5. The compound of Claim 4, or a pharmaceutically acceptable salt or solvate thereof, which is alkyl.

R. ^１０10 are each independently H and C _１－６1-6 6. A compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, selected from alkyl.

R. ^１1 is one, two, or three R ^８8 3. The compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a 5- or 6-membered heteroaryl optionally substituted with a group.

R. ^１1 is one or two R ^８8 8. A 5-membered heteroaryl optionally substituted with a group, wherein the 5-membered heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. A compound as described, or a pharmaceutically acceptable salt or solvate thereof.

R. ^１1 is one or two R ^８8 8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, which is a 6-membered heteroaryl optionally substituted with a group, wherein the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl Or a solvate.

R. ^８8 are each independently halogen, —C(O)OR ^１０10 , C _１－６1-6 alkyl, and —C _１－６1-6 Alkyl-C(O)OR ^１０10 A compound according to any one of claims 7-9, or a pharmaceutically acceptable salt or solvate thereof, selected from:

(i) R ^２2 is H, -OH, -N (R ^１０10 ) _２2 , or -O-C _１－６1-6 is alkyl, or
(ii) R ^２2 Ha-OCH _２2 CH _３3 A compound according to any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, which is

12. The compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-11, wherein n is 0.

or a pharmaceutically acceptable salt or solvate thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating inflammatory bowel disease in a patient and for modulating GPR35 activity Or the use of a solvate, optionally wherein said inflammatory bowel disease is selected from Crohn's disease, ulcerative colitis, and perianal Crohn's disease.

15. The pharmaceutical composition of claim 14 for use in treating inflammatory bowel disease in a patient and in modulating GPR35 activity, optionally wherein said inflammatory bowel disease is Crohn's disease, A pharmaceutical composition selected from ulcerative colitis and perianal Crohn's disease.