JPWO2019241461A5

JPWO2019241461A5 -

Info

Publication number: JPWO2019241461A5
Application number: JP2020569778A
Authority: JP
Publication date: 2022-01-14
Anticipated expiration: 2039-06-13

Claims

Equation (I)

[During the ceremony,
A is O, NH, or N (COCH ₃ );
R ¹ is (R ⁴ ) CONH-, or

And;
R ² is alkyl, (CO ₂ (R ⁵ )) alkyl, or (CON (R ⁶ ) (R ⁷ )) alkyl;
R ³ is a cyclo substituted with 0 to 3 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, CO ₂ R ⁵ and (R ⁶ ) (R ⁷ ) N. Alkoxy, tetrahydropyranyl, or Ar ¹ ;
R ⁴ is an alkyl, cycloalkyl, bicyclo [2.2.1-] substituted with 0-5 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and CO ₂ R ⁵ . 2] Alkoxy, or Ar ² ;
R ⁵ is hydrogen or alkyl;
R ⁶ is hydrogen, alkyl, alkylcarbonyl, or phenyl;
Is R ⁷ hydrogen or alkyl;
Alternatively, the bound (R ⁶ ) (R ⁷ ) N can be azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomol substituted with 0 to 3 substituents selected from halogens, alkyls, hydroxys, and alkoxys. Halinyldioxide;
Ar ¹ is phenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, or pyrazinyl; and
Ar ² is phenyl, biphenyl, naphthalenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, or quinoxalinyl]
Compound, or a pharmaceutically acceptable salt thereof.

The compound is of formula (Ia) :.

The compound of claim 1, or a pharmaceutically acceptable salt thereof.

R ¹

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

A compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R ² is alkyl.

The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R ² is (CO ₂ (R ⁵ )) alkyl or (CON (R ⁶ ) (R ⁷ )) alkyl.

Ar substituted with 0 to ³ substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, CO ₂ R ⁵ and (R ⁶ ) (R ⁷ ) N. The compound of claim ¹ or 2 , or a pharmaceutically acceptable salt thereof, which is 1.

Cyclo in which R ³ is substituted with 0 to 3 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, CO ₂ R ⁵ and (R ⁶ ) (R ⁷ ) N. The compound of claim 1 or 2, which is an alkyl or tetrahydropyranyl , or a pharmaceutically acceptable salt thereof .

1 or claim 1 or claim R ⁴ is Ar ² substituted with 0-5 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and CO ₂ R ⁵ . 2 compounds , or pharmaceutically acceptable salts thereof .

Alkyl, cycloalkyl, or bicyclo [2.2.1] in which R ⁴ is substituted with 0-5 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and CO ₂ R ⁵ . -2] A compound according to claim 1 or 2, which is an alkyl , or a pharmaceutically acceptable salt thereof .

Phenyl in which Ar ¹ is substituted with 0 to 3 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, CO ₂ R ⁵ and (R ⁶ ) (R ⁷ ) N. , Pyridynyl, pyridadinyl, pyrimidinyl, or pyrazinyl, the compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof .

Ar ² is substituted with phenyl, pyridinyl, pyridadinyl, pyrimidinyl, or pyrazinyl substituted with 0-5 substituents selected from cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and CO ₂ R ⁵ . A compound according to claim 1 or 2 , or a pharmaceutically acceptable salt thereof .

A composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Fibrosis of organs (eg liver, kidneys, lungs, heart and skin), liver diseases and conditions (eg acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, hypertonic hypertension, hepatic regeneration failure, non-alcoholic fat Hepatitis (NASH), liver dysfunction, and impaired hepatic blood flow), cell proliferative disorders, and cancer disorders (eg, solid tumors, metastasis of solid tumors, vascular fibroma, myeloma, multiple myeloma, Kaposi sarcoma, Leukemia, chronic lymphocytic leukemia (CLL) and moist metastasis of cancer cells), inflammatory diseases and conditions (eg psoriasis, nephropathy, and pneumonia), gastrointestinal diseases and conditions (eg hypersensitive bowel syndrome (IBS), Inflammatory bowel disease (IBD), and pancreatic secretion abnormalities), kidney diseases and conditions, urinary tract-related diseases and conditions (eg, benign prostatic hypertrophy, or neuropathic bladder, spinal cord tumors, disc hernia, spinal canal stenosis) Symptoms related to, and symptoms derived from diabetes), diseases and conditions of the lower urinary tract (eg, lower urinary tract obstruction), inflammatory diseases and conditions of the lower urinary tract (eg, urinary disorders and frequent urination), diseases and conditions of the pancreas, Diseases and conditions related to angiogenesis (eg arterial occlusion), chondrosis, brain-related diseases and conditions (eg cerebral infarction and cerebral bleeding), neuropathy pain and peripheral neuropathy, eye diseases and conditions (eg addition) One of claims 1 to 11 for treating age-related yellow spot degeneration (AMD), diabetic retinopathy, proliferative vitreous retinopathy (PVR), scarring hepatic plaque, and glaucoma filtration surgery scar). A pharmaceutical composition comprising the compound according to the above , or a pharmaceutically acceptable salt thereof .

13. The pharmaceutical composition of claim 13, wherein the disease or condition is renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis.