JPWO2021001538A5

JPWO2021001538A5 -

Info

Publication number: JPWO2021001538A5
Application number: JP2021577557A
Authority: JP
Publication date: 2023-07-07

Claims

A D-galactopyranose compound of formula (1),

During the ceremony,
the pyranose ring is α-D-galactopyranose,
A ¹ is R ¹ -Z;
During the ceremony,
Z is a 5-membered heterocyclic ring having at least one heteroatom selected from O, S and N, excluding 1,2,3-triazole, and is attached to α-D-galactopyranose;
—COOH; —CONR ^6a R ^7a (R ^6a and R ^7a are independently selected from H, C _1-3 alkyl, cyclopropyl ^and isopropyl, or R ^6a and R ^7a together with the nitrogen can form heterocycloalkyl), C _1-3 alkyl optionally substituted with F; cyclopropyl optionally substituted with F; OC _1-3 alkyl optionally substituted with F; O-cyclopropyl optionally substituted with F; O-isopropyl optionally substituted with F; NR ^8a R ^9a ( R ^8a and R ^9a are independently selected from H, C _1-3 alkyl and isopropyl); OH; and R ^10a -CONH- (R ^10a is selected from C _1-3 alkyl and cyclopropyl); ^aryl ^, such as ^phenyl or naphthyl, optionally substituted ^by selected groups; b) halogen; spiro heterocycle; CN; _1-3 alkyl, cyclopropyl and isopropyl); C _1-3 alkyl optionally substituted with F; cyclopropyl optionally substituted with F; isopropyl optionally substituted with F; OC _1-3 alkyl optionally substituted with F; O-cyclopropyl optionally substituted with F; O-isopropyl optionally substituted with F; NR ^14a R ^15a (R ^14a and R ^15a are independently selected from H, C _1-3 alkyl, cyclopropyl and isopropyl), C(=O)-R ^21a (R ^21a is selected from H and C _1-3 alkyl); OH; and R ^16a -CONH- (R ^16a is selected from C _1-3 alkyl and cyclopropyl), optionally substituted with a group selected from heterocycle such as heteroaryl or heterocycloalkyl,
X is selected from S, SO, _SO2 , O, C=O, and ^CR2bR3b , wherein ^R2b and ^R3b are independently selected from hydrogen, OH, or halogen ^;
B ¹ is a) CN, halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, OCH ₂ CH ₃ optionally substituted with F, OH, and R ^4b — C _1-6 alkyl substituted with a 5- or 6-membered heteroaromatic ring optionally substituted with a substituent selected from CONH— (R ^4b is selected from C _1-3 alkyl and cyclopropyl) or branched C _3-6 alkyl; or CN, halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, OCH ₂ CH ₃ optionally substituted with F, OH, and R ^5b C _1-6 alkyl substituted with phenyl optionally substituted with a substituent selected from —CONH— (R ^5b is selected from C _1-3 alkyl and cyclopropyl), b) halogen; CN; spiro heterocycle such as N-(2-oxa)-6-azaspiro[3.3]heptanyl; C ₂ -alkynyl; —COOH; —CONR ^6b R ^7b (R ^6b and R ^7b are independently H, C _1-3 alkyl, cyclopropyl and isopropyl, or R ^6b and R ^7b together with the nitrogen may form heterocycloalkyl); C _1- optionally substituted with F; _cyclopropyl optionally substituted with F; isopropyl optionally substituted with F; OC _1-3 alkyl optionally substituted with F; O-cyclopropyl optionally substituted with F O-isopropyl optionally substituted with F; NR ^8b R ^9b (R ^8b and R ^9b are independently selected from H, C _1-3 alkyl and isopropyl); OH; substituted with OH heterocycle optionally substituted with C _1-3 alkyl; and substituted with a group selected from R ^10b -CONH- (R ^10b is selected from C _1-3 alkyl and cyclopropyl) aryl such as phenyl or naphthyl , c) halogen, C ₂ -alkynyl, CN, methyl optionally substituted with F, OCH ₃ optionally substituted with F, C _5- optionally substituted with a substituent selected from OCH ₂ CH ₃ , OH, and R ^11b —CONH—, where R ^11b is selected from C _1-3 alkyl and cyclopropyl; ₇ cycloalkyl, and d) halogen; spiroheterocycle such as N-(2-oxa) ^-6 -azaspiro ^[ 3.3]heptanyl; C ₂ ^-alkynyl ; CN; and R ^13b are independently selected from H, C _1-3 alkyl, cyclopropyl and isopropyl); C _1-3 alkyl optionally substituted with F; cyclopropyl optionally substituted with F; Isopropyl optionally substituted with F; OC _1-3 alkyl optionally substituted with F; O-cyclopropyl optionally substituted with F; O-isopropyl optionally substituted with F; NR ^14b R ^15b (R ^14b and R ^15b are independently selected from H, C _1-3 alkyl and isopropyl); OH; optionally substituted with C _1-3 alkyl optionally substituted with OH a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from R ^16b -CONH-, where R ^{16b is} selected from C _1-3 alkyl and cyclopropyl; ring, e) C _1-6 alkyl or branched C _3-6 alkyl; f) C _2-6 alkynyl;
R ⁵⁰ is a) H, b) OH, c) phenyl substituted with one or more groups selected from halogen, phenyl, OH and halogen, CN, OR ^17b , NR 18b ^R 19b ^and CONH ₂ OC _1-6 alkyl optionally substituted with one or more (R ^17b is H, CN, halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, F is selected from the group consisting of optionally substituted OCH ₂ CH ₃ , OH, and R ^20b -CONH-, wherein R ^20b is selected from C _1-3 alkyl and cyclopropyl; R ^18b is H, CN, selected from the group consisting of halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, OCH ₂ CH ₃ optionally substituted with F, OH, and R ^21b -CONH- , R ^21b is selected from C _1-3 alkyl and cyclopropyl, and R ^19b is H, CN, halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, F optionally substituted OCH ₂ CH ₃ , OH, and R ^22b —CONH—, wherein R ^22b is selected from C _1-3 alkyl and cyclopropyl), d ) halogen , CN , OR ^23b , NR ^24b R ^25b , and a branched OC _3-6 alkyl optionally substituted with one or more of CONH ₂ (R ^23b is methyl optionally substituted with H, CN, halogen, F, selected from the group consisting of OCH ₃ optionally substituted with F, OCH ₂ CH ₃ optionally substituted with F, OH and R ^26b -CONH-, where R ^26b is C _1-3 alkyl and cyclopropyl R ^24b is selected from H, CN, halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, OCH ₂ CH ₃ optionally substituted with F, OH and R ^27b is selected from the group consisting of -CONH-, R ^27b is selected from C _1-3 alkyl and cyclopropyl, R ^25b is H, CN, halogen, methyl optionally substituted with F, F optionally substituted OCH ₃ , OCH ₂ CH ₃ optionally substituted with F, OH and R ²⁸ —CONH—, wherein R ²⁸ is selected from C _1-3 alkyl and cyclopropyl and e ) cyclic OC _3-6 alkyl optionally substituted with one or more of halogen , CN, OR ²⁹ , NR ³⁰ R ³¹ and CONH ₂ (R ²⁹ is H, CN, halogen, R ³² is selected from the group consisting of methyl optionally substituted with F, OCH ₃ optionally substituted with F, OCH ₂ CH ₃ optionally substituted with F, OH and R ³² —CONH—; is selected from C _1-3 alkyl and cyclopropyl, and R ³⁰ is H, CN, halogen, methyl optionally substituted with F, OCH ₃ optionally substituted with F, substituted with F OCH ₂ CH ₃ , OH and R ³³ —CONH—, R ³³ is selected from C _1-3 alkyl and cyclopropyl, R ³¹ is H, CN, halogen, F is selected from the group consisting of optionally substituted methyl, optionally F-substituted OCH ₃ , optionally F-substituted OCH ₂ CH ₃ , OH and R ³⁴ —CONH—, wherein R ³⁴ is C _1-3 alkyl and cyclopropyl);
A D-galactopyranose compound, or a pharmaceutically acceptable salt or solvate thereof.

Z is 1,2,4-triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxolyl, dithiolyl, thiazolyl, isothiazolyl, furanyl, thiophene, pyrrolyl, imidazolyl or

The compound of claim 1, wherein the asterisk on the carbon is attached to R1 and the asterisk on the nitrogen is attached to α-D-galactopyranose.

R ¹ is CN, OH, NH ₂ , F, Br, Cl, I, methyl optionally substituted with fluorine (F), OCH ₃ optionally substituted with F, and substituted with F The compound according to any one of claims 1 to 2, which is phenyl optionally substituted with a group selected from SCH ₃ .

CN; NR ^14a R ^15a ( ^{R 14a} ^and R ^15a are independently selected from H, C _1-3 alkyl, cyclopropyl and isopropyl), C( =O)—R ^21a (wherein R ^21a is selected from H and C _1-3 alkyl); C _1-3 alkyl optionally substituted with F; cyclopropyl optionally substituted with F; isopropyl optionally substituted with; O-cyclopropyl optionally substituted with F; O-isopropyl optionally substituted with F; OC _1-3 alkyl optionally substituted with F; according to any one of claims 1 to 2, selected from a 5- or 6-membered heteroaromatic ring optionally substituted with a group selected from SC _1-3 alkyl optionally substituted with Compound as described.

R ¹ is OH, NH ₂ , CN, Br, Cl, I, F, methyl optionally substituted with F, OCH ₃ optionally substituted with F, and SCH optionally substituted with F pyridinyl optionally substituted by a group selected from ₃ , or methyl optionally substituted by H, CN, Br, Cl, I, F, F, OCH ₃ optionally substituted by F, 5. The compound of claim 4, which is a pyrimidyl optionally substituted with a group selected from _SCH3 and optionally substituted with F.

R ¹ is a 5- or 6-membered heteroaromatic ring selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, and formulas 2-9, and an asterisk * is a heteroaromatic ring covalently attached to the Z substituent indicates the carbon atom of

OH; CN; SH; S ^— C _1-3 alkyl; C ^1-3 alkyl optionally substituted with ^F _; cyclopropyl optionally substituted with F; O-cyclopropyl optionally substituted with F; O-isopropyl optionally substituted with F; OC ₁ optionally substituted with F _-3 alkyl; NR ²⁴ R ²⁵ (wherein R ²⁴ is selected from H and C _1-3 alkyl, R ²⁵ is selected from H, C _1-3 alkyl and COR ²⁶ , R ²⁶ is H and C _1-3 alkyl A compound according to any one of claims 1 to 2, which is selected from

R ¹ is

is selected from the group consisting of
^R2 is selected from the group consisting of OH, methyl and halogen, preferably F, Cl and Br,
R ³ is selected from the group consisting of hydrogen, C _1-6 alkyl and halogen;
^R4 is selected from the group consisting of OH, _NH2 and halogen, preferably F, Cl and Br,
7. A compound according to claim 6, wherein R ⁵ is selected from the group consisting of hydrogen, C _1-6 alkyl and halogen.

A compound according to any one of claims 1 to 7, wherein X is selected from S, SO, _SO2 and O.

B1 is substituted with a group selected from halogen; CN; ethynyl; methyl optionally substituted with F; and heterocycle optionally substituted with C _1-3 alkyl optionally substituted with OH A compound according to any one of claims 1 to 8, which is selected from heteroaryl which is optionally

B1 is selected from Cl, Br, CN, methyl, _CF3 , azetidinyl; azetidinyl substituted with _CH2OH ; pyridinyl optionally substituted with a group selected from pyridinyl, pyrimidinyl, oxazolyl and thiazolyl 10. A compound according to claim 9.

B1 is C _1-3 alkyl optionally substituted with halogen, CN, F, and CONR ^6b R ^7b (R ^6b and R ^7b are independently H, C _1-3 alkyl, cyclopropyl, and isopropyl; or R ^6b and R ^7b can be taken together with the nitrogen to form a heterocycloalkyl, phenyl optionally substituted with a group selected from claims 1 to 8 A compound according to any one of

R ⁵⁰ is substituted with at least one from the group consisting of H, OH, OC _1-6 alkyl, C _1-4 alkyl, phenyl and phenyl substituted with one or more groups selected from OH and halogen A compound according to any one of claims 1 to 11, selected from C _1-4 alkyl.

3-chlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside,
5-chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D - a galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D- galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D - a galactopyranoside,
5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D- galactopyranoside,
5-bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D - a galactopyranoside,
5-ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D - a galactopyranoside,
5-chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D - a galactopyranoside,
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1- thio-α-D-galactopyranoside,
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio - α-D-galactopyranoside,
5-chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D- galactopyranoside,
5-chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio- α-D-galactopyranoside,
5-chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio - α-D-galactopyranoside,
5-chloro-2-methylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio- α-D-galactopyranoside,
5-bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio- α-D-galactopyranoside,
2-cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio- α-D-galactopyranoside,
5-chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galacto pyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galacto pyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(5-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galacto pyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(4-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galacto pyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(1H-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α- D-galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(1-methyl-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio- α-D-galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(1H-imidazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyra nosid,
5-chloropyridin-3-yl 3-deoxy-3-[4-(oxazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside ,
5-chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside ,
5-chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside ,
5-chloropyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galacto pyranoside,
5-bromopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galacto pyranoside,
5-chloro-2-cyanophenyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galacto pyranoside,
5-chloro-2-cyanopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α - D-galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galacto pyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1- thio-α-D-galactopyranoside,
5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1- thio-α-D-galactopyranoside,
5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1- thio-α-D-galactopyranoside,
5-chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O- methyl-1-thio-α-D-galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,3-imidazol-1-yl]-1-thio-α-D- galactopyranoside,
5-chloro-[3,3-bis(hydroxymethyl)azetidin-1-yl]pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1, 2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside,
5-chloropyridin-3-yl 3-deoxy-3-[3-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D- galactopyranoside,
3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside,
3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside,
3,4-dichlorophenyl 3-deoxy-3-[5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-α-D-galacto pyranoside,
3,4-dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α- D-galactopyranoside,
5-chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methyl-1 - thio-α-D-galactopyranoside,
5-chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1- thio-α-D-galactopyranoside, and 5-chloro-2-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazole-1- yl]-2-O-methyl-1-thio-α-D-galactopyranoside; or a pharmaceutical salt or solvate thereof. Compound as described.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and optionally a pharmaceutically acceptable excipient.

15. A pharmaceutical composition according to claim 14 for use in a method for treating disorders associated with binding of galectin-3 to its ligand in mammals such as humans.

atopic dermatitis; acute coronary syndrome; fibrosis such as pulmonary fibrosis, liver fibrosis, renal fibrosis, ophthalmologic fibrosis and cutaneous and cardiac fibrosis local fibrosis such as Dupuytren's disease, Peyronie's disease; fibrotic complications of other treatments such as coronary artery stents, biliary stents, cerebral artery stents, ureteral stents; scleroderma; scarring; keloid formation; COVID-19; Acute Lung Injury; ARDS; Viral Pneumonitis, Abnormal Scarring; Surgical Adhesions; Septic Shock; cancer, female cancer such as breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, brain cancer such as medulloblastoma, glioma, meningioma, sarcoma of bone and muscle and other sarcomas, Alzheimer's disease; TGFβ-driven bone diseases such as osteogenesis imperfecta; pulmonary hypertension; autologous such as psoriasis, rheumatoid arthritis, rheumatoid lung Immune diseases; Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; viral infections such as influenza virus, HIV, herpes virus, coronavirus, hepatitis C; metabolic disorders; heart disease; angiogenesis, such as ocular neovascularization or diseases or conditions associated with ocular neovascularization, such as neovascularization associated with cancer; and eye diseases such as age-related macular degeneration and corneal neovascularization; atherosclerosis; diabetes; type I diabetes; type 2 diabetes; insulin resistance; Interstitial lung disease, such as Hermanski-Pudrac syndrome, liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; uterine diseases such as uterine fibroids and uterine or cervical fibrosis. A pharmaceutical composition for use according to claim 15 , selected from the group.