JPWO2021174048A5

JPWO2021174048A5 -

Info

Publication number: JPWO2021174048A5
Application number: JP2022551554A
Authority: JP
Publication date: 2024-02-22

Claims

A compound of formula (2),
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Z is −P(=O)(R ⁵ )OR ⁶ ,
R ⁵ is C ₁ -C ₆ alkyl;
R ⁶ is hydrogen or C ₁ -C ₆ alkyl;
R ¹ , R ² , and R ³ are each independently hydrogen, halogen, or C ₁ -C ₆ alkyl;
R ⁴ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl;
Y2 ^is N or CH,
L ¹ is ^* -O-CH ₂ -, ^* -CH ₂ -O-, ^* -NR ⁷ -CH ₂ -, ^* -NR ⁷ -C(O)-, ^* -C(O)-NR ⁷ - , or ^* -C(O)-CH2- _, where ^* represents a connection to ring B;
R ⁷ is hydrogen or C ₁ -C ₆ alkyl;
Ring B is a 3-6 membered heterocycloalkylene, where the heterocycloalkylene is unsubstituted or substituted with 1, 2, 3, or 4 R ^B substituents;
Alternatively, ring B is a C ₃ -C ₆ cycloalkylene, where the cycloalkylene is unsubstituted or substituted with 1, 2, 3, or 4 R ^B substituents;
Ring A is aryl or heteroaryl, where aryl or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R ^A substituents ;
L ² is a single bond or C ₁ -C ₆ alkylene, where alkylene is unsubstituted or -OH, C ₁ -C ₆ alkyl, and -O-(C ₁ -C ₆ alkyl ) with 1, 2, or 3 substituents selected from the group consisting of
Each R ^A independently represents halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ fluoroalkyl, -L ^A -CN, -L ^A -OH , -LA ^-OR 10 ^, -LA ^-NR 11 R ¹¹ , -LA ^-C (=O)R ¹⁰ , -LA ^-C (=O)OR ¹¹ , -LA ^-OC ( ⁼ O) R ¹¹ , -LA ^-C (=O)NR ¹¹ R ¹¹ , -LA ^-NR 11 C(=O)R ¹¹ , -LA ^-NR ¹¹ C ⁽ =O) NR ¹¹ R ¹¹ , ^-LA -OC(=O)NR ¹¹ R ¹¹ , -LA ^-NR 11 ^C (=O)OR ¹⁰ , -LA ^-OC (=O)OR ¹⁰ , -LA ^-aryl , ^-LA -heteroaryl, -L ^A - (C ₃ -C ₁₀ cycloalkyl), or -L ^A - (3- to 10-membered heterocycloalkyl), where alkyl, alkenyl, alkynyl, fluoroalkyl, aryl, heteroaryl, Cycloalkyl and heterocycloalkyl are each independently unsubstituted or halogen, -CN, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ hydroxy Substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, -O-(C ₁ -C ₆ alkyl), and -O-(C ₁ -C ₆ fluoroalkyl) is,
each R ^B is independently halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ fluoroalkyl;
Each L ^A is independently a single bond or C ₁ -C ₆ alkylene, where alkylene is unsubstituted or halogen, -CN, -OH, -O-(C ₁ -C ₆ alkyl), and C ₁ -C ₆ alkyl,
Each R ¹⁰ is independently C ₁ -C ₆ alkyl, where each alkyl is independently unsubstituted or halogen, -OH, C ₁ -C ₆ alkyl, and C ₁ substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of -C ₆ hydroxyalkyl,
R ¹¹ is each independently hydrogen, C ₁ -C ₆ alkyl, or monocyclic heteroaryl, where alkyl and heteroaryl are each independently unsubstituted or halogen, substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of -OH, C ₁ -C ₆ alkyl, and C ₁ -C ₆ hydroxyalkyl,
Alternatively, two R ^11s on the same nitrogen atom together with the nitrogen to which they are attached form a 3- to 6-membered N-heterocycloalkyl, where the heterocycloalkyl is a non- substituted or with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, -OH, C ₁ -C ₆ alkyl, and C ₁ -C ₆ hydroxyalkyl compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

R ^１1 ,R ^２2 , and R ^３3 are each independently hydrogen, halogen, or C _１1 -C _４4 is alkyl, and
R ^４4 is unsubstituted C _３3 -C _６6 5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, which is cycloalkyl.

Formula (III)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in which:
R ^１1 ,R ^２2 , and R ^３3 are each independently hydrogen, -F, -Cl, or C _１1 -C _４4 5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, which is alkyl.

L ^１1 teeth ^＊* -O-CH _２2 -or ^＊* -CH _２2 -O-, where ^＊* represents a connection to ring B, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

Ring B is a 3-6 membered heterocycloalkylene, where the heterocycloalkylene is unsubstituted or has 1, 2, 3, or 4 R ^ＢB 12. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, substituted with a substituent.

Formula (XV)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in which:
W is N, CH, or CR ^ＡA and
R ^ＡA are each independently -F, -Cl, C _１1 -C _７7 alkyl, C _１1 -C _４4 Fluoroalkyl, -OH, or -OR ^１０10 and,
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein n is 0, 1, or 2.

Formula (XVa-i)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Isomers, or prodrugs.

Formula (VII)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein p and q are each independently 1 or 2. A described compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

Formula (VIIa) or Formula (VIIb)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Isomers, or prodrugs.

Ring B is C _３3 -C _６6 cycloalkylene, where cycloalkylene is unsubstituted or has 1, 2, 3, or 4 R ^ＢB 12. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, substituted with a substituent.

Formula (XIV)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in which:
W is N, CH, or CR ^ＡA and
R ^ＡA are each independently -F, -Cl, C _１1 -C _７7 alkyl, C _１1 -C _４4 Fluoroalkyl, -OH, or -OR ^１０10 and,
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein n is 0, 1, or 2.

Formula (XIVa-i)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Isomers, or prodrugs.

Z is -P(=O)(CH _３3 ) OH, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof. body, or prodrugs.

comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient. , pharmaceutical composition.

16. A pharmaceutical composition according to claim 15 for use in the treatment of diseases or disorders involving the gut-brain axis, comprising:
A pharmaceutical composition, wherein said disease or disorder is associated with GPR40 activity.

17. The pharmaceutical composition of claim 16, wherein the disease or disorder is a metabolic disorder.

17. The pharmaceutical composition according to claim 16, wherein the disease or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, non-alcoholic steatohepatitis, or hypertension.

17. The pharmaceutical composition according to claim 16, wherein the disease or disorder is a nutritional disorder.

17. The pharmaceutical composition according to claim 16, wherein the disease or disorder is short bowel syndrome, intestinal failure, or intestinal dysfunction.

further comprising one or more additional therapeutic agents for use in treating said disease or disorder, said one or more additional therapeutic agents including a TGR5 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, 17. A pharmaceutical composition according to claim 16, selected from a PDE4 inhibitor, a DPP-4 inhibitor, a GLP-1 receptor agonist, a GOAT inhibitor, metformin, or a combination thereof.