US 2026/0258007 A1 · COMPOUNDS, COMPOSITIONS AND METHODS OF USE TO TREAT HYPOPARATHYROIDISM AND OSTEOPOROSIS

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
Q is O or S;
V, W, and X are independently N or CR1;
provided that at least one of V, W, and X is CR1;
Y is (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl:
each of which substituents is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
Z is NR4R5 or OR6;
R1 is independently for each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, fluoro, chloro, cyano, hydroxyl, or (C1-C6)alkoxy;
R2 is (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C8)cycloalkyl;
R3 is hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, (C1-C6)hydroxyalkyl, NR11R12, NC(O)R13, OC(O)NR11R12, or NR14SO2R15;
or R2 and R3 together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl or a 4- to 7-membered heterocycloalkyl;
wherein (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R4 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
wherein (C1-C6)alkyl is optionally substituted with one, two or three substituents selected independently for each occurrence from R4a, halo, hydroxyl, cyano, carboxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, C(O)NR11R12, NR11R12, OC(O)NR11R12 and (C1-C6)alkoxy;
and wherein (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, 5- to 10-membered heteroaryl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl C(O)NR11R12, NR11R12, NC(O)OR13, NC(O)R13, OC(O)NR11R12, and SO2NR11R12;
R4a is (C3-C8)cycloalkyl, phenyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)alkylsulfonyl;
R5 is hydrogen or (C1-C6)alkyl;
or R4 and R5 taken together with the nitrogen atom to which they are attached form an optionally 4- to 7-membered heterocycloalkyl;
wherein 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, carboxyl, 5- to 10-membered heteroaryl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)carboxyalkyl, (C1-C6)alkylsulfonyl, NR14SO2R15, and C(O)NR11R12;
R6 is hydrogen or (C1-C6)alkyl;
R7 is hydrogen or (C1-C6)alkyl;
or R7 and Y taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl;
R11 and R12 are independently for each occurrence selected from hydrogen, (C1-C6)alkyl, and (C3-C8)cycloalkyl;
or R1 and R12 taken together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl;
R13 is independently for each occurrence selected from (C1-C6)alkyl and (C3-C8)cycloalkyl;
and
R14 is independently for each occurrence selected from hydrogen, (C1-C6)alkyl, and (C3-C8)cycloalkyl, and R15 is independently for each occurrence selected from (C1-C6)alkyl and (C3-C8)cycloalkyl;
or R14 and R15 taken together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl.

27 more elements

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
V, W, and X are independently N or CR1;
provided that at least one of V, W, and X is CR1;
Y is (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl:
each of which substituents is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
Z is NR4R5 or OR6;
R1 is independently for each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, fluoro, chloro, cyano, hydroxyl, or (C1-C6)alkoxy;
R2 is (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C8)cycloalkyl;
R3 is hydroxyl, (C1-C6)alkoxyalkyl, or —NH2;
or R2 and R3 together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl or a 4- to 7-membered heterocycloalkyl;
wherein (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R4 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
wherein (C1-C6)alkyl is optionally substituted with one, two or three substituents selected independently for each occurrence from R4a, halo, hydroxyl, cyano, carboxy, (C1-C6)alkylsulfonyl, and (C1-C6)alkoxy;
and wherein (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R4a is (C3-C8)cycloalkyl, phenyl, or 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R5 is hydrogen or (C1-C6)alkyl;
or R4 and R5 taken together with the nitrogen atom to which they are attached form an optionally 4- to 7-membered heterocycloalkyl;
wherein 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, carboxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R6 is hydrogen or (C1-C6)alkyl;
and
R7 is hydrogen or (C1-C6)alkyl;
or R7 and Y taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

21 more elements

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
V, W, and X are independently N or CR1;
provided that at least one of V, W, and X is CR1;
Y is (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl;
Z1 is NR4R5 or OR6;
R1 is independently for each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, fluoro, chloro, cyano, hydroxyl, or (C1-C6)alkoxy;
R2 is (C1-C6)haloalkyl or (C1-C6)alkyl;
R3 is hydroxyl;
or R2 and R3 together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl or a 4- to 7-membered heterocycloalkyl;
wherein (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R4 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
wherein (C1-C6)alkyl is optionally substituted with one, two or three substituents selected independently for each occurrence from R4a, halo, hydroxyl, and (C1-C6)alkoxy;
and wherein (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R4a is (C3-C8)cycloalkyl, phenyl, or 4- to 7-membered heterocycloalkyl;
each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R5 is hydrogen or (C1-C6)alkyl;
or R4 and R5 taken together with the nitrogen atom to which they are attached form an optionally 4- to 7-membered heterocycloalkyl;
wherein 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R6 is hydrogen or (C1-C6)alkyl;
and
R7 is hydrogen or (C1-C6)alkyl;
or R7 and Y taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

21 more elements

A compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof;
wherein:
A is 5- to 10-membered heteroaryl;
Q is S or O;
V, W, and X are independently N or CR1;
provided that at least one of V, W, and X is CR1;
Y is (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl;
each of which substituents is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R1 is independently for each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, fluoro, chloro, cyano, hydroxyl, or (C1-C6)alkoxy;
R2 is (C1-C6)haloalkyl, (C1-C6)alkyl, or (C1-C6)cycloalkyl;
R3 is hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, (C1-C6)hydroxyalkyl, NR11R12, NC(O)R13, OC(O)NR11R12, NR11SO2R12;
or R2 and R3 together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl or a 4- to 7-membered heterocycloalkyl;
wherein (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R7 is hydrogen or (C1-C6)alkyl;
or R7 and Y taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl;
R8, R9 and R10 are independently for each occurrence H, (C1-C6)alkyl, or carboxy;
wherein each (C1-C6)alkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from the group consisting of (C1-C6)alkoxy, hydroxy, fluoro, chloro, cyano, and NR11R12,
R11 and R12 are independently for each occurrence selected from hydrogen, (C1-C6)alkyl, and (C3-C8)cycloalkyl;
or R11 and R12 taken together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl;
R13 is independently for each occurrence selected from (C1-C6)alkyl and (C3-C8)cycloalkyl;
and
R14 is independently for each occurrence selected from hydrogen, (C1-C6)alkyl, and (C3-C8)cycloalkyl, and R15 is independently for each occurrence selected from (C1-C6)alkyl and (C3-C8)cycloalkyl;
or R14 and R15 taken together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl.

21 more elements

A compound of Formula (IIb):

or a pharmaceutically acceptable salt thereof;
wherein:
V, W, and X are independently N or CR1;
provided that at least one of V, W, and X is CR1;
Y is (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each of which is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl;
each of which substituents is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
U is N or CR10;
R1 is independently for each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, fluoro, chloro, cyano, hydroxyl, or (C1-C6)alkoxy;
R2 is (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C8)cycloalkyl;
R3 is hydroxyl, (C1-C6)alkoxyalkyl, or —NH2;
or R2 and R3 together with the carbon atom to which they are attached form a (C1-C6)cycloalkyl or a 4- to 7-membered heterocycloalkyl;
wherein (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl;
R7 is hydrogen or (C1-C6)alkyl;
or R7 and Y taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl;
R8, R9 and R10 are independently for each occurrence H or (C1-C6)alkyl;
wherein each (C1-C6)alkyl is optionally substituted with one, two, or three substituents selected independently for each occurrence from the group consisting of hydroxy, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, fluoro, chloro, cyano, and NR11R12;
and
R11 and R12 are each independently hydrogen or (C1-C6)alkyl;
or R11 and R12 taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

17 more elements

Compounds, compositions and methods of use to treat hypoparathyroidism and osteoporosis

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Compounds, compositions and methods of use to treat hypoparathyroidism and osteoporosis

Life of this patent

Abstract

Claims121