Granted Patent B2

US 12,729,196 · App. 18/257,123 · Granted Sep 8, 2026

Inventors: Jonas Brånalt (Gothenberg, SE); Björn Holm (Gothenberg, SE); Maria Johansson (Gothenberg, SE); Olle Karlsson (Gothenberg, SE); Daniel Laurent Knerr (Gothenberg, SE); Anneli Nordqvist (Gothenberg, SE); Robert John Sheppard (Gothenberg, SE); Marianne Swanson (Gothenberg, SE); Anna Tomberg (Gothenberg, SE)

Assignee: AstraZeneca AB

C07D417/12A61P1/16C07D417/14C07D487/04C07D487/10C07D491/107C07D491/113C07D493/10C07D495/10C07D498/08

Abstract

Claims (81)

1 . A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is selected from the group consisting of —S—, —S(O)—, and —S(O) 2 —;

R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 -alkyl, and C 1-6 -alkoxy;

R 2 is selected from the group consisting of:

(a) heterocyclyl containing a total of 4 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or completely unsaturated monocyclic or fused bicyclic ring, (ii) has one, two, or three nitrogen ring atoms with the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogen, and (b) the C 1-6 -alkyl may be further substituted with one or more hydroxy;

(b) heterocyclyl containing a total of 5 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or completely unsaturated monocyclic or fused bicyclic ring, (ii) has (a) one nitrogen ring atom and one oxygen ring atom with the remaining ring atoms being carbon, or (b) one nitrogen ring atom and one sulfur ring atom with the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl may be further substituted with one or more halogen; and

(c) spiro heterocyclyl containing a total of 6 to 11 ring atoms, wherein the spiro heterocyclyl: (i) contains two saturated rings, (ii) has: (a) one or two nitrogen ring atoms with the remaining ring atoms being carbon, (b) one or two nitrogen ring atoms and one or two oxygen ring atoms with the remaining ring atoms being carbon, or (c) one nitrogen ring atom and one sulfur ring atom with the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, and C 1-6 -alkylcarbonyl;

R 3 is selected from the group consisting of hydrogen, halogen, and C 1-3 -alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, and C 1-3 -alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, and C 1-3 -alkyl; and

R 6 is selected from the group consisting of hydrogen, halogen, and C 1-3 -alkyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 .

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —S—.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (III-A):

or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are as defined in claim 1 .

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (III-B):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are as defined in claim 1 .

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (III-C):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are as defined in claim 1 .

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (III-D):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 are as defined in claim 1 .

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (III-E):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 6 are as defined in claim 1 .

9 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (IV-A):

or a pharmaceutically acceptable salt thereof, wherein R 2 is as defined in claim 1 .

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is heterocyclyl containing a total of 4 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or completely unsaturated monocyclic or fused bicyclic ring, (ii) has one, two, or three nitrogen ring atoms with the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl, and wherein: (a) the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkoxy, C 1-3 -alkoxy-C 2-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl, C 3-6 -cycloalkylcarbonyl, C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, phenyl, tolyl, C 1-3 -alkoxyphenyl, phenyl-C 1-3 -alkyl, C 1-3 -alkoxyphenyl-C 1-3 -alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrooxepanyl may be further substituted with one or more halogen, and (b) the C 1-6 -alkyl may be further substituted with one or more hydroxy.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is heterocyclyl containing a total of 5 to 10 ring atoms, wherein the heterocyclyl ring: (i) is a saturated, partially saturated, or completely unsaturated monocyclic or fused bicyclic ring, (ii) has (a) one nitrogen ring atom and one oxygen ring atom with the remaining ring atoms being carbon, or (b) one nitrogen ring atom and one sulfur ring atom with the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and wherein the C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, C 1-3 -alkylcarbonyl-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl may be further substituted with one or more halogen.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is spiro heterocyclyl containing a total of 6 to 11 ring atoms, wherein the spiro heterocyclyl: (i) contains two saturated rings, (ii) has: (a) one or two nitrogen ring atoms with the remaining ring atoms being carbon, (b) one or two nitrogen ring atoms and one or two oxygen ring atoms with the remaining ring atoms being carbon, or (c) one nitrogen ring atom and one sulfur ring atom with the remaining ring atoms being carbon, and (iii) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, and C 1-6 -alkylcarbonyl.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 20a and R 20b are independently selected from the group consisting of hydrogen and C 1-3 -alkyl;

R 20c and R 20d are independently selected from the group consisting of hydrogen, fluoro, hydroxy, C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-3 -alkoxy, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, phenyl, tolyl, phenyl-C 1-3 -alkyl, morpholinyl, C 1-3 -alkylsulfonyl-C 1-3 -alkyl, and C 1-3 -alkyl-carbonylamino-C 1-3 -alkyl; and wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 1-3 -alkoxy, C 3-6 -cycloalkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, phenyl, and phenyl-C 1-3 -alkyl may be further substituted with one or more halogen; and

R 20e and R 20f are independently selected from the group consisting of hydrogen and C 1-3 -alkyl.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 30a and R 30b are independently selected from the group consisting of hydrogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy-C 1-3 -alkyl;

R 30c and R 30d are independently selected from the group consisting of hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl;

R 30e and R 30f are independently selected from the group consisting of hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, and C 1-3 -alkylsulfonyl-C 1-3 -alkyl; and

R 30g and R 30h are independently selected from the group consisting of hydrogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy-C 1-3 -alkyl.

15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 40a and R 40b are independently selected from the group consisting of hydrogen, C 1-3 -alkyl, and halo-C 1-3 -alkyl;

R 40c and R 40d are independently selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

R 40e and R 40f are independently selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, C 1-3 -alkyl, halo-C 1-3 -alkyl, cyclopropyl, and C 1-3 -alkoxy;

R 40g and R 40h are independently selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy; and

R 40i and R 40j are independently selected from the group consisting of hydrogen, C 1-3 -alkyl, and halo-C 1-3 -alkyl.

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 50a and R 50b are independently selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

R 50c and R 50d are independently selected from the group consisting of hydrogen, C 1-3 -alkyl, and halo-C 1-3 -alkyl, or together are oxo;

R 50e is selected from the group consisting of hydrogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy-C 2-3 -alkyl, C 1-3 -alkyl-carbonyl, and C 3-6 -cycloalkyl-carbonyl;

R 50f and R 50g are independently selected from the group consisting of hydrogen, C 1-3 -alkyl, and halo-C 1-3 -alkyl, or together are oxo;

R 50h and R 50i are independently selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy; and

R 50j is selected from the group consisting of hydrogen and fluoro.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 60a and R 60b are independently selected from the group consisting of hydrogen and C 1-3 -alkyl;

R 60c and R 60d are independently selected from the group consisting of hydrogen and C 1-3 -alkyl; and

R 60e and R 60f are independently selected from the group consisting of hydrogen and C 1-3 -alkyl.

18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 70a and R 70b are independently selected from the group consisting of hydrogen and C 1-3 -alkyl;

R 70c and R 70d are independently selected from the group consisting of hydrogen and C 1-3 -alkyl;

R 70e and R 70f are independently selected from the group consisting of hydrogen and C 1-3 -alkyl; and

R 70g and R 70h are independently selected from the group consisting of hydrogen and C 1-3 -alkyl.

19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl;

R 80a is selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

R 80b is selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

R 80c is selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy; and

R 80d is selected from the group consisting of hydrogen, fluoro, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy.

20 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Assignments (1)

Continuity (2)

References Cited (87)