# US 12,180,192 B2 · Modulators of THR-β and methods of use thereof

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- Number: US 12,180,192 B2
- Document ID: US12180192B2
- Status: Granted
- Kind: B2
- Application number: 17/330,232
- Filed: 2021-05-25
- Published: 2021-11-18
- Granted: 2024-12-31
- Earliest claimed: 2019-05-08
- Assignees: Aligos Therapeutics, Inc.
- Applicants: Aligos Therapeutics, Inc.
- Inventors: Koen Vandyck; Pierre Jean-Marie Bernard Raboisson; David McGowan; Jerome Deval
- Web page: https://patentgrep.com/patent/US12180192B2

## CPC

- C07D 403/14: containing three or more hetero rings
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are compounds of Formula I: TL-La-CE-HD (I) or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) CE is a moiety of Formula IV; iii) HD is a moiety of Formula V or VI; where the substituents are as defined herein. Disclosed are also pharmaceutical compositions comprising the above compounds, and methods of treating disease by administering or contact a patient with one or more of the above compounds.

## Claims

### Claim 1

A compound of Formula I′:
TL-La-CE-HD (I′)
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:
wherein:
each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8, is independently nitrogen or —CRb—, wherein each Rb is independently hydrogen, halogen, or lower alkyl;
R1 is hydrogen, an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, —CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ring structure;
R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or —CN;
R3 is hydrogen or lower alkyl;
R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ring structure; and
R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino;
or R4 and R5 taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, or optionally substituted heteroaryl group;
or R4 and R5 taken together along with the carbon atoms to which they are attached form a seven to eleven membered, optionally substituted spirocyclic ring or a seven to eleven membered, optionally substituted spiro-heterocyclic ring;
Alk is hydrogen or an optionally substituted alkyl; and
R11 is an aryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring system; or a bicyclic heterocyclic ring system;
ii) CE is a moiety of Formula IV
wherein:
each of R6 and R7 is independently selected from halogen or lower alkyl;
R8 is selected from hydrogen or lower alkyl;
or R6 is selected from halogen and lower alkyl, and R7 and R8 taken together, along with the carbon atoms to which they are attached, form a 4-, 5- or 6-membered non-aromatic carbocyclic ring;
Q7 is —CRc—, wherein Rc is hydrogen;
(TL) denotes the point where the moiety of Formula IV connects to TL-La-; and
(HD) denotes the point where the moiety of Formula IV connects to —HD;
iii) HD is a moiety of Formula V:
wherein:
R9 is —(C(Rd)2)n−N(Rd)2; wherein
each Rd is independently hydrogen or optionally substituted lower alkyl; and
each n is 0; and
La is —(C(Ra)2)z—; oxygen; or sulfur; wherein each Ra is a hydrogen; and z is 1.

### Claim 2 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
TL is a moiety of Formula IIIb:

### Claim 3 (depends on 2)

The compound of claim 2, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-C6 alkyl; C2-C10 alkenyl; a non-aromatic C3-C12 carbocyclic ring; a C6-C10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group; and R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, CN, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C6-C10 aralkoxy, or two Rg together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.

### Claim 4 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
TL is a moiety of Formula IIIa:

### Claim 5 (depends on 4)

The compound of claim 4, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIaa:
wherein each Rg is independently C1-C6 alkyl or the two Rg together with the atom(s) to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group.

### Claim 6 (depends on 4)

The compound of claim 4, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIab:
wherein Rg is C1-C6 alkyl.

### Claim 7 (depends on 4)

The compound of claim 4, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIac:
wherein Rg is C1-C6 alkyl.

### Claim 8 (depends on 4)

The compound of claim 4, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIad:
wherein each Rg is independently hydrogen or C1-C6 alkyl.

### Claim 9 (depends on 4)

The compound of claim 4, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt wherein:
R4 is C1-C6 alkyl; C2-C10 alkenyl; a non-aromatic C3-C12 carbocyclic ring, a C6-C10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkyl group; a (heteroaryl)alkyl group; or —C(O)NRmRn;
Rm and Rn are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkoxy, a C6-C10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkyl group; or a (heteroaryl)alkyl group;
and R4 is optionally substituted with one to five Rg independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, C1-C6 alkoxy, and C6-C10 aralkoxy; and
R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino.

### Claim 10 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
TL is a moiety of Formula IIId:

### Claim 11 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
TL is a moiety of Formula IIa:

### Claim 12 (depends on 11)

The compound of claim 11, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, —CN, C1-C6 alkyl; a non-aromatic C3-C12 carbocyclic ring; a C6-C10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkyl group; or —C(O)—Rj; wherein Rj is —NRmRn or —ORm; Rm is hydrogen or C1-C6 alkyl; Rn is C1-C6 alkyl; or Rm and Rn, together with the nitrogen to which they are attached, form a ring structure; and
R1 is optionally substituted with one to three Rk independently selected from phenyl and haloalkyl.

### Claim 13 (depends on 11)

The compound of claim 11, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen; halogen; C1-C6 alkyl optionally substituted with one to five substituents independently selected from the group consisting of hydroxy, halogen, and C1-C6 alkoxy; C3-C9 cycloalkyl optionally substituted with one to ten substituents independently selected from the group consisting of hydroxy, halogen, and C1-C6 alkoxy; or —CN.

### Claim 14 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt wherein:
TL is a moiety of Formula IIb:

### Claim 15 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen; —CN; C1-C6 alkyl; a non-aromatic C3-C12 carbocyclic ring; a C6-C10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkyl group; or —C(O)—Rj; wherein Rj is —NRmRn or —ORm; Rm is hydrogen or C1-C6 alkyl; Rn is C1-C6 alkyl; or Rm and Rn, together with the nitrogen to which they are attached, form a ring structure; and
R1 is optionally substituted with one to five Rk independently selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C6-C10 aralkoxy.

### Claim 16 (depends on 1)

The compound of claim 1, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt wherein:
TL is a moiety of Formula IIIc:

### Claim 17 (depends on 16)

The compound of claim 16, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R11 is a benzene optionally substituted with C1-C5 alkyl, halogen, or C3-C9 cycloalkyl; or naphthalene.

### Claim 18 (depends on 16)

The compound of claim 16, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is hydroxy, NH2, C1-C6 alkylamino, C1-C6 alkanoylamino, or C1-C6 alkylsulfonylamino.

### Claim 19 (depends on 1)

The compound of claim 1 selected from the group consisting of:
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 21 (depends on 1)

A method of treating a disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, wherein the disorder or disease is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.

### Claim 22 (depends on 1)

A method of treating a thyroid hormone receptor related disorder in a patient, the method comprising the steps of:
identifying a patient in need of treatment for the thyroid hormone receptor related disorder, and administering to the patient, or contacting the patient with, the compound of claim 1, or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof;
wherein the thyroid hormone receptor related disorder is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.

### Claim 23 (depends on 1)

A method of selectively modulating the activity of a thyroid hormone receptor beta (THR-β) comprising contacting the compound of claim 1, or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, with the thyroid hormone receptor.