# US 9,518,040 B2 · GDF-8 inhibitors

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- Number: US 9,518,040 B2
- Document ID: US9518040B2
- Status: Granted
- Kind: B2
- Application number: 14/833,689
- Filed: 2015-08-24
- Published: 2016-02-25
- Granted: 2016-12-13
- Earliest claimed: 2012-10-05
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Somasekhar Bhamidipati; Marina Gelman; Pingyu Ding; Rajinder Singh; Jeffrey Clough; Todd Kinsella; Donald Payan
- Web page: https://patentgrep.com/patent/US9518040B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/18: of the parathyroid hormones
- A61P 5/24: of the sex hormones
- A61P 5/26: Androgens
- A61P 5/44: Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
- A61P 5/48: of the pancreatic hormones
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/26: Radicals substituted by halogen atoms or nitro radicals
- C07D 401/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 453/02: containing not further condensed quinuclidine ring systems
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07F 9/65038: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Described are GCF-8 inhibitors of the formula (I), and pharmaceutically acceptable salts thereof, wherein n, R1, R2, R5, R6, X and Z are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for inhibiting GDF-8 in a cell and methods for treating a patient suffering from a disease or disorder, wherein the patient would therapeutically benefit from an increase in mass or strength of muscle tissue.

## Claims

### Claim 1

A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
X is N;
R1 is halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C3-8cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R10, or —C1-6alkyl-R10, wherein
R10 is —OR, —SR, —NRaRa, —C(O)R, —C(O)OR, —C(O)NRaRa, —S(O)2NRaRa, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —O(CH2)mC(O)NRaRa, —N(R)C(O)OR, —N(R)C(O)NRaRa, —N(R)S(O)2NRaRa or —N(R)S(O)2R;
R2 is hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C3-8cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R10, or —C1-6alkyl-R10, wherein R10 is —OR, —SR, —NRaRa, —C(O)R, —C(O)OR, —C(O)NRaRa, —S(O)2NRaRa, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —O(CH2)mC(O)NRaRa, —N(R)C(O)OR, —N(R)C(O)NRaRa, —N(R)S(O)2NRaRa or —N(R)S(O)2R;
or when R1 and R2 are attached to adjacent carbon atoms they are optionally taken together with the atoms to which they are attached to form a 5- or 6-membered ring optionally substituted with one or two groups that are each independently halogen, oxo, oxime, imino, C1-6alkyl, C1-6haloalkyl, or R10;
each Ra is independently R or, two Ra together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl group, optionally including 1-4 additional heteroatoms selected from O, N and S and optionally substituted with 1-4 R groups;
each Rb is independently halogen, cyano, oxo, C1-6alkyl, C1-6haloalkyl, or —OR;
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
R5 and R6 are each independently hydrogen, halogen, C1-6alkyl optionally substituted with 1-3 Rb, C1-6haloalkyl, C3-8cycloalkyl optionally substituted with one or two Rb, heteroaryl optionally substituted with one or two Rb, aryl optionally substituted with one or two Rb, heterocyclyl(C1-6alkyl) optionally substituted with one or two Rb, —OR, —SR, —NRaRa, —OC(O)R, —C(O)NRaRa, —OC(O)NRaRa, —C(O)OR, —N(R)C(O)R, —N(R)S(O)2R, or R5 and R6 are optionally taken together with the atoms to which they are attached to form a 5- or 6-membered ring optionally including 1-3 additional heteroatoms selected from O, N and S and optionally substituted with 1-4 Rb;
Z is (a) a fused bicyclic ring of the formula,
wherein
ring A is a phenyl or 5- or 6-membered heteroaryl,
ring B is a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
or (b) pyridinyl or pyrimidinyl,
wherein
Z is optionally substituted by one or two groups that are each independently halogen, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), heteroaryl(C1-6alkyl), —RZ, or —C1-6alkyl-RZ, wherein the C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), and heteroaryl(C1-6alkyl) are each optionally substituted by one or two groups that are each independently halogen, C1-6alkyl, or RZ;
and RZ is cyano, —CF3, —OR, —SR, —NRaRa, —C(O)R, —C(O)OR, —C(O)NRaRa, —S(O)2NRaRa, —S(O)2R0, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NRaRa, —N(R)C(O)OR, —N(R)C(O)NRaRa, —N(R)S(O)2R, or —OP(O)(OR)2;
or Z is (c) phenyl substituted with 1, 2, 3, 4, or 5 groups that are each independently a halogen;
wherein each R is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl(heteroaryl)-, heterocyclyl(aryl)-, heteroaryl(heterocyclyl)-, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), or heteroaryl(C1-6alkyl), each optionally substituted by 1-5 groups that are each independently Rb, —OR0, —SR0, —N(R0)2, —C(O)R0, —C(O)OR0, —C(O)N(R0)2, —S(O)2N(R0)2, —OC(O)R0, —N(R0)C(O)R0, —OC(O)OR0, —O(CH2)mC(O)N(R0)2, —N(R0)C(O)OR0, —N(R0)C(O)N(R0)2, or —N(R0)S(O)2R0
and each R0 is independently hydrogen, C1-6haloalkyl, C1-6alkyl optionally substituted with 1-3 Rb, C3-8cycloalkyl optionally substituted with one or two Rb or, alternatively two R0 together with a nitrogen atom to which they are bound form a 3-8 membered heterocyclyl group, optionally including 1-4 additional heteroatoms selected from O, N and S and optionally substituted with 0-3 Rb and R groups.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1 of the formula,

### Claim 3 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein R1 is halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C3-8cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R10, or —C1-6alkyl-R10, wherein R10 is —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, or —N(R)S(O)2R, and
R2 is hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C3-8cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R10, or —C1-6alkyl-R10, wherein R10 is —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, or —N(R)S(O)2R.

### Claim 4 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein R1 is halogen, or C1-6alkyl, and R2 is hydrogen, halogen, or C1-6alkyl.

### Claim 5 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein R1 is fluoro and R2 is methyl.

### Claim 6 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein ring A is a phenyl or pyridyl ring.

### Claim 7 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein Z is of the formula,
wherein each is optionally substituted by one or two groups that are each independently halogen, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), heteroaryl(C1-6alkyl), —RZ, or —C1-6alkyl-RZ, wherein the C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), and heteroaryl(C1-6alkyl) are each optionally substituted by one to four groups that are each independently C1-6alkyl or —RZ.

### Claim 8 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein Z is of the formula,
wherein each is optionally substituted by one or two groups that are each independently halogen, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), heteroaryl(C1-6alkyl), —RZ, or —C1-6alkyl-RZ, wherein the C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), and heteroaryl(C1-6alkyl) are each optionally substituted by one to four groups that are each independently C1-6alkyl or —RZ.

### Claim 9 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein Z is
wherein RZ1 is hydrogen, C1-6alkyl, C1-6haloalkyl, or —C1-6alkyl-RZ; and
RZ2 is hydrogen, halogen, or C1-6alkyl.

### Claim 10 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein Z is
wherein
Q is —O—, —S—, or —N(RZ1)—; and
RZ1 is hydrogen, C1-6alkyl, C1-6haloalkyl, or —C1-6alkyl-RZ; and
RZ2 is hydrogen, halogen, or C1-6alkyl.

### Claim 11 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein Z is phenyl substituted with 1, 2, 3, 4, or 5 groups that are each independently halogen.

### Claim 12 (depends on 1)

The compound or pharmaceutically acceptable salt of any one of claim 1, wherein Z is pyridinyl or pyrimidinyl optionally substituted by one or two groups that are each independently halogen, C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), heteroaryl(C1-6alkyl), —RZ, or —C1-6alkyl-RZ, wherein the C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkyl(C1-6alkyl), heterocyclyl(C1-6alkyl), aryl(C1-6alkyl), and heteroaryl(C1-6alkyl) are each optionally substituted by one or two groups that are each independently halogen, C1-6alkyl, or —RZ; and RZ is cyano, —CF3, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NRaRa, —S(O)2NRaRa, —S(O)2R0, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NRaRa, —N(R)C(O)OR, —N(R)C(O)NRaRa, —N(R)S(O)2R, or —OP(O)(OR)2.

### Claim 13 (depends on 1)

The compound of claim 1 that is
5-(2-(6-Methylpyridin-2-yl)pyridin-3-yl)-1H-indazole;
2′-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-2,3′-bipyridine;
6-(6-Methyl-[2,3′-bipyridin]-2′-yl)quinoxaline;
5-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
6-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1H-benzo[d]imidazole;
6-(6-Methyl-[2,3′-bipyridin]-2′-yl)isoquinoline.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.