# US 10,370,367 B2 · IRAK inhibitors and method for making and using

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- Number: US 10,370,367 B2
- Document ID: US10370367B2
- Status: Granted
- Kind: B2
- Application number: 15/793,770
- Filed: 2017-10-25
- Published: 2018-04-26
- Granted: 2019-08-06
- Earliest claimed: 2016-10-26
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Hui Li; Thilo Heckrodt; Yan Chen; Ryan Kelley; Darren McMurtrie; Kin Tso; Vanessa Taylor; Rajinder Singh; Rose Yen; Jack Maung
- Web page: https://patentgrep.com/patent/US10370367B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed embodiments concern interleukin receptor associated kinases (IRAK) inhibitors, such as oxazole compounds, and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

## Claims

### Claim 1

A compound, having a formula
and/or a salt thereof, wherein:
at least one of R1 and R2 is heteroaryl, and the remaining R1 or R2 is H, alkyl, or haloalkyl;
R3 is H, aliphatic, heteroaliphatic, heterocyclyl, amide, aromatic, or araliphatic;
R4 is H or alkyl;
R5 is H or alkyl; and
each R6 independently is H, alkyl, haloalkyl, halogen, alkyl phosphate or alkylphosphonate.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is heteroaryl and R2 is H.

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least one of R1 and R2 is nitrogen-containing heteroaryl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein at least one of R1 and R2 is 6-membered heteroaryl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3 is Ra, Rb,Ra substituted with 1, 2, or 3 Rb, Ra substituted with Rb and Rc, Ra substituted with Rc, —(CRaRa)n—Ra, —(CH2)n—Ra, —(CRaRa)n—Rb, —(CH2)n—Rb, —[(CH2)m—O—]n—Ra, —[(CH2)m—O—]n—[Ra substituted with 1, 2 or 3 Rb], or —(CH2)m—O—(CH2)m—O—Ra wherein each m and n independently are 1, 2 or 3;
Ra is independently for each occurrence H, D, C1-6alkyl, C1-6haloalkyl C3-6cycloalkyl, C3-6heteroalicyclyl,
where Y and Z independently are —CH2, —CHRb, O or NRd;
Rb is independently for each occurrence —OH, —CF3, —ORc, —NRdRd, or halogen;
Rc is independently for each occurrence C1-6alkyl, C3-6heteroalicyclyl, C1-6alkyl substituted with 1, 2 or 3 Re, C3-6cycloalkyl substituted with 1, 2 or 3 Re, or C3-6heteroalicyclyl substituted with 1, 2 or 3 Re;
Rd is independently for each occurrence H, C1-6alkyl optionally substituted with 1, 2 or 3 Re, or two Rd groups together with the nitrogen bound thereto form a C3-6heteroalicyclyl moiety optionally substituted with C1-6alkyl and optionally interrupted with one or two —O— or —N(Rg) wherein Rg is R70; and
Re is independently for each occurrence C1-6alkyl, or —ORa.

### Claim 6 (depends on 5)

The compound of claim 5, wherein each R6 independently is H, halogen, alkyl, or Ra substituted with —OP(O)(Rf)2, and Rf is independently for each occurrence —ORa, —O−M+ where each M+ independently is an alkali metal ion or an ammonium ion.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound, and/or salt thereof, has a formula
R7 is H, alkyl, alkyl phosphate or alkylphosphonate; and
each of R8 and R9 is independently H, alkyl, haloalkyl, halogen.

### Claim 8 (depends on 7)

The compound of claim 7, wherein one of R8 and R9 is H and the other of R8 and R9 is H or F.

### Claim 9 (depends on 7)

The compound of claim 7, wherein R7 is H.

### Claim 10 (depends on 7)

The compound of claim 7, wherein R7 is CH2OP(═O)(OR′)2, and each OR′ independently is OH, —Oalkyl, or —O−M+ where M+ is a positive counter ion.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is
each of Z1, Z2, Z3 and Z4 independently is N or CR10, where at least one of Z1, Z2, Z3 and Z4 is N; and
each R10 independently is H, halogen, or aliphatic.

### Claim 12 (depends on 11)

The compound of claim 11, wherein the compound, and/or a salt thereof, has a formula
R7 is H, alkyl, alkyl phosphate or alkylphosphonate; and
each of R8 and R9 is independently H, alkyl, haloalkyl, halogen.

### Claim 13 (depends on 12)

The compound of claim 12, wherein the compound, and/or salt thereof, has a formula selected from
and
R11, R12, R13, and R14, if present, are independently H, halogen, or alkyl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein the compound has a formula

### Claim 15 (depends on 14)

The compound of claim 14, wherein R11, R12, R13, and R14 independently is H, F, CF3, or CF2.

### Claim 16 (depends on 15)

The compound of claim 15, wherein R2, R4 and R5 are H.

### Claim 17 (depends on 16)

The compound of claim 16, wherein R3 is H, alkyl, cycloalkyl, heteroaliphatic, or heterocycloaliphatic.

### Claim 18 (depends on 16)

The compound of claim 16, wherein R3 is C1-6alkyl, tetrahydropyran, unsubstituted heteroaliphatic, heteroaliphatic substituted with halogen, unsubstituted cyclobutyl, cyclobutyl substituted with OH, alkoxy, or heterocycloaliphatic, unsubstituted cyclohexyl, or cyclohexyl substituted with —OH, alkoxy or heterocycloaliphatic.

### Claim 19

A compound, selected from:
I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-2: N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-3: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-4: N-(3-(6-(difluoromethyl)pyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-5: N-(3-(6-(difluoromethyl)pyridin-2-yl)-1-((1R,4r)-4-((2R,6S)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-6: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-4-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-7: N-(3-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-8: sodium (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
I-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-10: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-12: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-13: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-14: N-(5-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-15: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-16: di-tert-butyl ((4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl) phosphate;
I-17: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-18: sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
I-19: 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-20: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-21: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-22: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-23: N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-24: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-25: N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-26: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,3r)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-27: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-28: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3,5,6-trifluoropyridin-2-yl)-1H-pyrazol-4-y1)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-29: N-(3-(4,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-30: N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-31: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-32: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-33: N-(1-((1r,3r)-3-morpholinocyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-34: N-(1-((1s,3s)-3-morpholinocyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-35: 2-(3-fluoro-1H-pyrazol-4-yl)-N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrazin-2-y1)-1H-pyrazol-4-yl)oxazole-4-carboxamide formic acid salt;
I-36: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-(4-methylpiperazin-l-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-37: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-y1)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-38: N-(1-((1s,3s)-3-hydroxycyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide; or
I-39: 2-(3-fluoro-1H-pyrazol-4-yl)-N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrazin-2-y1)-1H-pyrazol-4-yl)oxazole-4-carboxamide.

### Claim 20 (depends on 1)

A composition, comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 20)

The composition of claim 20, further comprising an additional therapeutic agent.