# US 10,479,783 B2 · Compositions and methods for inhibition of the JAK pathway

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- Number: US 10,479,783 B2
- Document ID: US10479783B2
- Status: Granted
- Kind: B2
- Application number: 15/892,224
- Filed: 2018-02-08
- Published: 2018-06-14
- Granted: 2019-11-19
- Earliest claimed: 2010-07-28
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Hui Li; Thilo J. Heckrodt; Yan Chen; Darren John McMurtrie; Vanessa Taylor; Rajinder Singh; Pingyu Ding; Rose Yen
- Web page: https://patentgrep.com/patent/US10479783B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/14: Decongestants or antiallergics
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 59/002: {Heterocyclic compounds}
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- 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

Disclosed are compounds of formula I, compositions containing them, and methods of use for the compounds and compositions in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK 2 and JAK3, are therapeutically useful. Also disclosed are methods of making the compounds.

## Claims

### Claim 1

A compound of formula IA:
or salt thereof, wherein:
R1 is H, optionally substituted C1-6alkyl, C(O)—C1-6alkyl, CO2—C1-6alkyl or R50;
each R50 is —C(R9)2-A-R10, where A is O or S; each R9 is independently for each occurrence H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl or optionally substituted C7-16arylalkyl; or alternatively, two R9, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R10 is Ra, —P(O)(OR11)2, —P(O)(OR11)N(R12)2 or —P(O)(N(R12)2)2; each R11 is independently for each occurrence Ra or a monovalent cationic group; or two R11, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group; each R12 is independently for each occurrence Rc or —C1-3alkyl-N(Rc)2; or two R12, each on separate nitrogens of —P(O)(N(R12)2)2, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonic acid bisamide group; or one R12 along with R11, of the group —P(O)(OR11)N(R12)2, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonamidate group;
each of R2a-2e is independently for each occurrence Re, Rb, Re substituted with one or more of the same or different Ra and/or Rb, —ORe substituted with one or more of the same or different Ra and/or Rb, —SRe substituted with one or more of the same or different Ra and/or Rb, —C(O)Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)Re where Re is substituted with one or more of the same or different Ra and/or Rb, —S(O)2Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)—S(O)2Re where Re is substituted with one or more of the same or different Ra and/or Rb, —B(ORa)2, —B(N(Rc)2)2, —(C(Ra)2)m—Rb, —O—(C(Ra)2)m—Rb, —S—(C(Ra)2)m—Rb, —O—(C(Rb)2)m—Ra, —N(Ra)—(C(Ra)2)m—Rb, —O—(CH2)m—CH((CH2)mRb)Rb, —C(O)N(Ra)—(C(Ra)2)m—Rb, —O—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N((C(Ra)2)mRb)2, —S—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—(C(Ra)2)m—C(Ra)(Rb)2 or —N(Ra)—(C(Ra)2)m—C(O)—N(Ra)—(C(Ra)2)m—Rb; or
two of R2a-2d groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra and/or Rb;
each Ra is independently for each occurrence H, deuterium, C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each Rb is independently for each occurrence ═O, —ORa, —O—(C(Ra)2)m—ORa, haloC1-3alkyloxy, ═S, —SRa, ═NRa, ═NORa, —N(Rc)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O)2Ra, —SO3Ra, —S(O)N(Rc)2, —S(O)2N(Rc)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Rc)2, —C(O)Ra, —CO2Ra, —C(O)N(Rc)2, —C(NRa)—N(Rc)2, —C(NOH)—Ra, —C(NOH)—N(Rc)2, —OC(O)Ra, —OC(O)ORa, —OC(O)N(Rc)2, —OC(NH)—N(Rc)2, —OC(NRa)—N(Rc)2, —N(Ra)—S(O)2H, —[N(Ra)C(O)]nRa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Rc)2 or —[N(Ra)C(NRa)]n—N(Rc)2;
each Rc is independently for each occurrence Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different Ra and/or Rd groups;
each Rd is ═O, —ORa, haloC1-3alkyloxy, C1-6alkyl, ═S, —SRa, ═NRa, ═NORa, —N(Ra)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O2)Ra, —SO3Ra, —S(O)N(Ra)2, —S(O)2N(Ra)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Ra)2, —C(O)Ra, —CO2Ra, —C(O)N(Ra)2, —C(NRa)N(Ra)2, —C(NOH)Ra, —C(NOH)N(Ra)2, —OCO2Ra, —OC(O)N(Ra)2, —OC(NRa)N(Ra)2, —[N(Ra)C(O)]nRa, —(C(Ra)2)n—ORa, —N(Ra)—S(O)2Ra, —C(O)—C1-6haloalkyl, —S(O)2C1-6haloalkyl, —OC(O)Ra, —O(C(Ra)2)m—ORa, —S(C(Ra)2)m—ORa, —N(Ra)C1-6haloalkyl, —P(O)(ORa)2, —N(Ra)—(C(Ra)2)m—ORa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Ra)2, —[N(Ra)C(NRa)]fN(Ra)2 or —N(Ra)C(O)C1-6haloalkyl;
two Rd, taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra;
each Re is independently for each occurrence C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each m is 1, 2 or 3;
each n is 0, 1, 2 or 3;
R4 is H or optionally substituted C1-6alkyl; and
R5 is H, halo, —CN, optionally substituted C1-6alkyl, nitro, —N(Ra)2, —C(O)N(Ra)2, —CO2Ra or —C(O)Ra;
wherein the compound is not 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one.

### Claim 2

A compound of formula IA:
or salt thereof, wherein:
R1 is H, optionally substituted C1-6alkyl, C(O)—C1-6alkyl, CO2—C1-6alkyl or R50;
each R50 is —C(R9)2-A-R10, where A is O or S; each R9 is independently for each occurrence H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl or optionally substituted C7-16arylalkyl; or alternatively, two R9, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R10 is Ra, —P(O)(OR11)2, —P(O)(OR11)N(R12)2 or —P(O)(N(R12)2)2; each R11 is independently for each occurrence Ra or a monovalent cationic group; or two R11, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group; each R12 is independently for each occurrence Rc or —C1-3alkyl-N(Rc)2; or two R12, each on separate nitrogens of —P(O)(N(R12)2)2, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonic acid bisamide group; or one R12 along with R11, of the group —P(O)(OR11)N(R12)2, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonamidate group;
each of R2a-2d is independently for each occurrence Re, Rb, Re substituted with one or more of the same or different Ra and/or Rb, —ORe substituted with one or more of the same or different Ra and/or Rb, —SRe substituted with one or more of the same or different Ra and/or Rb, —C(O)Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)Re where Re is substituted with one or more of the same or different Ra and/or Rb, —S(O)2Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)—S(O)2Re where Re is substituted with one or more of the same or different Ra and/or Rb, —B(ORa)2, —B(N(Rc)2)2, —(C(Ra)2)m—Rb, —O—(C(Ra)2)m—Rb, —S—(C(Ra)2)m—Rb, —O—(C(Rb)2)m—Ra, —N(Ra)—(C(Ra)2)m—Rb, —O—(CH2)m—CH((CH2)mRb)Rb, —C(O)N(Ra)—(C(Ra)2)m—Rb, —O—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N((C(Ra)2)mRb)2, —S—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—(C(Ra)2)m—C(Ra)(Rb)2 or —N(Ra)—(C(Ra)2)m—C(O)—N(Ra)—(C(Ra)2)m—Rb; or
two of R2a-2d groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra and/or Rb;
R2e is halogen or methyl;
each Ra is independently for each occurrence H, deuterium, C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each Rb is independently for each occurrence ═O, —ORa, —O—(C(Ra)2)m—ORa, haloC1-3alkyloxy, ═S, —SRa, ═NRa, ═NORa, —N(Rc)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O)2Ra, —SO3Ra, —S(O)N(Rc)2, —S(O)2N(Rc)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Rc)2, —C(O)Ra, —CO2Ra, —C(O)N(Rc)2, —C(NRa)—N(Rc)2, —C(NOH)—Ra, —C(NOH)—N(Rc)2, —OC(O)Ra, —OC(O)ORa, —OC(O)N(Rc)2, —OC(NH)—N(Rc)2, —OC(NRa)—N(Rc)2, —N(Ra)—S(O)2H, —[N(Ra)C(O)]nRa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Rc)2 or —[N(Ra)C(NRa)]n—N(Rc)2;
each Rc is independently for each occurrence Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different Ra and/or Rd groups;
each Rd is ═O, —ORa, haloC1-3alkyloxy, C1-6alkyl, ═S, —SRa, ═NRa, ═NORa, —N(Ra)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O2)Ra, —SO3Ra, —S(O)N(Ra)2, —S(O)2N(Ra)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Ra)2, —C(O)Ra, —CO2Ra, —C(O)N(Ra)2, —C(NRa)N(Ra)2, —C(NOH)Ra, —C(NOH)N(Ra)2, —OCO2Ra, —OC(O)N(Ra)2, —OC(NRa)N(Ra)2, —[N(Ra)C(O)]nRa, —(C(Ra)2)n—ORa, —N(Ra)—S(O)2Ra, —C(O)—C1-6haloalkyl, —S(O)2C1-6haloalkyl, —OC(O)Ra, —O(C(Ra)2)m—ORa, —S(C(Ra)2)m—ORa, —N(Ra)C1-6haloalkyl, —P(O)(ORa)2, —N(Ra)—(C(Ra)2)m—ORa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]fN(Ra)2, —[N(Ra)C(NRa)]fN(Ra)2 or —N(Ra)C(O)C1-6haloalkyl;
two Rd, taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra;
each Re is independently for each occurrence C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each m is 1, 2 or 3;
each n is 0, 1, 2 or 3;
R4 is H or optionally substituted C1-6alkyl; and
R5 is H, halo, —CN, optionally substituted C1-6alkyl, nitro, —N(Ra)2, —C(O)N(Ra)2, —CO2Ra or —C(O)Ra.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1.

### Claim 4 (depends on 2)

A pharmaceutical composition comprising the compound according to claim 2.

### Claim 5 (depends on 1)

A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of the compound of claim 1, or a pharmaceutical composition thereof, effective to inhibit an activity of the JAK kinase.

### Claim 6 (depends on 2)

A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of the compound of claim 2, or a pharmaceutical composition thereof, effective to inhibit an activity of the JAK kinase.