WO2015091584A1 - Composés de thiazolopyridine, compositions et leur utilisation comme inhibiteurs de la kinase tyk2 - Google Patents

Composés de thiazolopyridine, compositions et leur utilisation comme inhibiteurs de la kinase tyk2 Download PDF

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WO2015091584A1
WO2015091584A1 PCT/EP2014/078108 EP2014078108W WO2015091584A1 WO 2015091584 A1 WO2015091584 A1 WO 2015091584A1 EP 2014078108 W EP2014078108 W EP 2014078108W WO 2015091584 A1 WO2015091584 A1 WO 2015091584A1
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alkylene
optionally substituted
alkyl
halogen
oxo
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PCT/EP2014/078108
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English (en)
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Emanuela Gancia
Yingjie Lai
Jun Liang
Calum Macleod
Steven R. Magnuson
Mohammed Sajad
Vickie H. TSUI
Karen Williams
Birong Zhang
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F. Hoffmann-La Roche Ag
Genentech, Inc.
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Publication of WO2015091584A1 publication Critical patent/WO2015091584A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a patient, and in particular to inhibitors of TYK2 kinase useful for treating diseases mediated by TYK2 kinase.
  • JAK Janus kinases
  • JAK2 cytoplasmic protein kinases that associate with type I and type II cytokine receptors and regulate cytokine signal transduction. Cytokine engagement with cognate receptors triggers activation of receptor associated JAKs and this leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately transcriptional activation of specific gene sets.
  • JAKl, JAK2 and TYK2 exhibit broad patterns of gene expression, while JAK3 expression is limited to leukocytes.
  • Cytokine receptors are typically functional as heterodimers, and as a result, more than one type of JAK kinase is usually associated with cytokine receptor complexes.
  • JAKs associated with different cytokine receptor complexes have been determined in many cases through genetic studies and corroborated by other experimental evidence.
  • JAKl is functionally and physically associated with the type I interferon (e.g., IFN alpha), type II interferon (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes.
  • JAKl knockout mice die perinatally due to defects in LIF receptor signaling. Characterization of tissues derived from JAKl knockout mice demonstrated critical roles for this kinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways.
  • a humanized monoclonal antibody targeting the IL-6 pathway was recently approved by the European Commission for the treatment of moderate-to- severe rheumatoid arthritis.
  • JAK2 JAK2 knockout mice die of anemia.
  • Kinase activating mutations in JAK2 e.g., JAK2 V617F
  • MPDs myeloproliferative disorders
  • JAK3 associates exclusively with the gamma common cytokine receptor chain, which is present in the IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21 cytokine receptor complexes.
  • JAK3 is critical for lymphoid cell development and proliferation and mutations in JAK3 result in severe combined immunodeficiency (SCID). Based on its role in regulating lymphocytes, JAK3 and JAK3- mediated pathways have been targeted for immunosuppressive indications (e.g., transplantation rejection and rheumatoid arthritis).
  • TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6, IL- 10, IL-12 and IL-23 cytokine receptor complexes. Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL- 10, IL- 12 and IL-23 signaling. A fully human monoclonal antibody targeting the shared p40 subunit of the IL- 12 and 11-23 cytokines
  • thiazolopyridine compounds that are inhibitors of TYK2 kinase, compositions containing these compounds and methods for treating diseases mediated by TYK2 kinase.
  • X is N or CR°
  • R is hydrogen, hydroxyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci 4 aryl, or 5- 10-membered heteroaryl, wherein R° maybe optionally substituted by R 10 ;
  • R 1 is hydrogen, halogen, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, -OR 8 , -SR 8 , - NR 8 R 9 ,
  • heterocyclyl 5-6-membered heteroaryl, C 6 -Ci 4 aryl, -(Ci-C 3 alkylene)CN, -(Ci- C 3 alkylene)OR 8 , -(Ci-C 3 alkylene)SR 8 , -(C1-C3 alkylene)NR 8 R 9 , -(C C 3 alkylene)CF 3 , -(C C 3 alkylene)N0 2 , -(C
  • each R and R is independently hydrogen, hydroxyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-10-membered heterocyclyl, C 6 -Ci 4 aryl, or 5- 10-membered
  • R and R are each independently optionally substituted by R ;
  • R" and R J are taken together with the atom to which they are attached to form a ring selected from C 3 -Cio cycloalkyl and 3- 10-membered heterocyclyl, wherein the ring may be optionally substituted by R 10 ;
  • R 4 is hydrogen, -NR 6 -, -NR 6 R 7 , -NR 6 C(0)-, -NR 6 C(0)0- -NR 6 C(0)NR 7 -, -
  • R 5 is absent, hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -Cio cycloalkyl, C 6 - C10 aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ; or
  • R 6 and R 7 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 11 , -NR n R 12 or C C 6 alkyl optionally substituted by halogen;
  • R and R are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • each R 10 is independently hydrogen, oxo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • C 3 -C6 cycloalkyl 3- 10-membered heterocyclyl, 5- 10-membered heteroaryl, C 6 -Ci 4 aryl, -(C1-C3 alkylene)CN, -(C1-C3 alkylene)OR u , -(C1-C3 alkylene)SR u , -(d- C 3 alkylene)NR u R 12 ,
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C 1 -C 3 alkylene)NR 13 R 14 , -(d- C 3 alkylene)C(0)R 13 , -(C1-C3 alkylene)S(0)R 13 , -(C1-C3 alkylene)S(0) 2 R 13 or Ci-Ce
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl optionally substituted by halogen, -CN or oxo; or
  • R and R 1 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen, oxo or OH;
  • R 13 and R 14 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by oxo or halogen.
  • R 1 is hydrogen, halogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, or C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted by R 10 ;
  • R is hydrogen or Ci-C 6 alkyl optionally substituted by R , or is taken together with R and the nitrogen to which they are attached to form a 3-10-membered heterocyclyl optionally substituted by R 10 ;
  • R is hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci 4 aryl,
  • R may be optionally substituted by R ; or is taken together with R and the nitrogen to which they are attached to form a 3- 10- membered heterocyclyl optionally substituted by R 10 ;
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -;
  • R 5 is hydrogen, Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5- 10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or
  • C 3 -C 6 cycloalkyl wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, Ci-C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ;
  • each R 10 is independently hydrogen, oxo, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(Ci-C 3 alkylene)OR 13 , -(C C 3 alkylene)NR 13 R 14 , -(C C 3 alkylene)C(0)R 13 , -(Ci-C 3 alkylene)S(0)R 13 , -(Ci-C 3 alkylene)S(0) 2 R 13 or Ci-Ce alkyl optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(Ci-C 3 alkylene)OR 13 , -(C C 3 alkylene)NR 13 R 14 , -(C C 3 alkylene)C(0)R 13 , -(C
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or Ci-Ce alkyl optionally substituted by halogen, -CN or oxo; or
  • R 11 and R 1 1 2" are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or C1-C 6 alkyl optionally substituted by halogen, oxo or OH;
  • R 13 and R 14 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by oxo or halogen,
  • R° is hydrogen, hydroxyl, or Ci-C 6 alkyl optionally substituted by R 10 ;
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, or C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted by R 10 ; 2 10 3
  • R is hydrogen or CrC 6 alkyl optionally substituted by R , or is taken together with R and the carbon to which they are attached to form a ring selected from C 3 -C 10 cycloalkyl and 3-10-membered heterocyclyl, wherein the ring is optionally substituted by R 10.
  • R is hydrogen, CrC 6 alkyl, C 3 -C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci 4 aryl,
  • R may be optionally substituted by R ; or is taken together with R and the carbon to which they are attached to form a ring selected from C 3 -C 10 cycloalkyl and 3- 10-membered heterocyclyl, wherein the ring is optionally substituted by R 10 ;
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -;
  • R 5 is hydrogen, Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5- 10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, Ci-C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ;
  • each R 10 is independently hydrogen, oxo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • C 3 -C 6 cycloalkyl 3- 10-membered heterocyclyl, 5- 10-membered heteroaryl, C 6 -Ci 4 aryl, -(C1-C3 alkylene)CN, -(C1-C3 alkylene)OR u , -(C1-C3 alkylene)SR u , -(d- C 3 alkylene)NR u R 12 ,
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C C 3 alkylene)NR 13 R 14 , -(C C 3 alkylene)C(0)R 13 , -(C1-C3 alkylene)S(0)R 13 , -(C1-C3 alkylene)S(0) 2 R 13 or Ci-C 6 alkyl optionally substituted by oxo, -CN or halogen; 11 12
  • R and R 1 " are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, C 6 -Ci4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl optionally substituted by halogen, -CN or oxo; or
  • R 11 and R 1 1 2" are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or CrC 6 alkyl optionally substituted by halogen, oxo or OH;
  • R 13 and R 14 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or CrC 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or CrC 6 alkyl optionally substituted by oxo or halogen.
  • composition comprising a compound of Formula I, II, III or any variations described herein (e.g., a compound of Examples 1-236 of Table 1), or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof; and optionally further comprising a pharmaceutically acceptable carrier, adjuvant, and/or vehicle.
  • a method of inhibiting TYK2 kinase activity in a cell comprising introducing into said cell an amount effective to inhibit said kinase of a compound of Formula I, II, III, or any variations described herein (e.g., a compound of Examples 1-236 of Table 1), or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease responsive to the inhibition of TYK2 kinase activity in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, II, III, or any variations described herein (e.g., a compound of Examples 1-236 of Table 1), or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the disease is an immunological or inflammatory disease, such as asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, lupus and multiple sclerosis.
  • an immunological or inflammatory disease such as asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, lupus and multiple sclerosis.
  • a compound of Formula I, II, III, or any variations described herein e.g., a compound of Examples 1-236 of Table 1
  • a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof in therapy.
  • a compound of Formula I, II, III, or any variations described herein e.g., a compound of Examples 1-236 of Table 1
  • a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof in the treatment of an immunological or inflammatory disease.
  • a compound of Formula I, II, III, or any variations described herein e.g., a compound of Examples 1-236 of Table 1
  • a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof in the manufacturing of a medicament for the treatment of a disease responsive to the inhibition of TYK2 kinase activity in a patient, such as an immunological or inflammatory disease.
  • kits for treating a disease or disorder responsive to the inhibition of TYK2 kinase comprising a compound of Formula I, II, III, or any variations described herein (e.g., a compound of Examples 1-236 of Table 1), or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • compositions comprising the thiazolopyridine compounds, and pharmaceutical formulations thereof, are useful in inhibiting TYK2 kinase activity in a cell, and in the treatment of diseases, conditions and/or disorders responsive to the inhibition of TYK2 kinase activity in a patient.
  • Alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkyl radical has one to eighteen carbon atoms ("Ci-Cig alkyl").
  • the alkyl radical is C 1 -C 12 , C 1 -C 10, Q-Cg, Ci-C 6 , C 1 -C5, C 1 -C4, or C 1 -C 3 alkyl.
  • alkyl groups include, but are not limited to, groups such as methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1- propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n- butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s- butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, - CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (
  • Alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • the alkenyl radical has two to eighteen carbon atoms ("C 2 -Cig alkenyl").
  • the alkenyl radical is C 2 -Ci 2 , C 2 -Cio , C 2 -Cg, C 2 -C 6 or C 2 -C 3 alkenyl.
  • Alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl radical has two to eighteen carbon atoms ("C 2 -Ci 8 alkynyl").
  • the alkynyl radical is C 2 -Ci 2 , C 2 -Cio , C 2 -Cg, C 2 -C 6 or C 2 -C 3 alkynyl.
  • alkynyl groups include, but are not limited to, groups such as ethynyl (-C ⁇ CH), prop-l-ynyl (- C ⁇ CCH 3 ), prop-2-ynyl (propargyl, -CH 2 C ⁇ CH), but-l-ynyl, but-2-ynyl and but-3-ynyl.
  • Alkylene refers to a saturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • the divalent alkylene group has one to eighteen carbon atoms ("C 1 -C 18 alkylene").
  • the divalent alkylene group is C Ci 2 , C 1 -C 10, Ci-C 8 , Ci-C 6 , C 1 -C5, C 1 -C4, or C C 3 alkylene.
  • alkylene groups include, but are not limited to, groups such as methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 2,2-propylene (-C(CH 3 ) 2 -), 1,2-propylene (-CH(CH 3 )CH 2 -), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,1 -dimethyl- 1,2- ethylene (-C(CH 3 ) 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • groups such as methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 2,2-propylene (-C(CH 3 ) 2 -), 1,2-propylene (-CH
  • Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted
  • the cycloalkyl group has 3 to 12 carbon atoms ("C 3 -Ci 2 cycloalkyl").
  • cycloalkyl is C 3 -C8, C 3 -Cio or C 5 -C 10 cycloalkyl.
  • the cycloalkyl group, as a monocycle is C 3 -C 4 , C 3 -C 6 or C 5 -C6 cycloalkyl.
  • the cycloalkyl group, as a bicycle is C 7 -Ci 2 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and
  • cyclododecyl Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • Exemplary bridged bicyclic cycloalkanes include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • the cycloalkyl group is a spiro cycloalkyl group, e.g., a C 5 -Ci 2 spiro cycloalkyl.
  • spiro cycloalkanes include, but are not limited to, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane and spiro[4.5]decane.
  • Aryl or “Ar” as used herein refers to a cyclic aromatic hydrocarbon group optionally substituted independently with one or more substituents described herein.
  • the aryl group has 6 to 20 annular carbon atoms ("C 6 -C 2 o aryl”).
  • the aryl group has 6 to 14 annular carbon atoms ("C 6 -Ci 4 aryl”).
  • the aryl group has 6 to 10 annular carbon atoms ("C 6 -C 10 aryl”).
  • the aryl group is a C 6 aryl group.
  • Aryl includes bicyclic groups comprising an aromatic ring with a fused non-aromatic or partially saturated ring.
  • aryl groups include, but are not limited to, phenyl, naphthalenyl, anthracenyl, indenyl, indanyl, 1,2-dihydronapthalenyl and 1,2,3,4-tetrahydronapthyl.
  • aryl includes phenyl.
  • Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five, for example 1-2, 1-3 or 1-4 substituents chosen from groups specified herein.
  • optional substituents on aryl are selected from halogen (F, CI, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example Ci-C 6 alkyl), alkoxy (for example Ci-C 6 alkoxy), benzyloxy, carboxy, protected carboxy,
  • alkylsulfonylaminoalkyl arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified.
  • One or more methine (CH) and/or methylene (CH 2 ) groups in these substituents may in turn be substituted with a similar group as those denoted above.
  • substituted phenyl examples include a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4- bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4- dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphen
  • di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl.
  • substituted phenyl represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3- chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4- nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl
  • Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3- ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (l-chloromethyl)benzyloxy -6- methyl sulfonyl aminophenyl groups.
  • Fused aryl rings may also be substituted with any, for example 1, 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.
  • Heterocycle refers to a saturated or partially unsaturated cyclic group (i.e., having one or more double and/or triple bonds within the ring), having at least one annular heteroatom independently selected from nitrogen, oxygen, phosphorus and sulfur, the remaining annular atoms being carbon.
  • the heterocyclyl group may be optionally substituted with one or more substituents described below.
  • heterocyclyl includes monocycles or bicycles having 1 to 9 annular carbon atoms (C 1 -C9) with the remaining ring atoms being heteroatoms selected from N, O, S and P.
  • heterocyclyl includes monocycles or bicycles having 1 to 5 annular carbon atoms (C 1 -C 5 ), 3 to 5 annular carbon atoms (C3-C 5 ), or 4 to 5 annular carbon atoms (C4-C 5 ), with the remaining ring atoms being heteroatoms selected from N, O, S and P.
  • heterocyclyl includes 3-10 membered rings, 3-7-membered rings or 3-6 membered rings, containing one or more heteroatoms independently selected from N, O, S and P.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings, containing one or more heteroatoms independently selected from N, O, S and P.
  • heterocyclyl includes bi- or polycyclic, spiro or bridged 4-, 5-, 6-, 7-, 8- and 9- membered ring systems, containing one or more heteroatoms independently selected from N, O, S and P.
  • bicycle systems include, but are not limited to, [3,5], [4,5], [5,5], [3,6], [4,6], [5,6], or [6,6] systems.
  • bridged ring systems include, but are not limited to [2.2.1], [2.2.2], [3.2.2] and [4.1.0] arrangements, and having 1 to 3 heteroatoms selected from N, O, S and P.
  • heterocyclyl includes spiro cyclic groups having 1 to 4 heteroatoms selected from N, O, S and P.
  • the heterocyclyl group may be a carbon-linked group or heteroatom-linked group.
  • Heterocyclyl includes a heterocyclyl group fused to a cycloalkyl group.
  • heterocyclyl groups include, but are not limited to, groups such as oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl,
  • the heterocyclyl groups herein are optionally substituted independently with one or more substituents described herein.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.
  • Heteroaryl or “HetAr” as used herein refers to an aromatic cyclic radical in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents described herein. In one example, the heteroaryl group contains 1 to 9 annular carbon atoms (C 1 -C9). In other examples, the heteroaryl group contains 1 to 5 annular carbon atoms (C 1 -C 5 ), 3 to 5 annular carbon atoms (C3-C 5 ), or 4 to 5 annular carbon atoms (C4-C 5 ).
  • exemplary heteroaryl groups include 5 to 6-membered rings, or monocyclic aromatic 5-, 6- and 7-membered rings containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • exemplary heteroaryl groups include fused ring systems of up to 9 carbon atoms wherein at least one aromatic ring contains one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • “Heteroaryl” includes heteroaryl groups fused with an aryl, cycloalkyl or heterocyclyl group.
  • heteroaryl groups include, but are not limited to, groups such as pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, be
  • the heterocyclyl or heteroaryl group is C-attached.
  • carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a piperidine (e.g., piperidin-2-yl, piperidin-3-yl or piperidin-4-yl), position 2, 3,
  • a piperazine e.g., piperizin-2-yl or piperizin-3-yl
  • position 2, 3, 4, or 5 of a piperazine e.g., piperizin-2-yl or piperizin-3-yl
  • Non-limiting examples of carbon bonded heteroaryl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine (2-pyridyl, 3- pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl), position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, thiophene or pyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2, 3, 4, 5, 6, 7, or 8 of a quino
  • the heterocyclyl or heteroaryl group contains at least one annular nitrogen atom with is attached to the parent structure (i.e. N-attached).
  • the nitrogen bonded heterocyclyl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazolidine, 2-imidazoline, 3- imidazoline, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine or indoline, position 2 of an isoindoline, position 4 of a morpholine, and the like.
  • Non-limiting examples of N-attached heteroaryl group include bonding arrangements at position 1 of a pyrrole, imidazole, pyrazole, indole or IH-indazole, position 2 of a isoindole, position 9 of a carbazole or ⁇ -carboline, and the like.
  • Halo or halogen refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I). Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • An alkyl group in which each hydrogen is replaced with a halo group is referred to as a
  • perhaloalkyl A preferred perhaloalkyl group is trifluoroalkyl (-CF 3 ).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (-OCF 3 ).
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound provided herein.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine.
  • DMSO dimethyl sulfoxide
  • hydrate refers to the complex where the solvent molecule is water.
  • prodrug refers to a precursor or derivative form of a pharmaceutically active substance that is less efficacious to the patient or cytotoxic to tumor cells compared to the parent drug and is capable of being enzymatically or hydrolytically activated or converted into the more active parent form. See, e.g., Wilman, "Prodrugs in Cancer Chemotherapy” Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Harbor
  • prodrugs include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, ⁇ -lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs.
  • leaving group refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction.
  • Examples of leaving groups include, but are not limited to, halogen atoms, hydroxyl, alkoxy (for example -OR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally
  • sulfonyloxy for example -OS(0)i- 2 R, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally
  • sulfonyloxy groups include, but are not limited to,
  • alkylsulfonyloxy groups for example methyl sulfonyloxy (mesylate group) and
  • triflate group triflate group
  • aryl sulfonyloxy groups for example p- toluenesulfonyloxy (tosylate group) and /?-nitrosulfonyloxy (nosylate group)
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, phthalimido, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, benzyl, benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, and tetrahydropyranyl.
  • a "carboxy- protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include -CH 2 CH 2 S0 2 Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Third Ed., John Wiley & Sons, New York, 1999; and P. Kocienski, Protecting Groups, Third Ed., Verlag, 2003.
  • patient includes human patients and animal patients.
  • animal includes companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • patient is a human.
  • Treating” and “treatment” includes therapeutic treatment, wherein the object is to slow down (lessen) an undesired physiological change or disorder.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized ⁇ i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), whether detectable or undetectable, sustaining remission and suppressing reoccurrence.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.
  • a method may comprise prophylactic and/or preventative treatment.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune disease (e.g., lupus) and/or an inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g., asthma).
  • a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound provided herein.
  • “Pharmaceutically acceptable salts” include both acid and base addition salts. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /7-toluenesulfonate, and pamoate (i
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion, for example a dihydrochloride or diformate salt.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanes
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.
  • NSAID is an acronym for “non-steroidal anti-inflammatory drug” and is a
  • NSAIDs are unusual in that they are non-narcotic. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present.
  • NSAIDs are generally indicated for the symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic. Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase- 1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes.
  • COX-1 cyclooxygenase- 1
  • COX-2 cyclooxygenase-2
  • Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A 2 ).
  • Prostaglandins act (among other things) as messenger molecules in the process of inflammation.
  • COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
  • Combination therapy means a therapy that includes two or more different compounds.
  • a combination therapy comprising a compound detailed herein and another compound is provided.
  • the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • compounds of Formulae I, II, III, and variations described herein, wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a 13 C or 14 C carbon atom, or one or more nitrogen atoms are replaced by a 15 N nitrogen atom, or one or more sulfur atoms are replaced by a 33 S, 34 S or 36 S sulfur atom, or one or more oxygen atoms are replaced by a 17 O or 18 O oxygen atom are within the scope of this invention.
  • Other isotopes are described herein.
  • X is N or CR°
  • R° is hydrogen, hydroxyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci 4 aryl, or 5- 10-membered heteroaryl, wherein R° maybe optionally substituted by R 10 ;
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, -OR 8 , -SR 8 , - NR 8 R 9 ,
  • heterocyclyl 5-6-membered heteroaryl, C 6 -Ci 4 aryl, -(Ci-C 3 alkylene)CN, -(Ci- C 3 alkylene)OR 8 , -(C C 3 alkylene)SR 8 ,
  • each R and R is independently hydrogen, hydroxyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-10-membered heterocyclyl, C 6 -Ci 4 aryl, or 5- 10-membered
  • R and R are each independently optionally substituted by R ;
  • R" and R J are taken together with the atom to which they are attached to form a ring selected from C 3 -Cio cycloalkyl and 3- 10-membered heterocyclyl, wherein the ring may be optionally substituted by R 10 ;
  • R 4 is hydrogen, -NR 6 -, -NR 6 R 7 , -NR 6 C(0)-, -NR 6 C(0)0- -NR 6 C(0)NR 7 -, -
  • R 5 is absent, hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -Cio cycloalkyl, C 6 - C 10 aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, Ci-C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ; or
  • R 6 and R 7 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 11 , -NR n R 12 or Ci-C 6 alkyl optionally substituted by halogen;
  • R 8 and R 9 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • each R 10 is independently hydrogen, oxo, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C 1 -C 3 alkylene)NR 13 R 14 , -(d- C 3 alkylene)C(0)R 13 , -(C C 3 alkylene)S(0)R 13 , -(C C 3 alkylene)S(0) 2 R 13 or C C 6 alkyl optionally
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl optionally substituted by halogen, -CN or oxo; or 11 12
  • R and R 1 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen, oxo or OH;
  • R 13 and R 14 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or CrC 6 alkyl optionally substituted by oxo or halogen.
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:
  • X is N
  • R 1 is hydrogen, halogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, -CF 3 , C 3 - C 6 cycloalkyl, -(Ci-C 3 alkylene)CN, -(Ci-C 3 alkylene)OR 8 , -(Ci-C 3 alkylene)SR 8 , -(d- C 3 alkylene)NR 8 R 9 , -(Ci-C 3 alkylene)CF 3 , -(Ci-C 3 alkylene)N0 2 , -(d- C 3 alkylene)C(0)R 8 , -(C C 3 alkylene)C(0)OR 8 , -(C C 3 alkylene)C(0)NR 8 R 9 , -(C(C
  • R is hydrogen or Ci-C 6 alkyl optionally substituted by R , or is taken together with R and the nitrogen to which they are attached to form a 3-10-membered heterocyclyl optionally substituted by R 10 ;
  • R is hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci4 aryl,
  • R may be optionally substituted by R ; or is taken together with R and the nitrogen to which they are attached to form a 3- 10- membered heterocyclyl optionally substituted by R 10 ;
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -;
  • R 5 is hydrogen, CrC 6 alkyl, C3-C 10 cycloalkyl, C 6 -Cio aryl, or 5-10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C3-C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ;
  • R 8 and R 9 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • each R 10 is independently hydrogen, oxo, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • C3-C6 cycloalkyl 3-10-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -Ci 4 aryl, -(C1-C3 alkylene)CN, -(C1-C3 alkylene)OR u , -(C1-C3 alkylene)SR u , -(d-
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , -
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl optionally substituted by halogen, -CN or oxo; or R 11 and R 1 1 2" are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen,
  • R 13 and R 14 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or CrC 6 alkyl optionally substituted by oxo or halogen.
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:
  • X is CR°
  • R° is hydrogen, hydroxyl, or CrC 6 alkyl optionally substituted by R 10 ;
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, -CF 3 , C 3 -
  • R 2 is hydrogen or Ci-C 6 alkyl optionally substituted by R 10 , or is taken together with R 3 and the carbon to which they are attached to form a ring selected from C 3 -Cio cycloalkyl and 3-10-membered heterocyclyl, wherein the ring is optionally substituted by R 10 ;
  • R is hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, 3-10-membered heterocyclyl, C 6 -Ci4 aryl, or 5-10-membered heteroaryl, wherein R 3 may be optionally substituted by R 10 ; or is taken together with R and the carbon to which they are attached to form a ring selected from C 3 -Cio cycloalkyl and 3-10-membered heterocyclyl, wherein the ring is optionally substituted by R 1U ;
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -;
  • R 5 is hydrogen, Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5-10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, Ci-C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ;
  • R 8 and R 9 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • each R 10 is independently hydrogen, oxo, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C 1 -C 3 alkylene)NR 13 R 14 , -(d- C 3 alkylene)C(0)R 13 , -(C C 3 alkylene)S(0)R 13 , -(C C 3 alkylene)S(0) 2 R 13 or C C 6 alkyl optionally
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl optionally substituted by halogen, -CN or oxo; or R 11 and R 1 1 2" are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen,
  • R 13 and R 14 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or CrC 6 alkyl optionally substituted by oxo or halogen.
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C 6 alkynyl, -CN, -OR 8 , -SR 8 , -NR 8 R 9 , -CF 3 , -N0 2 , -C(0)R 8 , -C(0)OR 8 , -C(0)NR 8 R 9 , - NR 8 C(0)R 9 , -S(0)R 8 , -S(0) 2 R 8 , -NR 8 S(0)R 9 , -NR 8 S(0) 2 R 9 , -S(0)NR 8 R 9 , -S(0) 2 NR 8 R 9 , C 3 - C 6 cycloalkyl, 3-6-membered heterocyclyl, 5-6-membered heteroaryl, C 6 -Ci 4 ary
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 1 is hydrogen, halogen, Ci-C 6 alkyl or -CN.
  • R 1 is hydrogen.
  • R 1 is hydrogen or halogen (e.g., F, CI, or Br).
  • R 1 is fluoro, chloro, bromo or cyano.
  • R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 1 is halogen, -CN, -CF 3 or -N0 2 .
  • R 1 is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OR 8 , -SR 8 , -NR 8 R 9 , -C(0)R 8 , -C(0)OR 8 , - C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -S(0)R 8 , -S(0) 2 R 8 , -NR 8 S(0)R 9 , -NR 8 S(0) 2 R 9 , -S(0)NR 8 R 9 or -
  • R 1 is C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, 5-6- membered heteroaryl or C 6 -Ci4 aryl.
  • R 1 is -(Ci-C 3 alkylene)CN, -(Ci- C 3 alkylene)OR 8 , -(Ci-C 3 alkylene)SR 8 , -(Ci-C 3 alkylene)NR 8 R 9 , -(Ci-C 3 alkylene)CF 3 , -(d- C 3 alkylene)N0 2 , -(C C 3 alkylene)C(0)R 8 , -(C C 3 alkylene)C(0)OR 8 , -(C
  • R is hydrogen or Ci-C 6 alkyl.
  • R 8 is hydrogen.
  • R 8 is Ci-C 6 alkyl optionally substituted by halogen or oxo.
  • R 8 and R 9 are each independently hydrogen or Ci-C 6 alkyl.
  • R 8 is hydrogen and R 9 is hydrogen or Ci-C 6 alkyl.
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, - CN, -OR 8 , -SR 8 , -NR 8 R 9 , -CF 3 , -OCF 3 , -N0 2 , -C(0)R 8 , -C(0)OR 8 , -C(0)NR 8 R 9 , - NR 8 C(0)R 9 , -S(0)R 8 , -S(0) 2 R 8 , -NR 8 S(0)R 9 , -NR 8 S(0) 2 R 9 , -S(0)NR 8 R 9 , -S(0) 2 NR 8 R 9 , - (C 3 -C 6 cycloalkyl), -(3-6-membered heterocyclyl), -(5-6-membered heteroaryl) or -phenyl.
  • R 1 is hydrogen, halogen, -CF 3 or
  • R 1 is -(Ci-C 3 alkylene)OR 8. In certain embodiments, R 1 is -CH 2 OR8. In certain embodiments, R 1 is -CH 2 OH. In certain embodiments, R 1 is hydrogen, halogen, -CN, -CH 2 OH, -CF 3 or Ci-C 3 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is F or Br. In certain embodiments, R 1 is F, Br, CN or CH 2 OH.
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein X is N.
  • X is CR°.
  • R° is hydrogen, hydroxyl, or Ci-C 6 alkyl optionally substituted by R 10 .
  • R° is hydrogen, hydroxyl or unsubstituted Ci-C 6 alkyl.
  • R° is hydrogen or hydroxyl.
  • R° is hydrogen.
  • R° is hydroxyl.
  • R° is unsubstituted Ci-C 6 alkyl.
  • R° is C 3 -C 6 cycloalkyl, 3-10-membered heterocyclyl, C 6 -Ci4 aryl, or 5-10-membered heteroaryl.
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein each R 2 and R 3 is independently hydrogen, hydroxyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-10-membered heterocyclyl, C 6 -Ci4 aryl, or 5-10-membered heteroaryl, wherein R 2 and R 3 are each independently optionally substituted by R 10.
  • each R 2 and R 3 is independently hydrogen, Ci-C 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or 3-10-membered
  • R 2 is hydrogen or Ci-C 6 alkyl optionally substituted by R 10 and R 3 is Ci-C 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or 3-10-membered heterocyclyl optionally substituted by R 10.
  • R 2 is hydrogen and R 3 is Ci-C 6 alkyl optionally substituted by R 10 , C3-C6 cycloalkyl optionally substituted by R 10 , or 3-10-membered heterocyclyl optionally substituted by R 10.
  • R 2 is hydrogen and R 3 is Ci-C 6 alkyl optionally substituted by C 3 -C 6 cycloalkyl (e.g., cyclopentyl), -NR n R 12 (e.g., -N(CH 3 ) 2 ) or 3-10- membered heterocyclyl (e.g., morpholin4-yl).
  • C 3 -C 6 cycloalkyl e.g., cyclopentyl
  • -NR n R 12 e.g., -N(CH 3 ) 2
  • 3-10- membered heterocyclyl e.g., morpholin4-yl
  • R 2 is hydrogen and R 3 is C 3 -C 6 cycloalkyl (e.g., cyclopentyl or cyclohexyl) optionally substituted by hydroxyl, cyano, halo (e.g., fluoro), CrC 6 alkyl or CrC 6 alkyl substituted by hydroxyl, cyano or sulfonyl (e.g., CH 2 CH 2 OH, CH 2 CH 2 CN, or CH 2 CH 2 S0 2 CH 3 ).
  • C 3 -C 6 cycloalkyl e.g., cyclopentyl or cyclohexyl
  • halo e.g., fluoro
  • CrC 6 alkyl or CrC 6 alkyl substituted by hydroxyl, cyano or sulfonyl e.g., CH 2 CH 2 OH, CH 2 CH 2 CN, or CH 2 CH 2 S0 2 CH 3 ).
  • R 2 is hydrogen and R 3 is 3-10-membered heterocyclyl optionally substituted by Ci-C 6 alkyl or Ci-C 6 alkyl substituted by hydroxyl, cyano or sulfonyl (e.g., CH 2 CH 2 OH, CH 2 CH 2 CN, or CH 2 CH 2 S0 2 CH 3 ).
  • R 2 is CrC 6 alkyl optionally substituted by R 10 and R 3 is CrC 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or 3-10-membered
  • heterocyclyl optionally substituted by R 10 .
  • X is N and the -X(R 2 )(R 3 ) moiety is selected from the group consisting
  • R and R are taken together with the atom to which they are attached to form a ring selected from C3-C 10 cycloalkyl and 3-10-membered heterocyclyl, wherein the ring
  • X is N and R and R are taken together with the atom to which they are attached to form a 3-10-membered heterocyclyl
  • X is N and R and R are taken together with the atom to which they are attached to form a 4-9-membered heterocyclyl optionally
  • X is N and R and R are taken together with the atom to which they are attached to form a 4, 5, 6, 7, 8, or 9-membered heterocyclyl optionally
  • X is N and R and R are taken together with the atom to which they are attached to form a 5 or 6-membered heterocyclyl optionally substituted by R 10 .
  • X is N and R and R are taken together with the atom to which they are attached to form a 4-membered heterocyclyl (e.g., azetidinyl) optionally substituted by R 10 .
  • a 4-membered heterocyclyl e.g., azetidinyl
  • X is N and R and R are taken together with the atom to which they are attached to form a 5-membered heterocyclyl (e.g., pyrrolidinyl) optionally substituted by R 10 .
  • a 5-membered heterocyclyl e.g., pyrrolidinyl
  • X is N and R and R are taken together with the atom to which they are attached to form a 6-membered heterocyclyl (e.g., piperidinyl, piperazinyl or morpholinyl)
  • a 6-membered heterocyclyl e.g., piperidinyl, piperazinyl or morpholinyl
  • X is N and R and R are taken together with the atom to which they are attached to form a 7-membered heterocyclyl (e.g., azepanyl)
  • X is N and R and R are taken together with the atom to which they are attached to form an 8-membered heterocyclyl (e.g., azocanyl) optionally substituted by R 10 .
  • R and R are taken together with the atom to which they are attached to form an 8-membered heterocyclyl (e.g., azocanyl) optionally substituted by R 10 .
  • X is N and the -X(R )(R ) moiety is selected from the group consisting of
  • X is CR and R and R are taken together with the atom to which they are attached to form a ring selected from C 3 -C 10 cycloalkyl optionally substituted by R 10 .
  • X is CR where R is hydrogen or hydroxyl and R and R are taken together with the atom to which they are attached to form a cyclohexyl group optionally substituted by
  • Ci-C 6 alkyl e.g., methyl
  • X is CR and R and R are taken together with the atom to which they are attached to form a 3-10-membered heterocyclyl optionally substituted by R 10 .
  • X is CR and the -X(R )(R ) moiety is selected from the group consisting
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl or -CN
  • X is N
  • R is hydrogen or Ci-C 6 alkyl optionally substituted by R 10
  • R 3 is Ci-C 6 alkyl optionally substituted by R 10 , C 3 -C6 cycloalkyl optionally substituted by R 10 , or 3- 10-membered heterocyclyl optionally substituted by R 10 .
  • R is hydrogen, halogen, X is N and R and R are taken together with the atom to which they are attached to form a 4, 5, 6, 7, 8, or 9-membered heterocyclyl optionally substituted by R 10 .
  • R 1 is hydrogen
  • X is CR° where R° is hydrogen or
  • hydroxyl and R and R are taken together with the atom to which they are attached to form a cyclohexyl group optionally substituted by CrC 6 alkyl.
  • the compound is of Formula I, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- -NR 6 C(0)NR 7 -, - NR 6 S(0)-, -NR 6 S(0) 2 - -NR 6 S(0)NR 7 - or -NR 6 S(0) 2 NR 7 -; R 5 is hydrogen, C C 6 alkyl, C 2 - C alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -Cio aryl, 3- 10-membered heterocyclyl or 5- 10- membered heteroaryl, wherein R 5 is optionally substituted by R 10 ; and R 6 and R 7 are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6
  • R 4 is hydrogen and R is absent. In some embodiments, R 4 is -NR 6 R 7 , R 5 is absent, and R 6 and R 7 are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR n , -NR n R 12 or Ci-C 6 alkyl optionally substituted by halogen.
  • R 4 is -NR 6 R 7 ; R 5 is absent; and R 6 and R 7 are independently hydrogen,
  • R 4 is -NR 6 -. In certain embodiments, R 4 is -NR 6 C(0)-. In certain embodiments, R 4 is -NR 6 C(0)0-. In certain embodiments, R 4 is -NR 6 C(0)NR 7 -. In certain embodiments, R 4 is -NH-. In certain embodiments, R 4 is -NHC(O)-. In certain embodiments, R 4 is -NHC(0)0-. In certain embodiments, R 4 is -NHC(0)NH-.
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -. In certain embodiments, R 4 is -NH-, -NHC(O)- or -NHC(0)NH-.
  • R 5 is hydrogen. In certain embodiments, R 5 is CrC 6 alkyl optionally substituted by halogen, oxo, -OR 11 , -SR 11 , -CN, C 3 -C 10 cycloalkyl, -C(0)R n or -NR n R 12 . In certain embodiments, R 5 is Ci-C 6 alkyl optionally substituted by halogen, oxo,
  • R 5 is methyl, ethyl, isopropyl, tert-butyl, - CH 2 OH, -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 or -CH 2 CH 2 NH 2 .
  • R 5 is methyl, ethyl, isopropyl, tert-butyl, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 or - CH 2 CH 2 NH 2 .
  • R 5 is C 3 -C 10 cycloalkyl optionally substituted by R 10 . In certain embodiments, R 5 is C 3 -C 6 cycloalkyl optionally substituted by halogen. In certain embodiments, R 5 is cyclopropyl optionally substituted by halogen. In certain embodiments, R 5 is cyclopropyl. In certain embodiments, R 5 is cyclopropyl. In certain embodiments, R 5 is selected from:
  • R 5 is C 6 -C 10 aryl optionally substituted by R 10 .
  • R 5 is selected from phenyl, naphthalenyl, dihyrdoindenyl and tetrahydronaphthalenyl, wherein R 5 is optionally substituted by R 10 .
  • R 5 is phenyl optionally substituted by R 10 .
  • R 5 is phenyl.
  • R 5 is phenyl optionally substituted by -0(CH 2 ) 2 pyrrolidinyl.
  • R 5 is 3-10-membered heterocyclyl optionally substituted by R 10 .
  • R 5 is 3-7-membered heterocyclyl optionally substituted by R 10 . In certain embodiments, R 5 is 5-10-membered heteroaryl optionally substituted by R 10 . In certain embodiments, R 5 is pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl or isoxazolyl, wherein said R 5 is optionally substituted by R 10 .
  • R 5 is 5-6-membered heteroaryl, wherein R 5 is optionally substituted by R 10 , wherein R 10 is C C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 , -NR n R 12 , -CF 3 , -C(0)R n , - C(0)OR n , -C(0)NR n R 12 , -NR n C(0)R 12 , -S(0)i_ 2 R n , -NR n S(0)i_ 2 R 12 , -S(0)i_ 2 NR n R 12 , C 3 - C 6 cycloalkyl, 3-6-membered heterocyclyl, -C(0)(3-6-membered heterocyclyl), 5-6-membered heteroaryl or phenyl, wherein R 10 is independently optionally substituted by halogen, Ci-C 3 alkyl, oxo, -CF 3 , -OR 13 ,
  • R 5 is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, pyrazolyl, pyranyl, triazolyl, isoxazolyl, oxazolyl, imidazolyl, thiazolyl or thiadiazolyl, wherein R 5 is optionally substituted by 1, 2 or 3 R 10 .
  • R 5 is selected from:
  • R 5 is selected from:
  • R 5 is pyrimidinyl, pyridazinyl, or pyrazinyl, optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, -(C 0 -C 3 alkylene)CN, -(C 0 -C 3
  • R 10 is independently optionally substituted by halogen, Ci-C 3 alkyl, oxo, -CF 3 , -(Co-C 3 alkylene)OR 13 , -(C 0 -C 3 alkylene)NR 13 R 14 , -(C 0 -C 3 alkylene)C(0)R 13 or - (Co-C 3 alkylene)S(0)i_ 2 R 13 .
  • R 5 is selected from:
  • R 5 is pyrimidinyl optionally substituted by C 1 -C3 alkyl and -NR U R In certain embodiments, R 5 is pyrimidinyl optionally substituted by methyl and -NH 2 .
  • R 5 is pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, thiazolyl or
  • R 3 is optionally substituted by R , wherein R 1U is Ci-C 6 alkyl, halogen, - CN, -OR 11 , -SR 11 , -NR n R 12 , -CF 3 , -C(0)R n , -C(0)OR u , -C(0)NR n R 12 , -NR n C(0)R 12 , - S(0)i_ 2 R n , -NR n S(0)i_ 2 R 12 , -S(0)i_ 2 NR n R 12 , C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, C(0)(3-6-membered heterocyclyl), 5-6-membered heteroaryl or phenyl, wherein R 10 is
  • R is pyrazolyl optionally substituted by R
  • R 5 is selected from the group consisting of methyl, ethyl, 2-propyl, cyclopropyl, 2-methylcyclopropyl, 2-fluorocyclopropyl, 2-(hydroxymethyl)cyclopropyl, cyclopropylmethyl,v "v A F v
  • the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , -NHC(0)OR 5 or - NHC(0)NHR 5 .
  • the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , - NHC(0)OR 5 or -NHC(0)NHR 5 , wherein R 5 is other than hydrogen.
  • - 4-R 5 is -NH 2 .
  • 4-R 5 moiety is selected from the group consisting of:
  • R 1 is hydrogen or halogen
  • X is N
  • R is h Ci-C 6 alkyl, R is optionally substituted Ci-C 6 alkyl, R is -NR 6 -, -NR 6 C(0)- or -NR 6 C(0)NR 7 - and R 5 is optionally substituted Ci-C 6 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3-10-membered heterocyclyl or optionally substituted 5-10-membered heteroaryl.
  • R 1 is hydrogen, fluoro, chloro or bromo, is 2 3
  • X N, R and R are taken together with the atom to which they are attached to form an optionally substituted piperidinyl (e.g., 3-cyanopiperidin-l-yl), and the -R 4 -R 5 moiety is -NH- (optionally substituted pyrimidinyl) (e.g., (6-aminopyrimidin-4-yl)amino), -NHC(0)-(optionally substituted cyclopropyl) (e.g., cyclopropanecarbonylamino), or -NHC(0)NH-( optionally substituted Ci-C 6 alkyl) (e.g., isopropylurido).
  • R 1 is hydrogen
  • X is CR° where 0 s hydrogen or hydroxy, 2 d 3
  • R i R an R are taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl and the -R 4 -R 5 moiety is (6- aminopyrimidin-4-yl)amino or cyclopropanecarbonylamino.
  • R 1 is hydrogen; and the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , - NHC(0)OR 5 or -NHC(0)NHR 5 , wherein R 5 is other than hydrogen. In certain embodiments, R 1 is hydrogen; and the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , -NHC(0)OR 5 or -NHC(0)NHR 5 , wherein R 5 is other than hydrogen.
  • R 1 is hydrogen, halogen or -CN; and the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , -NHC(0)OR 5 or -NHC(0)NHR 5 , wherein R 5 is other than hydrogen.
  • X is N;
  • R 1 is hydrogen, halogen or -CN; and the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , -NHC(0)OR 5 or -NHC(0)NHR 5 , wherein R 5 is other than hydrogen.
  • R 1 is hydrogen, halogen or -CN;
  • X is CR°;
  • R° is hydrogen or hydroxyl; and the group -R 4 -R 5 is -NHR 5 , -NHC(0)R 5 , -NHC(0)OR 5 or - NHC(0)NHR 5 , wherein R 5 is other than hydrogen.
  • R 10 is independently halogen. In certain embodiments, R 10 is independently F. In certain embodiments, R 10 is independently -CN.
  • R 10 is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, -OR 13 or -NR 13 R 14 .
  • R 10 is methyl, ethyl, isopropyl, -CH 2 OH, - CH 2 CH 2 OH, -CH(OH)CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CF 3 , - C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -CH 2 thiomorpholinyl dioxide, -CH 2 morpholinyl, (R)- CH(OH)CH 3 , (R)-CH(NH 2 )CH 3 , (S)-CH(OH)CH 3 , (S)-CH(NH 2 )CH 3 or -C(0)morpholinyl.
  • R 10 is methyl.
  • R 10 is independently C 3 -C 6 cycloalkyl optionally substituted by halogen, oxo or Ci-C 3 alkyl. In certain embodiments, R 10 is independently cyclopropyl. In certain embodiments, R 10 is independently 3-6 membered heterocyclyl or -C(0)(3-6 membered
  • heterocyclyl wherein said heterocyclyl is independently optionally substituted by -OR , -(Ci- C 3 alkylene)OR 13 , -NR 13 R 14 , -(d-C 3 alkylene)NR 13 R 14 , halogen, -CN, oxo or Ci-C 6 alkyl optionally substituted by oxo or halogen.
  • said heterocyclyl is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or aziridinyl, wherein said heterocyclyl is independently optionally substituted by oxo, -CH 2 OH, -CH 2 CH 2 OH, -OH, methyl or -CF 3 .
  • R 10 is independently selected from:
  • R 10 is independently -OR 11 , -(C C 3 alkylene)OR n , -SR 11 or -(C C 3 alkylene)SR n .
  • R 10 is -OH, -OCH 3 , -CH 2 OH, -CH 2 CH 2 OH, -
  • R 10 is -OH or -OCH 3 .
  • R 10 is -OH, -OCH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 2 OH, -C(CH 3 ) 2 OH. (R)-CH(OH)CH 3 or (S)-CH(OH)CH 3 .
  • R 10 is independently -NR n R 12 or -(Ci-C 3 alkylene)NR n R 12 .
  • R 10 is -NH 2 , -NHCH 3 , -NHC(0)CH 3 , -N(CH 3 ) 2i -N(CH 2 CH 2 OH) 2i -
  • R 10 is -NH 2 , -NHCH 3 , -NHC(0)CH 3 , -N(CH 3 ) 2a -N(CH 2 CH 2 OH) 2a -NHCH 2 CH 2 OH a - N(CH 3 )CH 2 CH 2 OH i -NHCH 2 C(CH 3 ) 2 OH, -N(CH 3 )CH 2 C(CH 3 ) 2 OH, 4-hydroxyaziridin-l-yl, morpholinyl, dioxothiomorpholinyl, piperidinyl, 4-hydroxypiperidinyl, 4-methylpiperazinyl, pyrrolidinyl, -CH 2 thiomorpholinyl dioxide, -CH 2 morpholinyl, (R)-CH(NH 2 )CH 3 , (S)- CH(NH 2 )CH 3 or 4-(2-hydroxyethyl)piperazinyl.
  • R 10 is independently -C(0)NR n R 12 . In certain embodiments, R 10 is - C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 or -C(0)morpholinyl.
  • R 10 is independently selected from F, -CN, methyl, ethyl, isopropyl, - CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 NH 2 , -CH 2 NHCH 3 , - CH 2 N(CH 3 ) 2 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NHCH 3 , -NHC(0)CH 3 , -N(CH 3 ) 2i - N(CH 2 CH 2 OH) 2a -NHCH 2 CH 2 OH a -N(CH 3 )CH 2 CH 2 OH a -NHCH 2 C(CH 3 ) 2 OH, - N(CH 3 )CH 2 C(CH 3 ) 2 OH, -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 OH,
  • R and R are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl
  • R and R are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen, oxo or OH.
  • R and R are independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen, oxo, -CN, -OR 16 or -NR 16 R 17 , or are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or C C 3 alkyl optionally substituted by halogen, oxo or OH.
  • R and R are independently hydrogen, methyl, -C(0)CH 3 , 2- hydroxy-2-methylpropyl or 2-hydroxyethyl, or are taken together with the atom to which they attached to form a azetidinyl, pyrrolidinyl, morpholinyl, dioxothiomorpholinyl, piperazinyl or piperidinyl ring optionally substituted by halogen, oxo or Ci-C 3 alkyl optionally substituted by
  • R and R are independently hydrogen, methyl, - C(0)CH 3 , 2-hydroxy-2-methylpropyl or 2-hydroxyethyl.
  • R 13 and R 14 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo. In some embodiments, R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo.
  • R 13 and R 14 are independently hydrogen or C 1 -C 3 alkyl. In certain embodiments, R 13 and R 14 are independently hydrogen or methyl.
  • R 16 and R 17 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo. In some embodiments, R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by oxo or halogen.
  • R 16 and R 17 are each independently hydrogen or C 1 -C 3 alkyl. In certain embodiments, R 16 and R 17 are each independently hydrogen or methyl.
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, or C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted by R 10 ;
  • R is hydrogen or Ci-C 6 alkyl optionally substituted by R , or is taken together with R and the nitrogen to which they are attached to form a 3-10-membered heterocyclyl optionally substituted by R 10 ;
  • R is hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci 4 aryl,
  • R may be optionally substituted by R ; or is taken together with R and the nitrogen to which they are attached to form a 3- 10- membered heterocyclyl optionally substituted by R 10 ;
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -;
  • R 5 is hydrogen, Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5- 10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ;
  • each R 10 is independently hydrogen, oxo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • C3-C6 cycloalkyl 3-10-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -Ci 4 aryl, -(C 1 -C3 alkylene)CN, -(C C 3 alkylene)OR u , -(C C 3 alkylene)SR u , -(C
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(Ci-C 3 alkylene)OR 13 , -(C C 3 alkylene)NR 13 R 14 , -(C C 3 alkylene)C(0)R 13 , -(C C 3 alkylene)S(0)R 13 , -(C C 3 alkylene)S(0) 2 R 13 or C C 6 alkyl optionally substituted by oxo,
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen, -CN or oxo; or
  • R 11 and R 1 1 2" are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen, oxo or OH;
  • R 13 and R 14 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo;
  • R 16 and R 17 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by oxo or halogen.
  • the compound is of Formula II, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 1 is hydrogen, halogen, Ci-C 6 alkyl or -CN. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is hydrogen or halogen (e.g., F, CI, or
  • R 1 is fluoro, chloro, bromo or cyano. In some embodiments, R 1 is
  • Ci-C 6 alkyl e.g., CH 3 .
  • R 1 is Ci-C 6 alkyl optionally substituted by R 10 .
  • R 1 is Ci-C 6 alkyl optionally substituted by halogen (e.g., -CF 3 ). In some embodiments, R 1 is C 2 -C6 alkenyl optionally substituted by R 10 or C 2 -C6 alkynyl optionally substituted by R 10 . In some embodiments, R 1 is C 3 -C 6 cycloalkyl optionally substituted by R 10 .
  • the compound is of Formula II, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 2 is hydrogen or Ci-C 6 alkyl optionally substituted by R 10 and R 3 is Ci-C 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or 3-10-membered heterocyclyl optionally substituted by R 10.
  • R 2 is hydrogen and R 3 is Ci-C 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or 3-10-membered heterocyclyl optionally substituted by R 10 .
  • R 2 is hydrogen and R 3 is Ci-C 6 alkyl optionally substituted by C 3 -C 6 cycloalkyl
  • R 2 is hydrogen and R 3 is C 3 -C 6 cycloalkyl (e.g., cyclopentyl or cyclohexyl) optionally substituted by hydroxyl, cyano, halo (e.g., fluoro), Ci-C 6 alkyl or Ci-C 6 alkyl substituted by hydroxyl, cyano or sulfonyl (e.g., CH 2 CH 2 OH, CH 2 CH 2 CN, or
  • R 2 is hydrogen and R 3 is 3-10-membered heterocyclyl optionally substituted by Ci-C 6 alkyl or Ci-C 6 alkyl substituted by hydroxyl, cyano or sulfonyl (e.g., CH 2 CH 2 OH, CH 2 CH 2 CN, or CH 2 CH 2 S0 2 CH 3 ).
  • R 2 is C C 6 alkyl optionally substituted by R 10 and R 3 is Ci-C 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or 3-10-membered heterocyclyl optionally substituted by R 10 .
  • R 2 and R 3 are taken together with the atom to which they are attached to form a ring selected from C 3 -Cio cycloalkyl and 3-10-membered heterocyclyl, wherein the ring may be optionally substituted by R 10.
  • R 2 and R 3 are taken together with the atom to which they are attached to form a 3-10-membered heterocyclyl optionally substituted by R 10.
  • R 2 and R 3 are taken together with the atom to which they are attached to form a 4-9-membered heterocyclyl optionally substituted by R 10 .
  • R 2 and R 3 are taken together with the atom to which they are attached to form a 4, 5, 6, 7, 8, or 9-membered heterocyclyl optionally substituted by R 10. In some embodiments, R 2 and R are taken together with the atom to which they are attached to form a 5 or 6-membered heterocyclyl optionally substituted by R 10. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached to form a 4-membered heterocyclyl (e.g., azetidinyl) optionally substituted by R 10.
  • R 2 and R 3 are taken together with the atom to which they are attached to form a 5-membered heterocyclyl (e.g., pyrrolidinyl) optionally substituted by R 10. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached to form a 6-membered heterocyclyl (e.g., piperidinyl, piperazinyl or morpholinyl) optionally substituted by R 10. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached to form a 7-membered heterocyclyl (e.g., azepanyl) optionally substituted by R 10. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached to form an 8-membered heterocyclyl (e.g., azocanyl) optionally substituted by R 10 .
  • a 5-membered heterocyclyl e.g., pyrrolidinyl
  • the -N(R 2 )(R 3 ) moiety is selected from the group consisting of:
  • the -N R R moiet is selected from the rou consistin of: wherein the wavy line represents the point of attachment in
  • R 1 is hydrogen, halogen, CrC 6 alkyl or -CN
  • R is hydrogen or CrC 6 alkyl optionally substituted by R 10
  • R 3 is CrC 6 alkyl optionally substituted by R 10 , C3-C6 cycloalkyl optionally substituted by R 10 , or 3-10-membered heterocyclyl optionally substituted by R 10
  • R 1 is hydrogen, halogen, and R 2 and R 3 are taken together with the atom to which they are attached to form a 4, 5, 6, 7, 8, or 9-membered heterocyclyl optionally substituted by R 10 .
  • the compound is of Formula II, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 4 is -NR 6 -, -NR 6 C(0)- or -NR 6 C(0)NR 7 -. In some embodiments, R 4 is -NR 6 -. In some embodiments, R 4 is -NR 6 C(0)-. In some embodiments, R is -NR 6 C(0)NR 7 -.
  • R 6 and R 7 are each independently hydrogen, CrC 6 alkyl optionally substituted by halogen, oxo, -CN, -OR 11 or -NR n R 12 , or C 3 -C 6 cycloalkyl optionally substituted by halogen, Ci-C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 .
  • RR 66 iiss hhyyddrrooggeenn or Ci-C 6 alkyl.
  • R 6 is hydrogen.
  • R is hydrogen.
  • R 4 is -NH-, -NHC(O)- or -NHC(0)NH-. In some embodiments, R is - NH-. In some embodiments, R 4 is -NHC(O)-. In some embodiments, R 4 is -NHC(0)NH-. In some embodiments, R 4 is -NHC(0)0-.
  • the compound is of Formula II, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 5 is optionally substituted CrC 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl or optionally substituted 5- 10-membered heteroaryl.
  • R 5 is hydrogen.
  • R 5 is Ci-C 6 alkyl optionally substituted by R 10 .
  • R 5 is CrC 6 alkyl (e.g., methyl, ethyl and 2-propyl).
  • R 5 is CrC 6 alkyl substituted by C 3 -C6 cycloalkyl (e.g., cyclopropylmethyl). In some embodiments, R 5 is C3-C 10 cycloalkyl optionally substituted by R 10 . In some embodiments, R 5 is C 3 -C 6 cycloalkyl optionally substituted by R 10 . In some embodiments, R 5 is C 3 -C 6 cycloalkyl (e.g., cyclopropyl).
  • R 5 is C 3 -C 6 cycloalkyl substituted by halogen (e.g., 2-fluorocyclopropyl) or C 3 -C 6 cycloalkyl substituted by CrC 6 alkyl which is optionally further substituted by halogen or hydroxyl (e.g., 2-methylcyclopropyl and 2-hydroxy methylcyclopropyl).
  • halogen e.g., 2-fluorocyclopropyl
  • CrC 6 alkyl which is optionally further substituted by halogen or hydroxyl (e.g., 2-methylcyclopropyl and 2-hydroxy methylcyclopropyl).
  • R 5 is C3-C6 cycloalkyl substituted with 1-3 substituents independently selected from fluoro, methyl and hydroxymethyl.
  • R 5 is 5-10-membered heteroaryl optionally substituted by R 10 . In some embodiments, R 5 is 5 or 6-membered heteroaryl optionally substituted by R 10 . In some embodiments, R 5 is 5-membered heteroaryl optionally substituted by R 10 . In some embodiments, R 5 is 5-membered heteroaryl (e.g., thiazolyl and thiadiazolyl). In some embodiments, R 5 is 5- membered heteroaryl substituted by CrC 6 alkyl (e.g., 4-methylthiazol-2-yl, 5-methylthiazol-2-yl and 5-methyl- l,3,4-thiadiazol-2-yl).
  • R 5 is 6-membered heteroaryl optionally substituted by R 10 .
  • R 5 is 6-membered heteroaryl (e.g., 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl, pyrazin-2-yl and pyridazin-3-yl).
  • R 5 is 6-membered heteroaryl substituted by 1-4 substituents independently selected from Ci-C 6 alkyl, -CN, -CF 3 , halogen -OR 11 , -(Ci- C 3 alkylene)OR u , -NR n R 12 , -NR n C(0)R 12 , -S(0) 2 NR n R 12 , and 3-10-membered heterocyclyl
  • R is 6- membered heteroaryl substituted by 1-4 substituents independently selected from -CN, -CF 3 , - CH 3 , -CH(CH 3 ) 2 , -CH 2 OH,-OCH 3 , -CH 2 OCH 3 , -NH 2 , -NHC(0)CH 3 , -NHCH 2 CH 2 OH, - NHCH 2 C(CH 3 ) 2 OH, -NHCH3, -N(CH 3 ) 2 , -S(0) 2 N(CH 3 ) 2 , azetidin-l-yl, morpholin-4-yl, 4- methylpiperzin-l-yl and 4-(2-hydroxyethyl)piperzin- l-yl.
  • R 5 is 2-pyridyl optionally substituted by 1-3 substituents independently selected from -CN, -CF 3 , -CH 3 , - CH(CH 3 ) 2 , -CH 2 OH,-OCH 3 , -CH 2 OCH 3 , -NH 2 , -NHC(0)CH 3 , -NHCH 2 CH 2 OH, - NHCH 2 C(CH 3 ) 2 OH, -NHCH3, -N(CH 3 ) 2 , -S(0) 2 N(CH 3 ) 2 , azetidin-l-yl, morpholin-4-yl, 4- methylpiperzin-l-yl and 4-(2-hydroxyethyl)piperzin-l-yl.
  • R 5 is pyrimidin-4-yl optionally substituted by 1-2 substituents independently selected from -CN, - CF 3 , -CH 3 , -CH(CH 3 ) 2 , -CH 2 OH,-OCH 3 , -CH 2 OCH 3 , -NH 2 , -NHC(0)CH 3 , -NHCH 2 CH 2 OH, -NHCH 2 C(CH 3 ) 2 OH, -NHCH 3 , -N(CH 3 ) 2 , -S(0) 2 N(CH 3 ) 2 , azetidin-l-yl, morpholin-4-yl, 4- methylpiperzin-l-yl and 4-(2-hydroxyethyl)piperzin-l-yl.
  • R 5 is pyridazin-3-yl optionally substituted by 1-2 substituents independently selected from -CN, -CF 3 , -CH 3 , -CH(CH 3 ) 2 , -CH 2 OH,-OCH 3 , -CH 2 OCH 3 , -NH 2 , -NHC(0)CH 3 , -NHCH 2 CH 2 OH, - NHCH 2 C(CH 3 ) 2 OH, -NHCH 3 , -N(CH 3 ) 2 , -S(0) 2 N(CH 3 ) 2 , azetidin-l-yl, morpholin-4-yl, 4- methylpiperzin-l-yl and 4-(2-hydroxyethyl)piperzin-l-yl.
  • R 5 is pyrazin- 2-yl optionally substituted by 1-2 substituents independently selected from -CN, -CF 3 , -CH 3 , - CH(CH 3 ) 2 , -CH 2 OH,-OCH 3 , -CH 2 OCH 3 , -NH 2 , -NHC(0)CH 3 , -NHCH 2 CH 2 OH, - NHCH 2 C(CH 3 ) 2 OH, -NHCH 3 , -N(CH 3 ) 2 , -S(0) 2 N(CH 3 ) 2 , azetidin-l-yl, morpholin-4-yl, 4- methylpiperzin-l-yl and 4-(2-hydroxyethyl)piperzin-l-yl.
  • R 5 is selected from the group consisting of methyl, ethyl, 2-propyl, cyclopropyl, 2-meth lcyclopropyl, 2-fluorocyclopropyl, 2-(hydroxymethyl)cyclopropyl,
  • the compound is of Formula II, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein the -R 4 -R 5 moiety is -NHR 5 , -NHC(0)R 5 , -NHC(0)OR 5 or - NHC(0)NHR 5 , wherein R 5 is other than hydrogen.
  • the -R 4 -R 5 moiety is selected form the rou consistin of
  • the compound is of Formula II where R 1 is hydrogen or halogen, R 2 is hydrogen or optionally substituted Ci-Ce alkyl, R 3 is optionally substituted Ci-C 6 alkyl, R 4 is -NH-, -NHC(O)- or -NHC(0)NH- and R 5 is optionally substituted CrC 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl or optionally substituted 5 or 6-membered heteroaryl.
  • R 1 is hydrogen, fluoro, chloro or
  • R and R are taken together with the atom to which they are attached to form an optionally substituted piperidinyl (e.g., 3-cyanopiperidin- l-yl), and the -R 4 -R 5 moiety is -NH- (optionally substituted pyrimidinyl) (e.g., (6-aminopyrimidin-4-yl)amino), -NHC(0)-(optionally substituted cyclopropyl) (e.g., cyclopropanecarbonylamino), or -NHC(0)NH-( optionally substituted Ci-C 6 alkyl) (e.g., isopropylurido).
  • pyrimidinyl e.g., (6-aminopyrimidin-4-yl)amino
  • -NHC(0)-(optionally substituted cyclopropyl) e.g., cyclopropanecarbonylamino
  • Ci-C 6 alkyl e.g., isoprop
  • R° is hydrogen, hydroxyl, or Ci-C 6 alkyl optionally substituted by R 10 ;
  • R 1 is hydrogen, halogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, or C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted by R 10 ;
  • R is hydrogen or Ci-C 6 alkyl optionally substituted by R , or is taken together with R and the carbon to which they are attached to form a ring selected from C 3 -C 10 cycloalkyl and 3-10-membered heterocyclyl, wherein the ring is optionally substituted by R 10 ;
  • R is hydrogen, CrC 6 alkyl, C 3 -C 6 cycloalkyl, 3- 10-membered heterocyclyl, C 6 -Ci 4 aryl,
  • R may be optionally substituted by R ; or is taken together with R and the carbon to which they are attached to form a ring selected from C 3 -C 10 cycloalkyl and 3- 10-membered heterocyclyl, wherein the ring is optionally substituted by R 10 ;
  • R 4 is -NR 6 -, -NR 6 C(0)-, -NR 6 C(0)0- or -NR 6 C(0)NR 7 -;
  • R 5 is hydrogen, Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5- 10-membered heteroaryl, wherein R 5 is optionally substituted by R 10 ;
  • R 6 and R 7 are each independently hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, Ci-C 6 alkyl, oxo, -CN, -OR 11 or -NR n R 12 ; each R 10 is independently hydrogen, oxo, CrC 6 alkyl, C 2 -C6 alkenyl, C 2 -C 6 alkynyl, halogen,
  • C3-C6 cycloalkyl 3-10-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -Ci 4 aryl, -(C 1 -C3 alkylene)CN, -(C C 3 alkylene)OR u , -(C C 3 alkylene)SR u , -(C
  • each R 10 is independently optionally substituted by halogen, oxo, -OR 13 , -NR 13 R 14 , - C(0)R 13 , -S(0)R 13 , -S(0) 2 R 13 , -(Ci-C 3 alkylene)OR 13 , -(Ci-C 3 alkylene)NR 13 R 14 , -(d- C 3 alkylene)C(0)R 13 , -(C C 3 alkylene)S(0)R 13 , -(C C 3 alkylene)S(0) 2 R 13 or C C 6 alkyl optionally substituted by ox
  • R and R 1 " are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -Ci 4 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 16 , -NR 16 R 17 or C C 6 alkyl optionally substituted by halogen, -CN or oxo; or
  • R 11 and R 1 1 2" are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, -OR 16 , -NR 16 R 17 or Ci-C 6 alkyl optionally substituted by halogen, oxo or OH;
  • R 13 and R 14 are each independently hydrogen or Ci-C 6 alkyl optionally substituted by halogen or oxo; or
  • R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C 6 alkyl optionally substituted by halogen or oxo; and R 16 and R 17 are each independently hydrogen or CrC 6 alkyl optionally substituted by halogen or oxo; or
  • R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or CrC 6 alkyl optionally substituted by oxo or halogen.
  • the compound is of Formula III, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R° is hydrogen, hydroxyl or unsubstituted Ci-C 6 alkyl. In some embodiments, R° is hydrogen or hydroxyl. In some embodiments, R° is hydrogen. In some embodiments, R° is hydroxyl. In some embodiments, R° is CrC 6 alkyl optionally substituted by R 10 .
  • the compound is of Formula III, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 1 is hydrogen, halogen, CrC 6 alkyl or -CN.
  • R 1 is hydrogen.
  • R 1 is hydrogen or halogen (e.g., F, CI, or Br).
  • R 1 is fluoro, chloro, bromo or cyano.
  • R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 1 is Ci-C 6 alkyl optionally substituted by R 10 .
  • R 1 is CrC 6 alkyl optionally substituted by halogen (e.g., -CF 3 ). In some embodiments, R 1 is C 2 -C6 alkenyl optionally substituted by R 10 or C 2 -C 6 alkynyl optionally substituted by R 10 . In some embodiments, R 1 is C 3 -C 6 cycloalkyl optionally substituted by R 10 .
  • the compound is of Formula III, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 2 is hydrogen or CrC 6 alkyl optionally substituted by R 10 and R 3 is CrC 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , or
  • R 2 and R 3 are taken together with the atom to which they are attached to form a ring selected from C 3 -
  • Cio cycloalkyl optionally substituted by R 10 .
  • R° is hydrogen or hydroxyl and R 2 and R 3 are taken together with the atom to which they are attached to form a cyclohexyl group optionally substituted by Ci-C 6 alkyl (e.g., methyl).
  • R 2 and R 3 are taken together with the atom to which they are attached to form a 3-10-membered heterocyclyl optionally substituted by R 10 .
  • R 1 is hydrogen
  • R0 is hydrogen or hydroxyl
  • R 2 and R 3 are taken together with the atom to which they are attached to form a cyclohexyl group optionally substituted by CrC 6 alkyl.
  • the compound is of Formula III, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R 4 is -NR 6 -, -NR 6 C(0)- or -NR 6 C(0)NR 7 - and R 5 is optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl or optionally substituted 5-10-membered heteroaryl.
  • R 4 is -NR 6 - or -NR 6 C(0)-.
  • R 5 is C 3 -C 10 cycloalkyl optionally substituted by R 10 .
  • R 5 is C 3 -C 6 cycloalkyl optionally substituted by R 10 . In some embodiments, R 5 is 5 or 6-membered heteroaryl optionally substituted by R 10 . In some embodiments, R 6 is hydrogen. In some embodiments, R 6 and R 7 are hydrogen.
  • R 4 is -NH- or -NHC(O)- and R 5 is optionally substituted C 3 -C 10 cycloalkyl or optionally substituted 5 or 6-membered heteroaryl.
  • R 4 is - NH- and R 5 is optionally substituted 6-membered heteroaryl (e.g., 6-aminopyrimid-4-yl).
  • R 4 is -NHC(O)- and R 5 is C3-C 6 cycloalkyl (e.g., cyclopropyl).
  • the -R 4 -R 5 moiety is selected from the group consisting of: wherein the wavy line represents the point of attachment in Formula III
  • R 4 and R 5 described for Formula III may be combined with each and every variation of R 1 described for Formula III, and/or each and every variation of R 0 , R 2 and R 3 described for Formula III as if each and every combination is individually described.
  • R 1 is hydrogen
  • R° is hydrogen or hydroxy
  • R 2 and R 3 are taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl and the -R 4 -R 5 moiety is (6-aminopyrimidin-4-yl)amino or cyclopropanecarbonylamino.
  • each and every variation of R 1 , R 2 , R 3 , R 4 and R 5 described for Formula I or variations thereof may be applicable to Formula II and/or Formula III as if each and every combination is individually described.
  • Each and every variation of R 1 , R 2 , R 3 , R 4 and R 5 described for Formula II or III or variations thereof may be applicable to Formula I as if each and every combination is individually described.
  • the invention relates to one or more of the compounds depicted in Table 1 (e.g., compounds of Example Nos. 1-236 of Table 1), and uses thereof. In one embodiment, the invention relates to one or more of the compounds in Example Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 16, 17, 18, 21, 22, 42, 43, 126 and 127, and uses thereof.
  • the compounds provided herein may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds provided herein, including but not limited to: diastereomers, enantiomers, and atropisomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention, as defined by the claims, embrace both solvated and unsolvated forms.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • the present invention also embraces isotopically-labeled compounds of Formulae I, II, III, and variations described herein, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the invention.
  • Exemplary isotopes that can be incorporated into compounds of Formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • isotopically- labeled compounds of Formulae I, II, III, and variations described herein are useful in compound and/or substrate tissue distribution assays, tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • compositions comprising a compound as detailed herein are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2% or 1% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the invention embraces pharmaceutical
  • compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided.
  • the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the invention includes methods of making the compounds (as well as compositions comprising the compounds) described herein.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter.
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • Compounds described herein e.g., Formulae I, II, III and variations thereof
  • processes well-known in the chemical arts can be used, in addition to, or in light of, the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)), or Comprehensive Heterocyclic Chemistry, Editors Katrizky and Rees, Pergamon Press, 1984.
  • Compounds described herein may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds described herein (e.g., Formulae I, II, III and variations thereof).
  • Libraries of compounds described herein may be prepared by a combinatorial "split and mix approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds described herein (e.g., Formulae I, II, III and variations thereof), enantiomers, diasteriomers or pharmaceutically acceptable salts thereof.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • reaction Schemes 1-5 depicted below provide routes for synthesizing the compounds of Formulae I, II, III and variations thereof, as well as key intermediates.
  • reaction Schemes 1-5 depicted below provide routes for synthesizing the compounds of Formulae I, II, III and variations thereof, as well as key intermediates.
  • the amine displacement of methyl sulfone and the palladium-catalyzed coupling reaction can be carried out in one-pot, by mixing all the starting materials together and then heating the reaction mixture to 150 °C, typically done in a microwave irradiator.
  • Bromide 6 can be coupled with BocNH 2 in the presence of catalytic amount of Pd 2 (dba) 3 and xantphos, followed by subsequent reaction with TFA which leads to amine 7 (Scheme 3).
  • Compound 7 can react with an acid chloride to provide amide 4.
  • the amino group in 7 can also be coupled with an aryl chloride, under palladium-catalyzed conditions, to give 5.
  • compound 7 when treated with an isocyanate, compound 7 is transformed to urea 8.
  • C5-substituted pyridine also undergoes reaction with potassium ethyl xanthate, followed by methylation to give methyl sulphide 9 (Scheme 4).
  • Oxidation of methyl sulphide to methyl sulfone with urea hydrogen peroxide complex also leads to oxidation of pyridine to its corresponding N-oxide.
  • pyridine N-oxide 10 is transformed to compound 11.
  • the methyl sulfone in compound 11 can be displaced with an amine to give compound 12.
  • chloride 12 undergoes palladium-catalyzed coupling reactions, with an amide or an amine, to give compounds 13 or 14.
  • methyl sulfone 10 can also react with an amine, followed by treatment with POBr 3 that leads to bromide 15. Bromide 15 undergoes palladium-catalyzed coupling reactions with an amide or an amine to yield targ 13 or 14.
  • Scheme 5 outlines the preparation of compounds such as 20 and 21.
  • Benzothiazole is treated with w-butyllithium at -78 °C, followed by addition of a ketone to provide alcohol 16.
  • Alcohol is deoxygenated via a 2-step process.
  • dehydration of 16 leads to an olefin which is hydrogenated to give 17.
  • Oxidation of 17 with hydrogen peroxide in the presence of MeRe0 3 provides N-oxide 18.
  • N-oxide 18 undergoes rearrangement to give 2-iert-butylaminopyridine, which is deprotected with TFA to furnish amine 19.
  • Reaction of amine 19 with an acid chloride yields amide 20.
  • the amino group in 19 can be coupled with an aryl chloride, under palladium-catalyzed conditions, to provide compound 21.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S., Stereochemistry of Organic
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
  • Diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a- methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, -methoxy- -(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem. 47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers.
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • Another embodiment includes a method of manufacturing a compound of Formula I.
  • the method includes: a) reacting a compound of formula (i):
  • Lv is a leaving group, for example a halogen
  • X, R 1 , R2 and R 3 are as defined for Formula I, with a compound of the formula H-R 4 -R 5 under conditions sufficient to form a compound of Formula I; and (b) optionally further functionalizing said above compound.
  • Certain embodiments include a compound of formula (i), stereoisomers or pharmaceutically acceptable salts thereof. Certain embodiments include a compound of formula (i), stereoisomers or pharmaceutically acceptable salts thereof, wherein X, R 1 , R2 and R 3 are as defined for Formula I and the group -Lv is a halogen, -OR or -OS(0)i_ 2 R, wherein R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted. In certain embodiments, the group -Lv is halogen. Certain embodiments include a compound of formula (i) wherein the group -Lv is -Br or -I.
  • the conditions for reacting a compound of formula (i) with a compound of the formula H-R 4 -R 5 include transition metal catalyzed reaction conditions.
  • the transition metal catalyst is selected from a platinum, palladium or copper catalyst.
  • the catalyst is a Pd(0) catalyst.
  • Pd(0) catalysts for use in the method include tetrakis(tri-optionally substituted phenyl)phosphine palladium(O) catalyst, wherein said optional substituents on phenyl are selected from -OMe, -CF 3 , -OCF 3 , -Me and -Et and dipalladium(O) catalysts, such as tris(dibenzylideneacetone)dipalladium(0).
  • the conditions include heating the reactants under basic conditions, for example, in the presence of an inorganic base, for example, a cesium, potassium, ammonium, or sodium carbonate or bicarbonate base, for example Cs 2 C0 3 .
  • the conditions further include ligands to the transition metal catalyst.
  • a bidentate ligand is included, for example, the bidentate ligand xantphos is added.
  • compositions of any of the compounds detailed herein are embraced by this invention.
  • the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and
  • compounds of described herein may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical
  • the pH of the formulation depends on the particular use and the concentration of compound, and can range anywhere from about 3 to about 8.
  • a compound described herein e.g., Formulae I, II, III and variations thereof
  • the compounds described herein are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit TYK2 kinase activity. For example, such amount may be below the amount that is toxic to normal cells, or the patient as a whole.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound described herein (e.g., Formulae I, II, III and variations thereof) , which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • a compound described herein e.g., Formulae I, II, III and variations thereof
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • polyesters for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)
  • polylactides copolymers of L-glutamic acid and gamma-ethyl-L-glutamate
  • non-degradable ethylene-vinyl acetate non-degradable ethylene-viny
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, contain from about 5-100 mg of the compound of the invention.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, aerosols, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical
  • composition thereof or aid in the manufacturing of the pharmaceutical product (i.e.,
  • An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compound of the invention compounded with about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g., a phosphate buffer, adding a tonicifier, e.g., a salt such sodium chloride, if desired.
  • a suitable buffer solution e.g., a phosphate buffer
  • a tonicifier e.g., a salt such sodium chloride
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • the pharmaceutical composition also includes an additional therapeutic agent.
  • the additional therapeutic agent is selected from an anti- proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of Formulae I, II, III or variations thereof, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formulae I, II, III or variations thereof, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment includes a pharmaceutical composition comprising a compound of Formulae I, II, III or variations thereof, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of an immunological or inflammatory disease.
  • Another embodiment includes a pharmaceutical composition comprising a compound of Formulae I, II, III or variations thereof, or a stereoisomer or pharmaceutically acceptable salt thereof for use in the treatment of psoriasis or inflammatory bowel disease.
  • Compounds and compositions of the invention may be used in methods of administration and treatment as provided herein.
  • the compounds described herein e.g., Formulae I, II, III and variations thereof
  • inhibit TYK2 kinase activity Accordingly, the compounds are useful for reducing inflammation in particular patient tissue and cells.
  • Compounds described herein e.g., Formulae I, II, III and variations thereof
  • compounds are useful for inhibiting TYK2 kinase activity in cells in which, for example, the type I interferon, IL-6, IL-10, IL-12 and IL-23 signaling pathway is disruptive or abnormal, for example by binding to TYK2 kinase and inhibiting its activity.
  • the compounds described herein e.g., Formulae I, II, III and variations thereof
  • the invention provides methods of treatment of a disease responsive to the inhibition of TYK2 kinase activity in a patient.
  • a method of treating a disease responsive to the inhibition of TYK2 kinase activity in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., or a compound of Formulae I, II, III or variations thereof), or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., or a compound of Formulae I, II, III or variations thereof
  • a stereoisomer, tautomer, solvate or prodrug thereof e.g., a compound of Formulae I, II, III or variations thereof
  • a method of treating a disease responsive to the inhibition of TYK2 kinase activity in a patient comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g., or a compound of Formulae I, II, III or variations thereof), or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the composition further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • a method of treating or lessening the severity of a disease or condition responsive to the inhibition of TYK2 kinase activity in a patient includes the step of administering to a patient a therapeutically effective amount of a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof.
  • a compound of Formula I, II, or III, or any variation thereof described herein is administered to a patient in a therapeutically effective amount to treat or lessen the severity of a disease or condition responsive to the inhibition of TYK2 kinase activity, and the compound is at least 15 fold, alternatively 10 fold, alternatively 5 fold or more selective in inhibiting TYK2 kinase activity over inhibiting each of the other Janus kinase activities.
  • a compound of Formula I, II, or III, or any variation thereof described herein is administered to a patient in a therapeutically effective amount to treat or lessen the severity of a disease or condition responsive to the inhibition of TYK2 kinase activity, and the compound is at least 15 fold, alternatively 10 fold, alternatively 5 fold or more selective in inhibiting TYK2 kinase activity over inhibiting JAKl.
  • a compound of Formula I, II, or III, or any variation thereof described herein is administered to a patient in a therapeutically effective amount to treat or lessen the severity of a disease or condition responsive to the inhibition of TYK2 kinase activity, and the compound is at least 15 fold, alternatively 10 fold, alternatively 5 fold or more selective in inhibiting TYK2 kinase activity over inhibiting JAK2.
  • a compound of Formula I, II, or III, or any variation thereof described herein is administered to a patient in a therapeutically effective amount to treat or lessen the severity of a disease or condition responsive to the inhibition of TYK2 kinase activity, and the compound is at least 15 fold, alternatively 10 fold, alternatively 5 fold or more selective in inhibiting TYK2 kinase activity over inhibiting JAK3.
  • the disease responsive to the inhibition of TYK2 kinase activity is an inflammatory disease.
  • the disease responsive to the inhibition of TYK2 kinase activity is asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, lupus or multiple sclerosis.
  • Another embodiment includes a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof for use in therapy.
  • Another embodiment includes a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof for use in treating an
  • Another embodiment includes a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof for use in treating psoriasis or inflammatory bowel disease.
  • Another embodiment includes the use of a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof for treating an
  • Another embodiment includes the use of a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof for treating psoriasis or inflammatory bowel disease.
  • Another embodiment includes the use of a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof in the preparation of a medicament for the treatment of an immunological or inflammatory disease.
  • Another embodiment includes the use of a compound of Formula I, II, or III, or any variation thereof described herein, or stereoisomers, tautomers or salts thereof in the preparation of a medicament for the treatment of psoriasis or inflammatory bowel disease.
  • the disease or condition is stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, immunological disease, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammatory disease, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.
  • the disease or condition is an immunological disorder.
  • the disease is a myeloproliferative disorder.
  • the myeloproliferative disorder is polycythemia vera, essential
  • the disease is asthma.
  • the cardiovascular disease is restenosis, cardiomegaly, atherosclerosis, myocardial infarction or congestive heart failure.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.
  • the inflammatory disease is inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, contact dermatitis or delayed hypersensitivity reactions.
  • the inflammatory disease is asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis or delayed hypersensitivity reactions.
  • the autoimmune disease is lupus.
  • the disease is asthma, inflammatory bowel disease, Crohn's disease, pouchitis, microscopic colitis, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, lupus or multiple sclerosis.
  • Evaluation of drug-induced immunosuppression by the compounds of the invention may be performed using in vivo functional tests, such as rodent models of induced arthritis and therapeutic or prophylactic treatment to assess disease score, T cell-dependent antibody response (TDAR), and delayed-type hypersensitivity (DTH).
  • TDAR T cell-dependent antibody response
  • DTH delayed-type hypersensitivity
  • These assays may comprise B or T cell proliferation in response to mitogens or specific antigens, measurement of signaling through one or more of the Janus kinase pathways in B or T cells or immortalized B or T cell lines, measurement of cell surface markers in response to B or T cell signaling, natural killer (NK) cell activity, mast cell activity, mast cell degranulation, macrophage phagocytosis or kill activity, and neutrophil oxidative burst and/or chemo taxis.
  • NK natural killer
  • NK natural killer
  • mast cell activity mast cell activity
  • mast cell degranulation macrophage phagocytosis or kill activity
  • neutrophil oxidative burst and/or chemo taxis may be included.
  • the in vitro and ex vivo assays can be applied in both preclinical and clinical testing using lymphoid tissues and/or peripheral blood (House RV. "Theory and practice of cytokine assessment in immunotoxicology” (1999) Methods 19: 17-27; Hubbard AK. "Effects of xenobiotics on macrophage function: evaluation in vitro” (1999) Methods;19:8-16; Lebrec H, et al (2001 ) Toxicology 158 :25-29) .
  • Collagen-induced arthritis is an animal model of human rheumatoid arthritis (RA). Joint inflammation, which develops in animals with CIA, strongly resembles inflammation observed in patients with rheumatoid arthritis (RA). Blocking tumor necrosis factor (TNF) is an efficacious treatment of CIA, just as it is a highly efficacious therapy in treatment of RA patients.
  • CIA is mediated by both T-cells and antibodies (B-cells). Macrophages are believed to play an important role in mediating tissue damage during disease development.
  • CIA is induced by immunizing animals with collagen emulsified in Complete Freund's Adjuvant (CFA). It is most commonly induced in the DBA/1 mouse strain, but the disease can also be induced in Lewis rats.
  • CFA Complete Freund's Adjuvant
  • the T-cell Dependent Antibody Response is An assay for immune function testing when potential immunotoxic effects of compounds need to be studied.
  • TDAR is an assay for adult exposure immunotoxicity detection in mice based on the US National Toxicology Program (NTP) database (M.I. Luster et al (1992) Fundam. Appl. Toxicol. 18:200-210).
  • NTP National Toxicology Program
  • a TDAR is dependent on functions of the following cellular compartments: (1) antigen-presenting cells, such as macrophages or dendritic cells; (2) T-helper cells, which are critical players in the genesis of the response, as well as in isotype switching; and (3) B-cells, which are the ultimate effector cells and are responsible for antibody production.
  • antigen-presenting cells such as macrophages or dendritic cells
  • T-helper cells which are critical players in the genesis of the response, as well as in isotype switching
  • B-cells which are the ultimate effector cells and are responsible for antibody production.
  • Chemically-induced changes in any one compartment can cause significant changes in the overall TDAR (M.P. Holsapple In: G.R. Burleson, J.H. Dean and A.E. Munson, Editors, Modem Methods in Immunotoxicology, Volume 1, Wiley-Liss Publishers, New York, NY (1995), pp. 71-108).
  • this assay is performed either as an ELISA for measurement of soluble antibody (R.J. Smialowizc et al (2001) Toxicol. Sci. 61: 164-175) or as a plaque (or antibody) forming cell assay (L. Guo et al (2002) Toxicol. Appl. Pharmacol. 181:219-227) to detect plasma cells secreting antigen specific antibodies.
  • the antigen of choice is either whole cells (e.g., sheep erythrocytes) or soluble protein antigens (T. Miller et al (1998) Toxicol. Sci. 42: 129-135).
  • the compounds described herein may be administered by any route appropriate to the disease or condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, inhaled, intralesional, and intranasal.
  • routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, inhaled, intralesional, and intranasal.
  • the compounds may be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation. It will be appreciated that the route may vary with, for example, the condition of the recipient.
  • the compound may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form.
  • a dose to treat human patients may range from about 5 mg to about 1000 mg of a compound described herein (e.g., a compound of Formula I, II or III or any variation thereof).
  • a typical dose may be about 5 mg to about 300 mg of a compound described herein (e.g., a compound of Formulae I, II, III and variations thereof).
  • a dose may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound.
  • QD once a day
  • BID twice per day
  • toxicity factors may influence the dosage and administration regimen.
  • the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
  • the compounds described herein may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, such as an immunologic disorder (e.g., psoriasis or inflammation).
  • the compound is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second therapeutic compound that has antiinflammatory properties or that is useful for treating an inflammation or immune-response disorder.
  • the second therapeutic agent may be a NSAID or other anti-inflammatory agent.
  • the second therapeutic agent of the pharmaceutical combination formulation or dosing regimen can have complementary activities to the compound of Formula I, II or III or any variation thereof such that they do not adversely affect each other.
  • a composition of this invention comprises a compound of Formula I, II or III or any variation thereof, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent such as an NSAID.
  • a therapeutic agent such as an NSAID.
  • Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of TYK2 kinase in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, II or III or any variation thereof described herein, and further comprising, administering a second therapeutic agent.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • the combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein there is a time period while both (or all) active agents simultaneously exert their biological activities.
  • Suitable dosages for any of the above coadministered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemo therapeutic agents or treatments.
  • a compound of Formula I, II or III or any variation thereof described herein, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof may be combined with other therapeutic, hormonal or antibody agents such as those described herein, as well as combined with surgical therapy and radiotherapy.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I, II or III or any variation thereof described herein, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other immunological disorder method.
  • the amounts of the compound(s) of Formula I, II or III or any variation thereof described herein and the other pharmaceutically active immunologic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • compounds of the present invention are coadministered with any of anti- IBD agents, including but not limited to anti-inflammatory drugs, such as sulfasalazine, mesalamine or corticosteroids, such as budesonide, prednisone, cortisone or hydrocortisone, immune suppressing agents, such as azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol, methotrexate, cyclosporine or natalizumab, antibiotics, such as
  • metronidazole or ciprofloxacin such as psyllium powder, loperamide or methylcellulose
  • laxatives such as NSAIDs or acetaminophen
  • pain relievers such as NSAIDs or acetaminophen
  • iron supplements such as vitamin B supplements, vitamin D supplements and any combination of the above.
  • compounds of the present invention are administered with (e.g., before, during or after) other anti-IBD therapies, such as surgery.
  • compounds of the present invention are coadministered with any of anti- psoriasis agents, including but not limited to topical corticosteroids, vitamin D analogues, such as calcipotriene or calcitriol, anthralin, topical retinoids, such as tazarotene, calcineurin inhibitors, such as tacrolimus or pimecrolimus, salicylic acid, coal tar, NSAIDs, moisturizing creams and ointments, oral or injectible retinoids, such as acitretin, methotrexate, cyclosporine, hydroxyurea, immunomodulator drugs, such as alefacept, etanercept, infliximab or ustekinumab, thioguanine, and any combinations of the above.
  • topical corticosteroids including but not limited to topical corticosteroids, vitamin D analogues, such as calcipotriene or calcitriol, anth
  • compounds of the present invention are administered with (e.g., before, during or after) other anti-psoriasis therapies, such as light therapy, sunlight therapy, UVB therapy, narrow-band UVB therapy, Goeckerman therapy, photochemotherapy, such as psoralen plus ultraviolet A (PUVA), excimer and pulsed dye laser therapy, or in any combination of antipsoriasis agents and anti-psoriasis therapies.
  • compounds of the present invention are coadministered with any of antiasthmatic agents, including but not limited to beta2- adrenergic agonists, inhaled and oral corticosteroids, leukotriene receptor antagonist, and omalizumab.
  • compounds of the present invention are coadministered with an anti- asthmatic agent selected from a NSAID, combinations of fluticasone and salmeterol, combinations of budesonide and formoterol, omalizumab, lebrikizumab and corticosteroid selected from fluticasone, budesonide, mometasone, flunisolide and beclomethasone. Kits
  • kits for carrying out the methods of the invention which comprises one or more compounds described herein (e.g., Formulae I, II, III and variations thereof) or a pharmacological composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein (e.g., Formulae I, II, III and variations thereof) or a pharmaceutically acceptable salt thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of diseases, conditions and/or disorders responsive to the inhibition of TYK2 kinase activity in a patient.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein (e.g., Formulae I, II, III and variations thereof) and/or a second
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • kits for treating a disease or disorder responsive to the inhibition of aTYK2 kinase includes:
  • the kit further includes:
  • a second pharmaceutical composition which includes an immunologic agent.
  • the instructions include instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof.
  • first and second compositions are contained in separate containers. In one embodiment, the first and second compositions are contained in the same container.
  • Containers for use include, for example, bottles, vials, syringes, blister pack, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container includes a compound of Formula I or formulation thereof which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container includes a composition comprising at least one compound of Formula I.
  • the label or package insert indicates that the composition is used for treating the condition of choice, such as lupus.
  • the label or package inserts indicates that the composition comprising the compound of Formula I can be used to treat a disorder.
  • the label or package insert may indicate that the patient to be treated is one having a disorder characterized by overactive or irregular kinase activity.
  • the label or package insert may also indicate that the composition can be used to treat other disorders.
  • articles of manufacture comprising a compound of Formula I, II or III or any variation thereof described herein, or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • the article of manufacture may comprise (a) a first container with a compound of Formula I, II or III, or any variation thereof described herein, contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises an immunologic agent.
  • the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the first and second compounds can be used to treat patients at risk of stroke, thrombus or thrombosis disorder.
  • the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • Ringer's solution such as phosphate
  • Xantphos 4, 5 -B is(diphenylphosphino)-9 ,9 -dimethylxanthene
  • LCMS High Pressure Liquid Chromatography - Mass Spectrometry
  • Method A Experiments performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector.
  • the spectrometer has an electrospray source operating in positive and negative ion mode.
  • This system uses an Acquity BEH C18 1.7 ⁇ 100 x 2.1mm column, maintained at 40°C or an Acquity BEH Shield RP18 1.7 ⁇ 100 x 2.1mm column, maintained at 40°C and a 0.4 ml / minute flow rate.
  • the initial solvent system was 95% water containing 0.1 % formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was maintained for 0.8 minute before returning to 95% solvent A and 5% solvent B over the next 1.2 minutes. Total run time was 8 minutes.
  • Method B Experiments performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with a diode array and a Sedex 85 evaporative light scattering detector.
  • the spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Phenomenex Luna 3 micron CI 8(2) 30 x 4.6mm column and a 2 ml / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4.0 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.
  • Method C Experiments performed on a VG Platform II quadrupole mass spectrometer linked to a Hewlett Packard HP 1050 LC system with diode array detector and 100 position autosampler, using a Phenomenex Luna 3 ⁇ C 18 (2) 30 x 4.6mm and a 2 mL/minute flow rate.
  • the mobile phase consisted of formic acid 0.1% in water (solvent A) and formic acid 0.1% in acetonitrile (solvent B).
  • the initial solvent system was 95% solvent A and 5% solvent B for the first 0.3 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes.
  • the final solvent system was held constant for a further 1 minute.
  • Method D column: AgilentSD-C18, 2.1 X 30 mm, 1.8 um; mobile phase: A water with 0.5% TFA, B CH 3 CN with 0.5% TFA in 8.5 min; flow rate 0.4 mL/min; oven temperature 40 °C.
  • Method E column: XBridge C18, 4.6 X 50 mm, 3.5 um; mobile phase: A water (0.01% ammonia), B CH 3 CN; gradient: 5%-95% B in 8.0 min; flow rate: 1.2 mL/min; oven temperature 40 °C.
  • Method F column: XBridge C18, 4.6 X 50 mm, 3.5 um; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH 3 CN; gradient: 5%-95% B in 8.0 min; flow rate: 1.2 mL/min; oven temperature 40 °C.
  • Method G column: XBridge C18, 4.6 X 50 mm, 3.5 um; mobile phase: A water (0.05% TFA), B CH 3 CN (0.05% TFA); gradient: 5%-100% B in 1.6 min and hold at 100% AcCN for 1.4 min; flow rate: 2 mL/min; oven temperature 40 °C.
  • Method H column: Phenomenex Onyx Monolithic C18, 4.6 X 50 mm, 3.5 um; mobile phase: A water (0.05% TFA), B CH 3 CN (0.037% TFA); gradient: 2%-98% B in 3.2 min and hold at 98% AcCN for 0.4 min; flow rate: 2 mL/min; temperature 23 °C.
  • Retention time for each enantiomer was determined using either SFC or HPLC with a chiral column.
  • the column and mobile phases used for each enantiomer are specified below in the Examples. Conditions are: column dimension: 4.6x50 mm, 3 um; flow rate: 5 mL/min; pressure: 120 bars; temperature: 40 °C.
  • Microwave experiments were carried out using a Biotage Initiator 60TM which uses a single- mode resonator and dynamic field tuning. Temperature from 40-250°C can be achieved, and pressures of up to 30 bar can be reached.
  • Step 1 4-chlorothiazolo[5,4-c]pyridine-2(lH)-thione
  • a mixture of 3-bromo-2-chloropyridin- 4-amine (10 g, 48.2 mmol) and potassium ethyl xanthate (16.2 g, 101.2 mmol) in NMP (60 mL) was heated to 180 °C for 20 min when the reaction mixture turned dark red.
  • the reaction mixture was cooled to 23 °C, poured into water and AcOH (10% v/v, 600 mL).
  • the resulting precipitate was collected by filtration to give the desired product (8.37 g, 86 % yield) as grey solid.
  • LCMS (Method G): RT 1.36 min, m/z: 202 [M+H + ].
  • Step 3 4-chloro-2-(methylsulfonyl)thiazolo[5,4-c]pyridine
  • mCPBA 31 g, 138 mmol
  • the mixture was stirred for 1 hour at 0 °C and then 3 hours at 23 °C to give a white suspension.
  • the reaction mixture was filtered and the cake washed with DCM (30 mLx 3). The filtrate was washed with aq. Na 2 S 2 0 3 solution (10%, 200 mL), sat.
  • the reaction mixture was diluted with aq. Na 2 C0 3 solution (1M, 50 mL) and extracted with EtOAc (3x50 mL). Combined organic layers were dried over Na 2 S0 4 , filtered and concentrated.
  • the crude product was purified by chiral SFC (Phenomenex Lux-Cellulose-3 (21.2 x 150 mm, 5 urn), 30% Methanol w/ 0.1% NH OH / 70% C0 2 (flow rate 70 mL/min, 100 Bars, column temperature 40 °C) to separate the two enantiomers.
  • (+)-l-(4-chlorothiazolo[5,4-c]pyridin-2-yl)piperidine-3-carbonitrile could also be prepared by a one-pot procedure: A mixture of 4-chloro-2-methylsulfonyl-thiazolo[5,4- c]pyridine (100 mg, 0.4 mmol), piperidine-3-carbonitrile (49 mg, 0.4 mmol), potassium carbonate (117 mg, 0.8 mmol), Xantphos (6 mg, 0.01 mmol), Cs 2 C0 3 (397 mg, 1.2 mmol), 4,6- diaminopyrimidine (133 mg, 1.2 mmol) and Pd 2 (dba) 3 (12 mg, 0.01 mmol) in DMF (1 mL) and 1,4-dioxane (1 mL) was heated in a microwave reactor at 150 °C for 10 minutes.
  • the crude material was further purified by chiral SFC (Column: Chiralpak IB 21.2 x 150mm, 5 urn, mobile Phase: 30% Methanol w/ 0.1% NH 4 OH / 70% C0 2 , flow rate 70 mL/min, pressure: 100 Bars, temp: 40 °C) to give pure enantiomers.
  • Step 1 4-bromo-2-(methylthio)thiazolo[5,4-c]pyridine.
  • 4-chloro-2- methylsulfanyl-thiazolo[5,4-c]pyridine 5.0 g, 23.1 mmol
  • propionitrile 70 mL
  • bromo(trimethyl)silane 17.7 g, 115 mmol
  • the reaction mixture was heated at 115 °C under N 2 .
  • additional TMSBr 5.0 g, 32 mmol
  • Step 4 (+)-l-(4-aminothiazolo[5,4-c]pyridin-2-yl)piperidine-3-carbonitrile.
  • (+)-l-(2-(3-cyanopiperidin-l-yl)thiazolo[5,4-c]pyridin-4-yl)-3-isopropylurea To a suspension of l-(4-aminothiazolo[5,4-c]pyridin-2-yl)piperidine-3-carbonitrile (50 mg, 0.19 mmol) in 1,2-dichloroethane (3 mL) was added 2-isocyanatopropane (100 mg, 1.16 mmol). The mixture was heated at 80 °C under N 2 for 18 hours.
  • Step 1 7-Fluoro-lH-thiazolo[5,4-c]pyridine-2-thione.
  • NMP NMP
  • potassium ethyl xanthate 8.71 g, 54.0 mmol.
  • the reaction mixture was heated in the microwave reactor at 200 °C for 20 minutes, then cooled to room temperature and poured into water. After stirring for 10 minutes, the product was collected by filtration and washed with water. The product was dried in vacuo to afford the title compound as a pale yellow powder (2.97 g, 43% yield).
  • Step 4 4-Chloro-7-fluoro-2-methanesulfonylthiazolo[5,4-c]pyridine.
  • dichloroethane 100 mL
  • phosphorus oxychloride 4.0 mL, 42 mmol
  • the resultant mixture was allowed to cool to room temperature, quenched with ice and was then extracted with DCM (x2).
  • the combined organic extracts were dried (MgS0 4 ), filtered and concentrated in vacuo.
  • Step 5 ( ⁇ )-l-(4-Chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl) ⁇ iperidine-3-carbonitrile.
  • 4-chloro-7-fluoro-2-methanesulfonylthiazolo[5,4-c]pyridine (1.10 g, 4.1 mmol) in acetonitrile (5.0 mL) was added potassium carbonate (1.09 g, 7.9 mmol) and 3-cyanopiperidine (0.50 g, 4.6 mmol).
  • the reaction mixture was stirred at room temperature for 1 hour before pouring into water.
  • (+)-l-[4-(6-Aminopyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2-yl]- piperidine-3-carbonitrile A mixture of (+)-l-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)- piperidine-3-carbonitrile (0.332 g, 1.1 mmol), Xantphos (64 mg, 0.11 mmol), Cs 2 C0 3 (0.796 g, 2.44 mmol) and 6-amino-(pyrimidin-4-yl)-b 5 , -carbamic acid iert-butyl ester (0.341 g, 1.09 mmol) was purged with argon for two minutes.
  • Step 1 ( ⁇ )-l-[4-(6-Amino-2-methylpyrimidin-4-yl)- >is-carbamic acid tert-butyl ester-7- fluoro-thiazolo[5,4-c]pyridin-2-yl]-piperidine-3-carbonitrile.
  • Step 2 ( ⁇ )-l-[4-(6-Amino-2-methylpyrimidin-4-ylamino)-7-fluorothiazolo[5,4-c]pyridin-2- yl]-piperidine-3-carbonitrile.
  • (+)-l-[4-(6-amino-2-methylpyrimidin-4-ylamino)-7- fluorothiazolo[5,4-c]pyridin-2-yl]-piperidine-3-carbonitrile was the title compound as an off-white solid (6.0 mg, 8% yield).
  • Step 1 ( ⁇ )-l-(7-Fluoro-5-oxythiazolo[5,4 ]pyridin-2-yl)-piperidine-3-carbonitrile.
  • 3-cyanopiperidine (1.11 g, 10.1 mmol) in acetonitrile (20 mL) was added 7-fluoro-2- methanesulfonylthiazolo[5,4-c]pyridine-5-oxide (2.53 g, 10.2 mmol).
  • the reaction mixture was stirred at room temperature for 3 hours and then partitioned between DCM and water.
  • the aqueous layer was extracted with DCM (x2) and the combined organic extracts were dried (MgS0 4 ) and concentrated to dryness under reduced pressure.
  • Step 2 ( ⁇ )-l-(4-Bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl) ⁇ iperidine-3-carbonitrile.
  • (+)-l-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-piperidine-3-carbonitrile (1.50 g, 5.4 mmol) in acetonitrile (60 mL) was added phosphorus oxybromide (4.14 g, 14.4 mmol) and the reaction mixture was heated at 80 °C for 1 hour.
  • a second portion of phosphorus oxybromide was added (2.56 g, 9.0 mmol) and the reaction mixture heated at 80 °C for another 1 hour.
  • a third portion of phosphorus oxybromide was then added (5.21 g, 18 mmol), and after heating at 80 °C for additional 1 hour, the reaction mixture was cooled to room temperature and then poured onto ice.
  • the resultant mixture was extracted with ethyl acetate and the organic extracts were washed with water (x2), dried (MgS0 4 ) and concentrated to dryness under reduced pressure.
  • the resultant crude residue was triturated with propan-2-ol and dried to yield the title compound as a white powder (1.01 g, 55% yield).
  • the reaction mixture was purged with argon for five minutes, and then heated at 80 °C for 20 hours.
  • the resultant mixture was poured into ethyl acetate, dried (MgS0 4 ) and concentrated to dryness.
  • the crude residue was dissolved in DCM (5 mL), TFA (5 mL) was added and the reaction mixture stirred at room temperature for lh.
  • the resultant mixture was diluted with DCM and washed with saturated sodium hydrogen carbonate solution.
  • the aqueous layer was further extracted with DCM and the combined organic extracts were dried (MgS0 4 ) and concentrated to dryness.
  • Step 1 3-Carbamoyl-5-methylpiperidine-l-carboxylic acid tert-butyl ester (mixture of cis and trans isomers).
  • 5-methylnicotinamide 3.05 g, 22.4 mmol
  • absolute ethanol 110 mL
  • platinum oxide 0.98 g, 3.07 mmol
  • concentrated sulphuric acid 4 mL
  • the reaction mixture was stirred under an atmosphere of hydrogen (3.8 bar pressure) for 24 hours.
  • the resultant mixture was then purged with nitrogen, filtered through a pad of Celite, washed with propan-2-ol (x2) and concentrated under reduced pressure.
  • the reaction mixture was poured into ethyl acetate, dried (MgS0 4 ) and concentrated under reduced pressure.
  • the resultant residue was dissolved in DCM (5 mL) and TFA (5 mL) was then added.
  • the resultant mixture was stirred for 3 hours and then quenched with saturated sodium bicarbonate solution, before extracting with ethyl acetate (x6).
  • the combined organic extracts were dried (MgS0 4 ) and then concentrated under reduced pressure.
  • Step 1 Methyl l-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-hydroxypiperidine-3-carboxylate (mixture of cis and trans isomers).
  • the mixture of 4-chloro-2-methylsulfonyl-thiazolo[5,4- c]pyridine (2.02 g, 8.1 mmol), methyl 5-hydroxypiperidine-3-carboxylate hydrochloride (1.9 g, 9.3 mmol) and K 2 C0 3 (2.8 g, 20.3 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The mixture was diluted with water, extracted with EtOAc (2x), DCM (2x).
  • Step 2 5-(Benzyloxy)-l-(4-chlorothiazolo[5,4-c]pyridin-2-yl)piperidine-3-carboxylic acid (mixture of cis and trans isomers).
  • a solution of cis- and trans-methyl l-(4- chlorothiazolo[5,4-c]pyridin-2-yl)-5-hydroxy-piperidine-3-carboxylate (1.8 g, 5.48 mmol) and benzyl bromide (3.75 g, 21.9 mmol) in THF (10 mL) at 0 °C was added NaH (60% in mineral oil, 0.88 g, 21.9 mmol) in one portion.
  • the reaction mixture was slowly warmed to room temperature and stirred for 1.5 h. The mix was then re-cooled to 0 °C. NH 4 OH (28% in water, 4 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with water. The precipitated solid was collected by filtration, washed with water, dried in high vacuum to give the title compound (0.97 g, 44% yield) as a pale yellow solid.
  • Step 5 N-(2-(3-(Benzyloxy)-5-cyanopiperidin-l-yl)thiazolo[5,4-c]pyridin-4- yl)cyclopropanecarboxamide (mixture of cis and trans isomers).
  • Step 1 7-(4-Chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazine.
  • trans-Cyclopropanecarboxylic acid (2- ⁇ (2-cyanoethyl)-[4-(2-methanesulfonylethyl)- cyclohexyl]-amino ⁇ -7-fluorothiazolo[5,4-c]pyridin-4-yl)-amide
  • Step 1 trans- (4-Chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-[4-(2-methanesulfonylethyl)- cyclohexyl] -amine.
  • Step 2 tra «s-3- ⁇ (4-Chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-[4-(2-methanesulfonylethyl)- cyclohexyl]-amino ⁇ -propionitrile.
  • Step 3 trans- Cyclopropanecarboxylic acid (2- ⁇ (2-cyanoethyl)-[4-(2-methanesulfonylethyl)- cyclohexyl]-amino ⁇ -7-fluorothiazolo[5,4-c]pyridin-4-yl)-amide.
  • the mix was heated at 85 °C for 1 hour, then at 75 °C for 16 hours.
  • the reaction mixture was cooled to 23 °C, poured into sat. NaHC0 3 (100 mL), stirred for 10 min.
  • the aqueous layer was extracted with DCM (4x).
  • the combined organics were dried (Na 2 S0 4 ), filtered and concentrated.
  • the crude product was purified by silica flash chromatography (0-5% EtOAc/DCM) to give the title compound (1.04 g, 43% yield) as a white solid.
  • the mixture was sealed and irradiated in a microwave reactor at 100 °C for 40 min.
  • the reaction mixture was diluted with EtOAc (20 mL) and filtered.
  • the filtrate was concentrated to give a yellow residue which was dissolved in DCM (3 mL).
  • TFA (1 mL) was added dropwise and the mixture was stirred at 23 °C for 16 hours.
  • the reaction mixture was diluted with aq. Na 2 C0 3 solution (1M, 10 mL) and extracted with EtOAc (3x10 mL). Combined organic layers were dried over Na 2 S0 4 , filtered and concentrated.
  • the crude product was purified by chiral SFC (Chiralpax OJ 21.2 x 250 mm, 5 um @ 30% methanol with 0.1% NH 4 OH at 60 mL/min, 100 bars, 254 nm, 40 °C) to separate the two enantiomers.
  • the tube was sealed and heated at 140 °C in a microwave for 40 min.
  • the reaction mixture was cooled to room temperature, filtered through celite, washed with EtOAc, concentrated.
  • the residue was dissolved in DCM (3 mL), TFA (0.6 mL) was added.
  • the reaction mixture was stirred at 23 °C for 16 hours.
  • the reaction mixture was diluted with aq. Na 2 C0 3 solution (1M, 10 mL) and extracted with EtOAc (3x10 mL). Combined organic layers were dried over Na 2 S0 4 , filtered and concentrated.
  • the crude product was purified by chiral SFC (Chiralpax AD 21.2 x 250 mm, 5 um 45% methanol with 0.1% NH 4 OH / 55% C0 2 ) to separate the two enantiomers.
  • Step 1 l-Thiazolo[5,4-c]pyridin-2-yl-cyclohexanol.
  • thiazolo[5,4-c]pyridine (0.60 g, 4.41 mmol) in diethyl ether (50 mL) at -78 °C was added drop-wise w-butyllithium (2.5 N in hexanes, 1.9 mL, 4.63 mmol) and the reaction mixture was kept at -78 °C for 30 minutes.
  • Step 7 Cyclopropanecarboxylic acid (2-cyclohexylthiazolo[5,4-c]pyridin-4-yl)-amide.
  • a solution of cyclohexylthiazolo[5,4-c]pyridin-4-ylamine (19 mg, 0.08 mmol) and DIPEA (21 ⁇ , 0.16 mmol) in THF (1.0 mL) was added a solution of cyclopropanecarbonyl chloride (22 mg, 0.20 mmol) in THF (1.0 mL) and the reaction mixture was stirred at room temperature for 2 hours. After this time, HC1 (12 N, 0.5 mL) was added and the reaction mixture was stirred at 50 °C for 1 hour.
  • Step 2 l-(4-Aminothiazolo[5,4-c]pyridin-2-yl)-cyclohexanol.
  • l-(5- Oxythiazolo[5,4-c]pyridin-2-yl)-cyclohexanol 252 mg, 1.01 mmol
  • ammonium hydroxide 33%, 1.0 mL
  • /7-toluenesulfonyl chloride (194 mg, 1.02 mmol
  • Step 1 ⁇ 6-[2-(l-Hydroxycyclohexyl) hiazolo[5,4 ]pyridin-4-ylamino] ⁇ yrimidin-4-yl ⁇ - >is- carbamic acid tert-butyl ester.
  • Step 2 l-[4-(6-Aminopyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-cyclohexanol.
  • ⁇ 6-[2-(l-hydroxycyclohexyl)-thiazolo[5,4-c]pyridin-4-ylamino]-pyrimidin-4-yl ⁇ -b 5'- carbamic acid iert-butyl ester 50 mg, 0.09 mmol
  • TFA 1.0 mL
  • Step 1 ( ⁇ )-ci * s/tra «s-2-Methyl-l-thiazolo[5,4-c]pyridin-2-yl-cyclohexanol.
  • thiazolo[5,4-c]pyridine (1.20 g, 8.82 mmol) in diethyl ether (100 mL) at -78 °C
  • w-butyllithium 2.5 N in hexanes, 4.24 mL, 10.6 mmol
  • Step 3 ( ⁇ )-cis/tra «s-2-(2-Methylcyclohexyl)-thiazolo[5,4-c]pyridine.
  • Step 7 ⁇ 6-[2 (lR,2R/lS,2S)-2-Methylcyclohexyl) hiazolo[5,4 ]pyridin-4-ylamino]- pyrimidin-4-yl ⁇ -Z>i * s-carbamic acid tert-butyl ester.

Abstract

L'invention porte sur des composés de thiazolopyridine qui sont des inhibiteurs de la kinase TYK2, sur des compositions contenant ces composés et sur des procédés pour le traitement de maladies à médiation par la kinase TYK2. En particulier, l'invention porte sur des composés de formule (I), (II) ou (III), ou des stéréoisomères, tautomères, solvates, promédicaments ou sels pharmaceutiquement acceptables de ces derniers, dans laquelle formule X, R0, R1, R2, R3, R4 et R5 sont tels que définis dans la description, sur des compositions pharmaceutiques comprenant le composé et un vecteur, adjuvant ou véhicule pharmaceutiquement acceptable, sur des procédés d'utilisation du composé ou de la composition en thérapie, par exemple pour le traitement d'une maladie ou affection à médiation par la kinase TYK2 chez un patient.
PCT/EP2014/078108 2013-12-18 2014-12-17 Composés de thiazolopyridine, compositions et leur utilisation comme inhibiteurs de la kinase tyk2 WO2015091584A1 (fr)

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US10508113B2 (en) 2018-03-12 2019-12-17 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling
WO2020222773A1 (fr) 2019-04-30 2020-11-05 Celgene Corporation Polythérapies comprenant de l'aprémilast et des inhibiteurs de tyk2
WO2021180143A1 (fr) * 2020-03-10 2021-09-16 明慧医药（上海）有限公司 Inhibiteur de kinase jak et préparation et application de celui-ci
WO2023036707A1 (fr) 2021-09-07 2023-03-16 Bayer Aktiengesellschaft 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines substituées, leurs sels et leur utilisation en tant que substances actives herbicides
WO2023055901A2 (fr) 2021-09-30 2023-04-06 Bristol-Myers Squibb Company Méthodes de détermination de réactivité à des inhibiteurs de tyk2
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

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WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
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RU2759443C2 (ru) * 2017-08-11 2021-11-12 Тайген Биотекнолоджи Ко., Лтд. Трансизомерные гетероциклические соединения и их получение
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WO2020222773A1 (fr) 2019-04-30 2020-11-05 Celgene Corporation Polythérapies comprenant de l'aprémilast et des inhibiteurs de tyk2
WO2020223431A1 (fr) 2019-04-30 2020-11-05 Celgene Corporation Polythérapies comprenant de l'aprémilast et des inhibiteurs de tyk2
WO2021180143A1 (fr) * 2020-03-10 2021-09-16 明慧医药（上海）有限公司 Inhibiteur de kinase jak et préparation et application de celui-ci
WO2023036707A1 (fr) 2021-09-07 2023-03-16 Bayer Aktiengesellschaft 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines substituées, leurs sels et leur utilisation en tant que substances actives herbicides
WO2023055901A2 (fr) 2021-09-30 2023-04-06 Bristol-Myers Squibb Company Méthodes de détermination de réactivité à des inhibiteurs de tyk2
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