WO2019183186A1 - Heterocyclic compounds comprising pyridine useful as modulators of il-12, il-23 and/or ifn alpha responses - Google Patents

Heterocyclic compounds comprising pyridine useful as modulators of il-12, il-23 and/or ifn alpha responses Download PDF

Info

Publication number
WO2019183186A1
WO2019183186A1 PCT/US2019/023111 US2019023111W WO2019183186A1 WO 2019183186 A1 WO2019183186 A1 WO 2019183186A1 US 2019023111 W US2019023111 W US 2019023111W WO 2019183186 A1 WO2019183186 A1 WO 2019183186A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
amino
alkyl
methyl
carboxamide
Prior art date
Application number
PCT/US2019/023111
Other languages
French (fr)
Inventor
Zili Xiao
Michael G. Yang
Chunjian C. LIU
Trevor C. Sherwood
John L. Gilmore
David S. Weinstein
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to KR1020207029906A priority Critical patent/KR20200135425A/en
Priority to EP19715330.7A priority patent/EP3768667B1/en
Priority to CN201980020946.5A priority patent/CN111936486B/en
Priority to US16/982,937 priority patent/US11597721B2/en
Priority to JP2020550632A priority patent/JP2021518389A/en
Priority to ES19715330T priority patent/ES2944733T3/en
Publication of WO2019183186A1 publication Critical patent/WO2019183186A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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

Definitions

  • HETEROCYCLIC COMPOUNDS COMPRISING PYRIDINE USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHA RESPONSES
  • This invention relates to compounds useful in the modulation of IL-12, TL-23 and/or IFNa by acting on Tyk-2 to cause signal transduction inhibition.
  • amide-substituted heterocyclic compounds Provided herein are amide-substituted heterocyclic compounds, compositions comprising such compounds, and methods of their use.
  • the invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to the modulation of IL-12, IL-23 and/or IFNa in a mammal.
  • the heterodimeric cytokines interleukin (IL)-12 and IL-23 which share a common p40 subunit, are produced by activated antigen-presenting cells and are critical in the differentiation and proliferation of Thi and Th l7 cells, two effector T cell lineages which play key roles in autoimmunity.
  • IL-23 is composed of the p40 subunit along with a unique pi 9 subunit.
  • IL-23, acting through a heterodimeric receptor composed of IL- 23R and IE ⁇ 12Kb1 is essential for the survival and expansion of Thl7 cells which produce pro-inflammatory cytokines such as IL-17A, IL-17F, IL-6 and TNF-a
  • IL-12 in addition to the p4Q subunit in common with IL-23, contains a p35 subunit and acts through a heterodimeric receptor composed of IL-12R[T1 and IE- ! 2Kb2, IL-12 is essential for Till cell development and secretion of IFNy, a cytokine which plays a critical role in immunity by stimulating MHC expression, class switching of B cells to IgG subclasses,
  • mice deficient in either p40, p!9, or IL-23R are protected from disease in models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis, among others (Kyttaris, V.C. et al, "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice", J. Immunol., 184:4605-4609 (2010); Hong, K. et al., "IL-12, independently of IFN -gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder", J.
  • mKNA levels of pi 9, p4G, and p35 m active SLE patients were also shown to be significantly higher compared with those in inactive SLE patients (Huang, X. et al., "Dysregulated expression of interleukin-23 and interleukin- 12 subunits in systemic lupus erythematosus patients", Mod. Rheumatol, 17:220-223 (2007)), and T cells from lupus patients have a predominant Till phenotype (Tucci, M. et ak, "O verexpression of interleukin- 12 and T helper 1 predominance in lupus nephritis", Clin. Exp. Immunol, 154:247-254 (2008)).
  • anti-p40 treatment which inhibits both IL-12 and IL-23, as well as IL-23- specific anti-pI 9 therapies have been shown to be efficacious in the treatment of autoimmunity in diseases including psoriasis, Crohn's Disease and psoriatic arthritis (Leonardi, C.L. et al, "PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin- 12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)", Lancet, 371 : 1665-1674 (2008); Sandborn, W.J.
  • Type I group of interferons which include the IFNa members as well as IRNb, IFNs, IFNK and IFNco, act through a heterodimer IFNa/b receptor (IFNAR).
  • Type I IFNs have multiple effects in both the innate and adaptive immune systems including activation of both the cellular and humoral immune responses as w-ell as enhancing the expression and release of autoantigens (Hall, J.C. et al., "Type I interferons: crucial participants in disease amplification in autoimmunity", Nat. Rev. Rheumatol, 6:40-49 (2010)).
  • IFN interferon
  • IFNa type I interferon
  • IFNa signature type I IFN-regulated genes
  • IFNa A direct role for IFNa in the pathobiology of lupus is evidenced by the observation that the administration of IFNa to patients with malignant or viral diseases can induce a lupus-like syndrome. Moreover, the deletion of the IFNAR in lupus-prone mice provides high protection from
  • Tyrosine kinase 2 is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases and has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL-12, IL-23 and type 1 interferons m both mice (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12/Thl and IL-23/Thl7 Axes In vivo”, J Immunol., 187: 181-189 (2011); Prchal-Murphy, M.
  • J Immunol. 187: 181-189 (2011)
  • Prchal-Murphy M.
  • Tyk2 mediates the receptor-induced phosphorylation of members of the STAX family of transcription factors, an essential signal that leads to the dimerization of STAX proteins and the transcription of STAX- dependent pro-inflammatory genes.
  • Tyk2-deficieni mice are resistant to experimental models of colitis, psoriasis and multiple sclerosis, demonstrating the importance of Tyk2- mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al.,
  • Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility
  • Brain, 134:693-703 (2011) Genome-wide association studies have shown other variants of Tyk2 to be associated with autoimmune disorders such as Crohn's Disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al, "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci”, Arn. J. Hum. Genet., 90:636-647 (2012); Graham, D.
  • new compounds capable of modulating cy tokines and/or interferons such as IL-12, TL-23 and/or IFNa, and methods of using these compounds may provide substantial therapeutic benefits to a wide variety of patients in need thereof.
  • the invention is directed to compounds of Formula I, infra, that which are useful as modulators of IL-12, IL-23 and/or IFNa by inhibiting Tyk2-mediated signal transduction.
  • Tire present invention also provides processes and intermediates for making the compounds of the present invention.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention.
  • the present invention also provides a method for the modulati on of IL-12, IL-23 and/or IFNa by inhibiting Tyk-2-mediated signal transduction comprising administering to a host m need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.
  • the present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.
  • a preferred embodiment is a method for treating inflammatory and autoimmune diseases or diseases.
  • an inflammatory and autoimmune diseases or diseases for the purposes of this invention, an inflammatory and
  • autoimmune disease or disorder includes any disease having an inflammatory or autoimmune component.
  • the present invention also provides the use of the compounds of the present invention for the manufacture of a medicament for the treatment of cancers.
  • the present invention also provides the compounds of the present invention for use m therapy.
  • X is N or CH
  • Rl is selected from H, CD3, C 1-3 alkyl or C3-6 cycloalkyl
  • R 2 is -C(0)R 2a ; C1-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCFs, CN, NO2, -(CH2)rOR b ,
  • R 3 is H, C i-3 alkyl or C3-6 cycloalkykR 4 is H, C1-3 alkyl or C3-6 cycloalkyl;
  • R 5 is Cm alkyl substituted with 0-1 R 5a , Ci-4 alkoxy substituted with 0-1 R 5a , (CH 2 ) r -phenyl substituted with 0-3 R 5a or a -(CH 2 )-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0) P ;
  • R 5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CFs, CN,
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (CH 2 ) r -phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R 6a ;
  • R 6a is H, Ci -4 alkyl substituted with 0-3 R f , CF 3 , C3-10 cycloalkyl substituted with 0-1 R 1 , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R 7 is H, C 1 -3 alkyl or C3-6 cycloalkyl
  • R 11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 R 1 , (CH)r-phenyl substituted with 0-3 R d
  • R a at each occurrence is independently H, F, Cl, Br, OCF3, CF 3 , CHF 2 , CN,
  • R b is H, C1-6 alkyl substituted with 0-3 R d , C1-6 haloaikyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 ) r ⁇ 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 )t-phenyl substituted with 0-3 R d ;
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 ) r -C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 ) I -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(G) P ;
  • p 0, 1 , or 2;
  • r is O, 1, 2, 3, or 4;
  • X is N or CH
  • R 1 is selected from H, CDs, CM alkyl or C3-6 cycloalkyl
  • R 2 is -C(0)R a ; Ci-e alkyl, -(CH 2 )r-3-14 membered carbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO2, -(CH 2 )rOR b ,
  • R J is H, Ci-3 alkyl or C3-6 cycloaikykR 4 is H, C1-3 alkyl or C3-6 cycloalkyl;
  • R 5a (,CH 2 )r-phenyl substituted wath 0-3 R 5a or a ⁇ (CH 2 ) ⁇ 5 ⁇ 7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • R 5a is is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN,
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (CH 2 ) r -phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R 6a ;
  • R 6a is H, C 3 -4 alkyl substituted with 0-3 R f , CFs, C3-10 cycloalkyl substituted with 0-1 Rf (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R ! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 R d or ⁇ (CH 2 )r-5 ⁇ 7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R d ;
  • R a at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF 2 , CN,
  • R b is H, C1-6 alkyl substituted with 0-3 R d , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R d ;
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Cm alkyl, C3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 ) I -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q) P ;
  • p 0, 1 , or 2;
  • r is 0, ! . 2, 3, or 4;
  • X is N or CH
  • R 2 is ⁇ C(0)R 2a ; Ci-6 alkyl, -(CH2)r ⁇ 3-14 membered carbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCFs, CN, NO2, -(CH2)rOR b ,
  • R 3 is H, C i-3 alkyl or C3-6 cycloalkykR 4 is H, C1-3 alkyl or C3-6 cycloalkyl;
  • R 5 is Ci-4 alkyl substituted with 0-1 R 5a , Ci-4 alkoxy substituted with 0-1 R 5a , (CH 2 ) r -phenyl substituted with 0-3 R 5a or a -(CH 2 )-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0) P ;
  • R 5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CFs, CN,
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (CH 2 ) r -phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R 6a ;
  • R 6a is H, C 3 -4 alkyl substituted with 0-3 R f , CFs, C3-10 cycloalkyl substituted with 0-1 Rf (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R ! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 R d or ⁇ (CH 2 )r-5 ⁇ 7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R d ;
  • R a at each occurrence is independently H, F, Cl Br, OCF3, CF3, CHF 2 , CN,
  • R b is H, C1-6 alkyl substituted with 0-3 R d , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 ) phenyl substituted with 0-3 R d ;
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 ) I -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q) P ;
  • p 0, 1 , or 2;
  • r 0, 1, 2, 3, or 4;
  • X is N or CH
  • R 2 is -C(0)R a ; Cue alkyl, -(CH2)r-3-14 membered earbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO?., -(CH 2 )rOR b ,
  • J is H, C i-3 alkyl or C3-6 cycloaikykR 5 is Ci-4 alkyl substituted with 0-1 R 5a , Ci-4 alkoxy substituted with 0-1 R 3a , (CH2)r-phenyl substituted with 0-3 R: ' ’ 3 or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0) P ;
  • R 5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CF3, CN,
  • R 6 is Ci-4 alkyl substituted with 0-1 R 6a , (CH 2 ) r -phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R 6a ;
  • R 6a is H, C 3 -4 alkyl substituted with 0-3 R f , CFs, C3-10 cycloalkyl substituted with 0-1 Rf (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R ! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 R d or ⁇ (CH 2 )r-5 ⁇ 7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R d ;
  • R a at each occurrence is independently H, F, Cl Br, OCF3, CF3, CHF 2 , CN,
  • R b is H, C1-6 alkyl substituted with 0-3 R d , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 ) phenyl substituted with 0-3 R d ;
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 ) I -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q) P ;
  • p 0, 1 , or 2;
  • r 0, 1, 2, 3, or 4;
  • X is N or CH
  • R 2 is -C(0)R 2a ; Cs-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R a ;
  • R 2a at each occurrence is independently H, OCFh, CN, NO?., -(CH 2 )rOR b ,
  • R 5 is Ci-4 alkyl substituted with 0-1 R 5a , Ci-4 alkoxy substituted with 0-1 R 5a , (CH 2 ) r -phenyl substituted with 0-3 R 5a or a -(CH?)-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0) P ;
  • R 5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CFs, CN,
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (Cl I ' ⁇ . phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R 6a ;
  • R ba is H, Ci-4 alkyl substituted with 0-3 R f , CFi, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R H at each occurrence is independently H, C1-4 alkyl substituted with 0-3 R f , CFs, C3-10 cycloalky] substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d :
  • R a at each occurrence is independently H, F. Cl, Br, OCFs, CF3, CHF2, CN,
  • alkyl substituted with 0-3 R 1 C1-6 haloalkyl, C 2 -e alkenyl substituted with 0-3 R a , C 2 -e alkynyl substituted ith 0-3 R 3 , -(CH 2 )r-3-14 membered carbocycle or ⁇ (CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f ;
  • R b is H, Ci-6 alkyl substituted with 0-3 R d , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 ) f -phenyl substituted with 0-3 R d ;
  • R c is Ci-6 alkyl substituted with 0-3 R 1 , (CH 2 ) r ⁇ C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CFi 2 )r-phenyl substituted with 0-3 R f ;
  • R 1 is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3 -6 cycloalkyl, CFs, 0(CJ -6 alkyl) or a -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • p 0, l, or 2;
  • r 0, 1, 2, 3, or 4;
  • X is N or CH
  • R 2 is ⁇ C(0)R 2a ; Ci-6 alkyl, -(CH2)r-3-14 membered carbocyele substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rOR b ,
  • Ci-e alkyl substituted with 0-3 R a Ci-e haloaikyl, C2-6 alkenyl substituted with 0-3 R a , -(CH 2 )r-3-l4 membered carbocyele substituted with 0-1 R a or a -(CH 2 )r ⁇ 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 R a ;
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (CH2)r-phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R 6a ;
  • R 6a is H, Ci -4 alkyl substituted with 0-3 R f , CF: ⁇ , C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or ⁇ (CH 2 ) r -5 ⁇ 7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R H at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R f , CFs, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d
  • R a at each occurrence is independently H, F, Cl, Br, OCFs, CF3, CHF2, CN,
  • R b is H, C i-6 alkyl substituted with 0-3 R d , Ci-e haioalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R 1 or (ChbVplienyl substituted with 0-3 R d ;
  • R c is Ci-e alkyl substituted with 0-3 Ry (CH2)r-C3-6 cycloalkyl substituted with 0-3 R f or (CH2)r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloalkyl or (CHzfr-phenyl substituted with 0-3 R f ;
  • R 1 is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CFs, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • p 0, 1, or 2;
  • r 0, 1, 2, 3, or 4;
  • R 2 is -C(0)R 2a ; Ci-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO?., -(CH 2 )rOR b ,
  • R 6 is Ci-4 alkyl substituted with 0-1 R 6a , (CH 2 ) r -phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R 6a ;
  • R 6a is H, Ci-4 alkyl substituted with 0-3 R f , CFb, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 ) r -5-7 membered heterocycie containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R 11 at each occurrence is independently H, Cm alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d
  • R a at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF?, CN,
  • R b is H, Ci-6 alkyl substituted with 0-3 R d , C1-0 haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH?)r-5-7 membered heterocycie containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R d ;
  • R c is Ci -6 alkyl substituted with 0-3 R f , (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloalkyl or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • p 0, 1, or 2;
  • r 0, 1, 2, 3, or 4;
  • R 2 is ⁇ C(0)R 2a ; C1-6 alkyl, -(CH 2 )r-3-14 membered carbocycle substituted with 0-1 R 2a or a 5-12 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO2, -(CH 2 )rOR b , alkyl C 2 -6 alkenyl substituted with 0-3 R a , -(CH 2 ) f -3- 14 membered carbocycle substituted with 0-1 R a or a -(CH 2 ) r ⁇ 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-2 R a ;
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (CH 2 )r-phenyl substituted with 0-3 R 6a or a -(CH 2 )-5-7 rnerabered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R ba ;
  • R 6a is H, Ci-4 alkyl substituted with 0-3 R f , CFN, C -jo cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N. O, and S(0)p substituted with 0-3 R d ;
  • R 11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R 1 , CFh, Cs-io cycloalkyl substituted with 0-1 R f , (CH) -phenyi substituted with 0-3 R d or -(CH 2 )r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R a at each occurrence is independently H, F, Cl, Br, OCF3, CFb, CHF 2 , CN,
  • R b is FI, C i-6 alkyl substituted with 0-3 R d , Ci-e haioalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 ) r -5-7 membered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(Q) P substituted with 0-3 R 1 or (CH 2 )r-phenyl substituted with 0-3 R d ;
  • R c is Ci-e alkyl substituted with 0-3 Ry (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or !( 1 1’f-phens 1 substituted with 0-3 R f ;
  • 1 is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 )r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0) P ; p is 0, 1, or 2;
  • r is 0, 1 , 2 or 3;
  • R 2 is -C(0)R 23 or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO?., -(CH?) f OR b ,
  • R 6 is Ci -4 alkyl substituted with 0-1 R 6a , (CH 2 ) r -phenyl substituted with 0-3 R 6a or a -(CH?)-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R 6a ;
  • R 6a is H, Ci-4 alkyl substituted with 0-3 R f , CF3, C3-10 cy cloalkyl substituted with 0-1 R 1 , (CH)r-phenyl substituted with 0-3 R d or -(CH?)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R“ at each occurrence is independently H, Ci -4 alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d
  • R a at each occurrence is independently H, F, CL Br, OCF3, CF3, CHF 2 , CN,
  • R b is FI, Ci-6 alkyl substituted with 0-3 R d , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 ) r ⁇ 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 )t-phenyl substituted with 0-3 R d ;
  • R c is Ci -6 alkyl substituted with 0-3 R f , (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Cj-6 alkyl, C3-6 eycloalkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 eycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH 2 ) I -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • p 0, 1 , or 2;
  • r 0, 1, 2 or 3;
  • R 2 is -C(0)R 23 or a 5-12 membered heierocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCF3, CN, NO2, -(CH 2 )rOR b ,
  • R 6 is a -(CH 2 )-5-7 membered heierocy cle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R 6a ;
  • R 11 at each occurrence is independently H, Cm alkyl substituted with 0-3 R 1 , CF3, R 6a is H, C1-4 alkyl substituted with 0-3 R f , CF3, C3-30 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 ) r -5-7 membered heierocycle containing 1 -4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d ;
  • R ! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d
  • R a at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF 2 , CN,
  • R b is H, Ci-6 alkyl substituted with 0-3 R d , Ci-6 haloalkyi, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 ) r ⁇ 5-7 membered heierocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R* or (CH 2 )r-phenyl substituted with 0-3 R d ;
  • R c is Ci -6 alkyl substituted with 0-3 R 1 , (CH 2 )r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R 1 is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CFs, 0(CJ -6 alkyl) or a -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • p 0, 1, or 2;
  • r 0, 1, 2 or 3;
  • R 2 is -C(0)R 2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;
  • R 2a at each occurrence is independently H, OCFs, CN, NO2, -(CH 2 )rOR b ,
  • R 6 is a -(CH 2 )-5 -7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R 6a ;
  • R 6a is H, Ci -4 alkyl substituted with 0-3 R 1 .
  • R H at each occurrence is independently H, C1-4 alkyl substituted with 0-3 R f , CF3, C3-10 cycloalky] substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )t-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R d :
  • R a at each occurrence is independently H, F, Cl, Br, OCFs, CF3, CHF? stamp CN,
  • alkyl substituted with 0-3 R 1 C1-6 haloalkyl, C 2 -e alkenyl substituted with 0-3 R a , C 2 -e alkynyl substituted ith 0-3 R 3 , -(CH 2 )r-3-14 membered carbocycle or -(CH 2 ) r -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f ;
  • R b is H, Ci-6 alkyl substituted with 0-3 R d , Ci-e. haloalkyl, C3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P substituted with 0-3 R f or (CH 2 ) f -phenyl substituted with 0-3 R d ;
  • R c is Ci-6 alkyl substituted with 0-3 R 1 , (CH 2 ) r ⁇ C3-6 cycloalkyl substituted with 0-3 R 1 or (CH 2 )r-phenyl substituted with 0-3 R 1 ;
  • R d is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
  • R e is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH 2 )r-phenyl substituted with 0-3 R f ;
  • R f is independently at each occurrence, hydrogen, halo, CN, NH 2 , OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2) I -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0) P ;
  • p 0, 1, or 2;
  • r 0, 1, 2 or 3;
  • a pharmaceutical composition comprising one or more compounds of formula 1 and a pharmaceutically acceptable carrier or diluent.
  • Hie present invention is also directed to pharmaceutical compositions useful in treating diseases associated with the modulation of IL-12, IL-23 and/or IFNa by acting on Tyk-2 to cause signal transduction inhibition, comprising compounds of formula I, or pharmaceutically-acceptable salts thereof, and pharmaceutically -acceptable carriers or diluents.
  • the invention further relates to methods of treating diseases associated with the modulation of IL-12, IL-23, and/or IFNa, comprising administering to a patient in need of such treatment a therapeutically -effective amount of a compound according to formula I.
  • the present invention also provides processes and intermediates for making the compounds of the present invention.
  • the present invention also provides a method for treating proliferative, metabolic, al lergic, autoimmune and inflammatory diseases (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a host in need of such treatment a therapeutically effecti ve amount of at least one of the compounds of the present invention.
  • the present invention also provides a method of treating an infl ammatory' or autoimmune disease (or use of the compounds of the present invention for the
  • the present invention also provides a method for treating a disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory' bowel disease, psoriasis, Crohn's Disease, psoriatic arthritis, Sjogren's syndrome, systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult onset Stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis (a
  • thrombocytopenia atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyeiinating Polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary' inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyeiinating polyneuropathy.
  • CIDP Chronic Inflammatory Demyeiinating Polyneuropathy
  • the present invention also provides a method of treating an inflammatory or autoimmune disease (or use of the compounds of the present invention for the
  • a therapeutically-effective amount of a compound of Formula I wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's Disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.
  • SLE systemic lupus erythematosus
  • lupus nephritis cutaneous lupus
  • Crohn's Disease ulcerative colitis
  • type 1 diabetes psoriasis
  • rheumatoid arthritis systemic onset juvenile idiopathic arthritis
  • ankylosing spondylitis and multiple sclerosis.
  • the present invention also provides a method for treating a rheumatoid arthritis (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of rheumatoid arthritis, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I.
  • the present invention also provides a method of treating a condition (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these conditions) comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the condition is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neovasculization, and infantile haemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, multiple vaseulitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, Type I diabetes, membranous nephritis, inflammatory bowel
  • HUS/TTP thrombocytopenic purpura
  • the present invention also provides a method of treating an IL-12, IL-23, and/or IFNcx mediated disease (or use of the compounds of die present inv ention for the manufacture of a medicament for the treatment of these diseases), comprising
  • the present invention also provides a method of treating an IL-12, IL-23 and-'or IFNcx mediated disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising
  • the present invention also provides a method of treating diseases, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula I in combination with other therapeutic agents.
  • the present invention also provides the compounds of the present invention for use therapy.
  • compounds of formula I are selected from exemplified compounds or combinations of exemplified compounds or other embodiments herein.
  • any variable e.g, R
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 3 the definition of R 3
  • substituents and/or variables are permissible only if such combinations result m stable compounds.
  • nitrogen atoms e.g, amines
  • these can be converted to N -oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
  • an oxidizing agent e.g., MCPBA and/or hydrogen peroxides
  • ⁇ is used in structural formulas herein to depict the bond that is the poin t of attachment of the moiety' or substituent to the core or backbone structure.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH2 is attached through the carbon atom.
  • optionally substituted in reference to a particular moiety ' of the compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents.
  • optionally substituted alkyl encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.
  • alkyl or “alkyiene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • “Ci-io alkyl” (or alkyiene), is intended to include Ci, C?., Cy Cy Cs, C6, C?, Cs, (3 ⁇ 4, and Cio alkyl groups.
  • Ci-Ce alkyl denotes alkyl having 1 to 6 carbon atoms.
  • Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alky!
  • alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain.
  • C2-6 alkenyl (or alkenylene) is intended to include C2, Cy Cy Cs, and Ce alkenyl groups.
  • alkenyl examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4- methyl-3-pentenyl, and the like.
  • Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain.
  • C2-6 alkynyl (or alkynylene), is intended to include C2, Cs, Cy Cs, and Ce alkynyl groups; such as ethynyl, propyny!, butynyl, pentynyl, hexynyl and the like.
  • alkyl refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl.
  • aryl(Co-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(Co)alkyi.
  • heteroarylalkyl refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.
  • substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group these groups are substituted with one to three substituents as defined above for substituted alkyl groups.
  • alkoxy refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein.
  • alkoxy includes the group -O-Ci-eaikyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, feri-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3- methylpentoxy, and the like.
  • “Lower alkoxy” refers to alkoxy groups having one to four carbons.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • Keto substituents are not present on aromatic moieties.
  • substituents are named into the core structure. For example, it is to be understood that when (cyeloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent it is preferred that the presently recited compounds do not contain a N-halo, S(0)2H, or S(0)H group.
  • cycloalky G refers to cyclized alkyl groups, including mono-, bi- or poly cyclic ring systems.
  • C3-7 cycloalkyl is intended to include C3, Cy C. % Cc,, and C? cycloalkyl groups.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norhornyl, and the like.
  • Carbocyclic residue is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cydobutenyl, cyclopentyl, cydopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyi, cyclooctadienyl, [3.3.0]bicyclooctane,
  • carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • carbocycle When the term “carbocycle” is used, it is intended to include “aryl”.
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.
  • cycloalkyl includes
  • Preferred cycloalkyl groups include cyclopropyl, cydopenty!, cyclohexyl, and
  • halo or “halogen” refers to chloro, bromo, fluoro and iodo.
  • ha!oalkyi means a substituted alkyl having one or more halo substituents.
  • haloalkyi includes mono, bi, and trifluoromethyl.
  • haloalkoxy means an alkoxy group having one or more halo substituents.
  • haloalkoxy includes OCF3.
  • aryl groups include:
  • fluorenyl and the like, which optionally may be substituted at any available carbon or nitrogen atom.
  • a preferred aryl group is optionally-substituted phenyl.
  • heterocycle refers to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 1 l-membered bicychc groups, and 10- to 15- membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroato containing ring preferably having 1 , 2, or 3 heteroatoms selected from O, S, and N.
  • Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom.
  • the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quatemized.
  • the fused rings completing the bicychc and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated.
  • the heterocyclo group may be attached at any available nitrogen or carbon atom.
  • heterocycle As used herein the terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, and “heterocyclyl” include “heteroaryl” groups, as defined below.
  • exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidiny], isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, l-pyndonyl, 4-piperidonyl, tetrahydropyranyl, morphoiinyl, thia
  • heteroaryd refers to substituted and unsubstituted aromatic 5- or 6- membered monocyclic groups, 9- or lO-membered bicyclic groups, and 11- to 14- membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quatemized.
  • Heteroaryd groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non aromatic.
  • Exemplary monocyclic heteroaryd groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
  • Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, qumoxalinyl, indazolyl, pyrrolopyridyl,
  • Exemplar ⁇ ' tricyclic heteroaryl groups include carbazo!yl, benzmdolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • heteroaryl groups include:
  • h optionally may be substituted at any available carbon or nitrogen atom.
  • arylo e.g., phenyl
  • cycloalkyl e.g., cyclohexyl
  • heterocyclo e.g., pyrrolidinyl, piperidinyl, and morpholinyl
  • heteroaryl e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl
  • the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from those recited above for the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, as appropriate.
  • Carbocyclyl or “carbocyclic” refers to a saturated or unsaturated
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyelic carbocycles have 7 to 12 ring atoms, e.g, arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as5 a bicyclo [5,6] or [6,6] system.
  • Examples of mono- and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, l-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cydohex-3-enyl. phenyl and naphthyl.
  • the carbocyclic ring may be substituted in winch case the substituents are selected from those recited above for cycloalkyl and aryl groups.
  • heteroatoms shall include oxygen, sulfur and nitrogen.
  • the compounds of formul a I may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof.
  • the term "salt(s)” denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • the term “salt(s)” may include zwitterions (inner salts), e.g., when a compound of formula I, contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid.
  • Salts of the compounds of the formula I may be formed, for example, by reacting a compound of the formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifiuoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsuJfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2- hydrox ethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with me
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as tria!kylamines such as triethylamine, procaine, dibenzyl amine, N-benzyl- b-phenethylamine, 1 -ephenamine, TVpV'-dibenzylethylene-diamine, dehydroabietylamine, N-ethyipiperidine, benzylamine, dicyciohexylamme or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • tria!kylamines such as triethylamine, procaine, dibenzyl amine, N-benzyl- b-pheneth
  • Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g, dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, !auryi, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically-acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
  • the pharmaceutically-acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanihc, 2-acetoxy benzoic, fumaric, toluenesulfonic,
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic
  • the pharmaceutica!ly-acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th Editi on, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.
  • Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers).
  • the definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity .
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • Tire present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • isotopes of carbon include l3 C and i4 C.
  • Prodrugs and solvates of the inventive compounds are also contemplated.
  • the term "prodrug” denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula 1) is a prodrug within the scope and spirit of the invention.
  • compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se.
  • Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes.
  • esters of compounds of formula 1 include Ci-6alkylbenzyi, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,
  • Ci-e.alkanoyloxy-Ci-ealkyl e.g., acetoxymethyl, piva!oyloxy methyl or
  • Ci-6alkoxycarbonyloxy-C i-ealkyl e.g , methoxycarbonyl-oxymethyl or ethoxy carbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2- oxo-1, 3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
  • prodrug derivatives are well known in the art.
  • prodrug derivatives see:
  • solvates e.g , hydrates
  • Methods of solvation are eeneraliy known m the art.
  • the compounds of the invention modulate IL-23-stimulated and IFNa-stimulated cellular functions, including gene transcription.
  • Other types of cellular functions that may be modulated by the compounds of the instant invention include, but are not limited to, IL-12-stimulated responses.
  • compounds of formula I have utility in treating conditions associated with the modulation of the function of IL-23 or IFNa, and particularly the selective inhibition of function of IL-23, IL-12 and/or IFNa, by acting on ' Tyk2 to mediate signal transduction.
  • Such conditions include IL-23-, IL-12-, or IFNa-associated diseases in winch pathogenic mechanisms are mediated by these cytokines.
  • treating encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it;
  • compounds of Formula 1 are useful in treating IL-23-, IL-12- or IFNa- associated diseases including, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosis, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onset stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis;
  • inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease
  • autoimmune diseases such as Graves' disease, rhe
  • metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis;
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury', oncologic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS, respectively.
  • the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis.
  • Graves' disease autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs.
  • Preferred methods of treatment are those wherein the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.
  • preferred methods of treatment are those wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions inj ury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction.
  • Another preferred method of treatment is one in which the condition is multiple myeloma.
  • the present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically -effective amount of at least one compound of Formula I or a salt thereof.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit IL-23, IL-12 and/or IFNa function and/or treat diseases.
  • the methods of treating 1L-23-, IL-12 and/or IFNa-associated conditions may comprise administering compounds of Formula I alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions.
  • therapeutically effective amount is also intended to include an amount of the combination of compounds claimed that is effective to inhibit IL-23, IL-12 and/or IFNa function and/or treat diseases associated with IL-23, IL-12 and/or IFNa.
  • Such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAlDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, eelecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, lef!unomide, FK506 (tacrolimus, PROGRAF®); anti-malarials such as hydroxychloroquine; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-tx inhibitors such as temdap, anti-TNF antibodies or
  • therapeutic agents when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians ' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • PDR Physicians ' Desk Reference
  • such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the
  • the present invention also provides pharmaceutical compositions capable of treating IL-23-, IL-12- or IFNa-associated conditions by inhibiting Tyk2-mediated signal transduction, including TL-23-, IL-12- and/or IFNa-mediated diseases, as described above.
  • inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques s uch as those well known m the art of pharmaceutical formulation.
  • pharmaceutical additives e g., excipients, binders, preservatives, stabilizers, flavors, etc.
  • the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purvie of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms.
  • Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable
  • the compounds of Formula I may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin- related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated.
  • the compounds may be delivered orally, such as m the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrastema! injection or infusion techniques (e.g., as sterile injectable aq.
  • Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered.
  • the compounds may be administered in a form suitable for immediate release or extended release.
  • Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly m the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
  • compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).
  • compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcell ulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
  • the inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g. , with molded, compressed, or freeze-dried tablets.
  • compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included m such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG): an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g. , GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g. , CARBQPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, winch are solid at ordinary
  • the therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary' dosage amounts for a mammal of from about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of indi vidual divided doses, such as from 1 to 4 times per day.
  • the specific dose level and frequency of dosage for any particular subject may be varied and wall depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like.
  • this term is intended to include all subjects, most preferably mammalian species that are affected by modulation of IL-23, IL-12 and/or IFNa-mediated functions.
  • the compounds of the present invention may he synthesized by many methods available to those skilled m the art of organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art.
  • Preparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (1) can be prepared using procedures shown in the following Examples and related procedures.
  • the methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (1) can be prepared.
  • Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.
  • the phrase "dried and concentrated” generally refers to drying of a solution in an organic solvent over either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature suitable to the stability of the material being prepared).
  • Column chromatography was performed with pre-packed silica gel cartridges using an Isco medium pressure chromatography apparatus (Teledyne Corporation), eluting with the solvent or solvent mixture indicated.
  • the following abbreviations are used: Abbreviations
  • Method D (0C-ACN-AA-X6) W aters Acquit ⁇ UPLC BEH CI8, 2.1 x 50 mm, 1.7-mih particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 rnM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow 7 : 1.0 mL/min; Detection: UV at 220 nm.
  • Example 1 The Examples m Table 1 were prepared using a similar procedure used to prepare Example 1.
  • Step 1
  • the reaction was cooled to room temperature, diluted with EtOAc and filtered through a celite pad. The filtrate was washed with water twice, dried over sodium sulfate, filtered, and concentrated to afford a crude yellow solid. This crude yellow solid contained some desired material as well as leftover amine and catalyst. The rest of the product precipitated out and remained in the frit with the celite pad. The solid mixture from the frit was suspended in 20 mL of DMF which was then filtered.
  • the DMF filtrate was diluted with EtOAc (120 mL) and washed with water.
  • the organic layer was concentrated, suspended in DCM/EtzO and vacuumed dry in a frit.
  • the collected solid was triturated with w3 ⁇ 4ter and EtzO to provide 30 mg of brown solid.
  • the crude yellow solid from the initial reaction filtration and w'orkup was triturated with Et?.0 to give 98 mg of solid. Combined total of 128 mg of solid obtained, which was greater than quantitative recovery.
  • the filtrate was added to the material from above 4-((4-cyano-3- methoxypyridm-2 ⁇ yl)amino)-N-trideuteromethyl-6-((4-methylpyndin-2- yl)amino)pyridazine-3-carboxamide (0.122 g, 0.311 mmol) and the resulting mixture w'as sealed and heated to 85 °C. After 5 hours and 15 min, the reaction has finished. The reaction was cooled to room temperature, concentrated, and carried forward as is without purification.
  • This material was taken up in DMF and purified by preparative LC/MS with the following conditions: Column: XBndge CIS, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flows 20 mL/min.
  • Injection I conditions Column: Waters Acquit ⁇ ' UPLC BEH C18, 2.1 x 50 mm, 1.7-mih particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min;
  • This material was further purified by flash chromatograph (24 g silica gel, solid loading, 0-6% MeOH/CH2C12) to provide the desired product, 6-(cyclopropanecarboxamido)-4-((3'- methoxy-[2,4'-bipyridin]-2'-yl)amino)-N-trideuteromethylpyridazine-3-carboxamide (21.9 mg, 0.050 mmol, 39.5 % yield), as a pale yellow solid.
  • tetrakis(triphenyiphosphine)palladium(0) (112 mg, 0.097 mmol) in toluene (8 mL) was degassed and heated at 105 °C for 16 h. Upon cooling to rt, the mixture was diluted with ethyl acetate (15 mL) and filtered through C elite.
  • Example 93 The Examples in Table 3 w ? ere prepared using a similar procedure used to prepare Example 93.
  • Step 1
  • step one 320 mg, 0.916 mmol in anisole (2ml), TEA (51 1 m ⁇ ,

Abstract

Compounds having the following formula (I) or a stereoisomer or pharmaceutically-acceptable salt thereof, where R1, R2, R3, R4, and R5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

Description

HETEROCYCLIC COMPOUNDS COMPRISING PYRIDINE USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHA RESPONSES
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.
62/646432, filed March 22, 2018, the disclosure of which is incorporated herein by reference in its entirety .
FIELD OF THE INVENTION
This invention relates to compounds useful in the modulation of IL-12, TL-23 and/or IFNa by acting on Tyk-2 to cause signal transduction inhibition. Provided herein are amide-substituted heterocyclic compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to the modulation of IL-12, IL-23 and/or IFNa in a mammal.
BACKGROUND OF THE INVENTION
The heterodimeric cytokines interleukin (IL)-12 and IL-23, which share a common p40 subunit, are produced by activated antigen-presenting cells and are critical in the differentiation and proliferation of Thi and Th l7 cells, two effector T cell lineages which play key roles in autoimmunity. IL-23 is composed of the p40 subunit along with a unique pi 9 subunit. IL-23, acting through a heterodimeric receptor composed of IL- 23R and IE~12Kb1 , is essential for the survival and expansion of Thl7 cells which produce pro-inflammatory cytokines such as IL-17A, IL-17F, IL-6 and TNF-a
(McGeachy, M.J. et al, "The link between IL-23 and ThI7 cell-mediated immune pathologies", Semin. Immunol., 19:372-376 (2007)). These cytokines are critical in mediating the pathobiology of a number of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12, in addition to the p4Q subunit in common with IL-23, contains a p35 subunit and acts through a heterodimeric receptor composed of IL-12R[T1 and IE- ! 2Kb2, IL-12 is essential for Till cell development and secretion of IFNy, a cytokine which plays a critical role in immunity by stimulating MHC expression, class switching of B cells to IgG subclasses,
- i and the activation of macrophages (Grade, J.A. et al., "Interleukin- 12 induces interferon- gamma-dependent switching of IgG alloantibody subclass", Eur. J Immunol., 26: 1217- 1221 (1996); Schroder, K. et al., "Interferon-gamma: an overview of signals, mechanisms and functions", J. Leukoc. Biol, 75(2 }: 163· i 89 (2004)).
The importance of the p4Q-contaimng cytokines in autoimmunity is demonstrated by the discovery that mice deficient in either p40, p!9, or IL-23R are protected from disease in models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis, among others (Kyttaris, V.C. et al, "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice", J. Immunol., 184:4605-4609 (2010); Hong, K. et al., "IL-12, independently of IFN -gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder", J.
Immunol., 162:7480-7491 (1999); Hue, S. et al., "Interleukin-23 drives innate and T cell- mediated intestinal inflammation", ./. Exp. Med., 203:2473-2483 (2006); Cua, D.J. et al., "Interleukin-23 rather than interleukin- 12 is the critical cytokine for autoimmune inflammation of the brain", Nature, 421:744-748 (2003); Murphy, C.A. et ak, "Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation", J. Exp. Med. , 198: 1951-1957 (2003)).
In human disease, high expression of p4G and pi 9 has been measured in psoriatic lesions, and Thl7 ceils have been identified in active lesions in tire brain from MS patients and in the gut mucosa of patients with active Crohn's disease (Lee, E. et al., "Increased expression of interleukin 23 pI9 and p4G in lesional skin of patients with psoriasis vulgaris", Exp. Med., 199: 125-130 (2004); Tzartos, IS. et al., "Interleukin- 17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis", Am. J. Pathol, 172: 146-155 (2008)). The mKNA levels of pi 9, p4G, and p35 m active SLE patients were also shown to be significantly higher compared with those in inactive SLE patients (Huang, X. et al., "Dysregulated expression of interleukin-23 and interleukin- 12 subunits in systemic lupus erythematosus patients", Mod. Rheumatol, 17:220-223 (2007)), and T cells from lupus patients have a predominant Till phenotype (Tucci, M. et ak, "O verexpression of interleukin- 12 and T helper 1 predominance in lupus nephritis", Clin. Exp. Immunol, 154:247-254 (2008)).
Moreover, genome-wide association studies have identified a number of loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3, and STAT4 (Lees, C.W. et al., "New IBD genetics: common pathways with other diseases", Gut, 60:1739-1753 (2011); Tao, j.H. et al, "Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases", Mol. Biol. Rep., 38:4663-4672 (201 1); Cho, J.H. et al., "Recent insights into the genetics of inflammatory bowel disease",
Gastroenterology , 140: 1704-1712 (2011)).
Indeed, anti-p40 treatment, which inhibits both IL-12 and IL-23, as well as IL-23- specific anti-pI 9 therapies have been shown to be efficacious in the treatment of autoimmunity in diseases including psoriasis, Crohn's Disease and psoriatic arthritis (Leonardi, C.L. et al, "PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin- 12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)", Lancet, 371 : 1665-1674 (2008); Sandborn, W.J. et al, "Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease". Gastroenterology , 135: 1130-1141 (2008); Gottlieb, A. et al., "Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo- controlled, crossover trial". Lancet, 373:633-640 (2009)). Therefore, agents which inhibit the action of IL-12 and IL-23 may be expected to have therapeutic benefit in human autoimmune disorders.
The Type I group of interferons (IFNs), which include the IFNa members as well as IRNb, IFNs, IFNK and IFNco, act through a heterodimer IFNa/b receptor (IFNAR). Type I IFNs have multiple effects in both the innate and adaptive immune systems including activation of both the cellular and humoral immune responses as w-ell as enhancing the expression and release of autoantigens (Hall, J.C. et al., "Type I interferons: crucial participants in disease amplification in autoimmunity", Nat. Rev. Rheumatol, 6:40-49 (2010)).
In patients with systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease, increased serum levels of interferon (IFN)a (a type I interferon) or increased expression of type I IFN-regulated genes (a so-called IFNa signature) in peripheral blood mononuclear cells and in affected organs has been demonstrated in a majority of patients (Bennett, L. et al., "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood", ./ Exp. Med., 197:711-723 (2003); Peterson, K.S. et al., "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli", J. Clin. Invest., 113: 1722-1733 (2004)), and several studies have shown that serum IFNa levels correlate with both disease activity and severity (Bengtsson, A. A. et al., " Activation of type I interferon system m systemic lupus erythematosus correlates with disease activity7 but not with antiretroviral antibodies", Lupus, 9:664-671 (2000)). A direct role for IFNa in the pathobiology of lupus is evidenced by the observation that the administration of IFNa to patients with malignant or viral diseases can induce a lupus-like syndrome. Moreover, the deletion of the IFNAR in lupus-prone mice provides high protection from
autoimmunity, disease severity and mortality (Santiago-Raber, M.L. et al, "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice", J Exp. Med. , 197:777-788 (2003)), and genome-wade association studies have identified loci associated with lupus that encode factors that function in the type I interferon pathway, including 1RF5, IKBKE, TYK2, and STAT4 (Deng, Y. et al., "Genetic susceptibility to systemic lupus erythematosus in the genomic era", Nat. Rev. Rheumatol, 6:683-692 (2010);
Sandhng, J.K. et al, "A candidate gene study of the type 1 interferon pathway implicates IKBKE. and IL8 as risk loci for SLE", Eur. J. Hum. Genet., 19:479-484 (201 1)). In addition to lupus, there is evidence that aberrant activation of type I interferon-mediated pathways are important in the pathobiology of other autoimmune diseases such as Sjogren's syndrome and scleroderma (Bave, U. et al., "Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenic mechanism", Arthritis Rheum , 52: 1185-1195 (2005); Kim, D. et al., "induction of interferon -alpha by scleroderma sera containing autoantibodies to topoisomerase 1: association of higher interferon-alpha activity with lung fibrosis", Arthritis Rheum., 58:2163-2173 (2008)). Therefore, agents which inhibit the action of type I interferon responses may be expected to have therapeutic benefit in human autoimmune disorders.
Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases and has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL-12, IL-23 and type 1 interferons m both mice (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12/Thl and IL-23/Thl7 Axes In vivo”, J Immunol., 187: 181-189 (2011); Prchal-Murphy, M. et a] , "TYK2 kinase activity is required for functional type I interferon responses in vivo ", PLoS One , 7:e39141 (2012)) and humans (Mmegishi, Y et al, "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity", Immunity, 25:745-755 (2006)). Tyk2 mediates the receptor-induced phosphorylation of members of the STAX family of transcription factors, an essential signal that leads to the dimerization of STAX proteins and the transcription of STAX- dependent pro-inflammatory genes. Tyk2-deficieni mice are resistant to experimental models of colitis, psoriasis and multiple sclerosis, demonstrating the importance of Tyk2- mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al.,
"Involvement of Xyrosine Kinase-2 in Both the 1L- 12/Th 1 and lL-23/Thl7 Axes In vivo”, J. Immunol., 187: 181-189 (2011); Oyamada, A. et al, "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis", / Immunol., 183:7539-7546 (2009)).
In humans, individuals expressing an inactive variant of Tyk2 are protected from multiple sclerosis and possibly other autoimmune disorders (Couturier, N. et al.,
"Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility", Brain, 134:693-703 (2011)). Genome-wide association studies have shown other variants of Tyk2 to be associated with autoimmune disorders such as Crohn's Disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al, "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci”, Arn. J. Hum. Genet., 90:636-647 (2012); Graham, D. et ah, "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families", Rheumatology (Oxford), 46:927-930 (2007); Eyre, S. et al., "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis", Nat. Genet., 44: 1336-1340 (2012)).
In view of the conditions that may benefit by treatment involving the modulation of cytokines and/or interferons, new compounds capable of modulating cy tokines and/or interferons, such as IL-12, TL-23 and/or IFNa, and methods of using these compounds may provide substantial therapeutic benefits to a wide variety of patients in need thereof. SUMMARY OF THE INVENTION
The invention is directed to compounds of Formula I, infra, that which are useful as modulators of IL-12, IL-23 and/or IFNa by inhibiting Tyk2-mediated signal transduction.
Tire present invention also provides processes and intermediates for making the compounds of the present invention.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention.
The present invention also provides a method for the modulati on of IL-12, IL-23 and/or IFNa by inhibiting Tyk-2-mediated signal transduction comprising administering to a host m need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.
The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.
A preferred embodiment is a method for treating inflammatory and autoimmune diseases or diseases. For the purposes of this invention, an inflammatory and
autoimmune disease or disorder includes any disease having an inflammatory or autoimmune component.
The present invention also provides the use of the compounds of the present invention for the manufacture of a medicament for the treatment of cancers.
The present invention also provides the compounds of the present invention for use m therapy.
These and other features of the invention will be set forth in the expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
In a first aspect of the present invention, there is provided a compound of formula
CO
Figure imgf000008_0001
wherein
X is N or CH;
Rl is selected from H, CD3, C 1-3 alkyl or C3-6 cycloalkyl;
R2 is -C(0)R2a; C1-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCFs, CN, NO2, -(CH2)rORb,
Figure imgf000008_0002
-S(0)pNRuRn, -NRbS(0)pRc, -S(0)PRc, Ci-e alkyl substituted with 0-3 Ra, Ci-e haloalkyl, C2-6 alkenyl substituted with 0-3 Ra -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R3 is H, C i-3 alkyl or C3-6 cycloalkykR4 is H, C1-3 alkyl or C3-6 cycloalkyl;
R5 is Cm alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P;
R5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CFs, CN,
NO2, -ORe, -(CH2)rC(())Rc, -NReRe, -NReC(0)ORc, Ci-6 alkyl or (CH2)r-phenyl substituted with 0-3 R1;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R6a; R6a is H, Ci -4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 R1, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R7 is H, C 1-3 alkyl or C3-6 cycloalkyl;
R11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 R1, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN,
NO ·. -(CH2)rORb, -(CH2)rSRb, -(CH2 C(0)Rb, -(CH2)rC(Q)ORb, ~(CH2)rOC(G)Rb, -(CH2) rNR!1Rn, -(CH2)rC(0)NR] ]R! !, -(CH2>NRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRhCCOiNR1 ¾p, -S(0)pNRuRu, -NRbS(0)pRc, -S(0)Rc, -S(0)2R£, C1-6 alkyl substituted with 0-3 Rf, C 1-6 haloaikyl, C2-6 alkenyl substituted with 0-3 Ra, C2-e alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocyele or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf;
Rb is H, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloaikyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)t-phenyl substituted with 0-3 Rd;
Rc is C 1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, C1-6 alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(G)P;
p is 0, 1 , or 2;
r is O, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof. In a second aspect of the invention, there is provided a compound of the formula
Figure imgf000010_0001
wherein
X is N or CH;
R1 is selected from H, CDs, CM alkyl or C3-6 cycloalkyl;
R2 is -C(0)R a; Ci-e alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
-(Cl I '}=SRh. -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)rOC(0)Rb, CH2)rNR11R11,
-(CH2) C(0)NRnRn, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)0Rc, -NRbC(0)NRiiR11, -S(0)pNR!1Rn, -NRbS(0)pRc, -S(0) Rc, CM alkyl substituted with 0-3 Ra, CM haloalkyi, C2-e alkenyl substituted with 0-3 Ra, -(CH2)r-3-I4 membered carbocycle substituted with 0-1 R3 or a ~(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 R3;
RJ is H, Ci-3 alkyl or C3-6 cycloaikykR4 is H, C1-3 alkyl or C3-6 cycloalkyl;
3 is Ci -4 alkyl substituted with 0-1 R5a, C1-4 alkoxy substituted with 0-1
R5a,(,CH2)r-phenyl substituted wath 0-3 R5a or a ~(CH2)~5~7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
R5a is is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN,
N02, -ORe, -(CH2)rC(0)Rc, -NR'R-. -NReC(0)ORc, CM alkyl or (CH2)r-phenyl
substituted with 0-3 R1;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R6a; R6a is H, C 3 -4 alkyl substituted with 0-3 Rf, CFs, C3-10 cycloalkyl substituted with 0-1 Rf (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or ~(CH2)r-5~7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN,
Figure imgf000011_0001
C(Q)ORc, -NRbC(0)NRnRn, -S(0)pNR!1R13, -NRbS(0)PRf -S(0)Rf -S(0)2Rf Cm alkyl substituted with 0-3 Rf Ci-6 haloalkyl, Cm alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-l4 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rf;
Rb is H, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C 1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -ORf -(CH2)I€(0)Rc, -NReRe, -NReC(0)OR£, Cm alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, Cm alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q)P;
p is 0, 1 , or 2;
r is 0, ! . 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof. In a third aspect of the invention, there is provided a compound of the formula
Figure imgf000012_0001
wherein
X is N or CH;
R2 is ~C(0)R2a; Ci-6 alkyl, -(CH2)r~3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCFs, CN, NO2, -(CH2)rORb,
Figure imgf000012_0002
-S(0)pNRuRn, -NRbS(0)pRc, -S(0)PRc, Ci-e alkyl substituted with 0-3 Ra, Ci-e haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R3 is H, C i-3 alkyl or C3-6 cycloalkykR4 is H, C1-3 alkyl or C3-6 cycloalkyl;
R5 is Ci-4 alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P;
R5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CFs, CN,
NO2, -ORe, -(CH2)rC(())Rc, -NR¾e, -NReC(0)ORc, Ci-6 alkyl or (CH2)r-phenyl substituted with 0-3 R1;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R6a; R6a is H, C 3 -4 alkyl substituted with 0-3 Rf, CFs, C3-10 cycloalkyl substituted with 0-1 Rf (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or ~(CH2)r-5~7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl Br, OCF3, CF3, CHF2, CN,
NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb,
-(CH2)IOC (G)Rb, -(CH2)rNR11R11, ~(CH2)rC(0)NR33R3 f ~(CH2)rNRbC(Q)Rc, -(CH2)rNRb C(Q)ORc, -NRbC(0)NRnRn, -S(0)pNR!1R13, -NRbS(0)PRf -S(0)Rf -S(0)2Rf Cm alkyl substituted with 0-3 Rf Ci-6 haioalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-14 membered carbocycle or -(CH2)r~5~7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rf;
Rb is H, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2) phenyl substituted with 0-3 Rd;
Rc is C 1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -ORf -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, C1-6 alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q)P;
p is 0, 1 , or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof. In a 4th aspect of the invention, there is provided a compound of the formula
Figure imgf000014_0001
wherein
X is N or CH;
R2 is -C(0)R a; Cue alkyl, -(CH2)r-3-14 membered earbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH2)rORb,
-(CH?)rSRb, -(CH?)rC(0)Rb, -(CH2)rC(0)ORb, -(CH?)rOC(0)Rb, Ob^NR11^1,
-(CH2)rC(0)NR11R11, -(CH?)rNRbC (0)RC, -(CH2)rNRbC(0)ORc, -NRbC(0)NRiiR11, -S(0)pNR!1Rn, -NRbS(0)pRc, -S(0)PRc, CM alkyl substituted with 0-3 Ra, Ci-6 haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered earbocycle substituted with 0-1 R3 or a ~(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 R3;
J is H, C i-3 alkyl or C3-6 cycloaikykR5 is Ci-4 alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R3a, (CH2)r-phenyl substituted with 0-3 R:'’3 or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P;
R5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CF3, CN,
NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, CM alkyl or (CH2)r-phenyl substituted with 0-3 R1;
R6 is Ci-4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R6a; R6a is H, C 3 -4 alkyl substituted with 0-3 Rf, CFs, C3-10 cycloalkyl substituted with 0-1 Rf (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or ~(CH2)r-5~7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl Br, OCF3, CF3, CHF2, CN,
NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb,
-(CH2)IOC (G)Rb, -(CH2)rNR11R11, ~(CH2)rC(0)NR33R3 f ~(CH2)rNRbC(Q)Rc, -(CH2)rNRb C(Q)ORc, -NRbC(0)NRnRn, -S(0)pNR!1R13, -NRbS(0)PRf -S(0)Rf -S(0)2Rf Cm alkyl substituted with 0-3 Rf Ci-6 haioalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-14 membered carbocycle or -(CH2)r~5~7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rf;
Rb is H, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2) phenyl substituted with 0-3 Rd;
Rc is C 1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -ORf -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, C1-6 alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q)P;
p is 0, 1 , or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof. In a 5 th aspect of the invention, there is provided a compound of the formula
Figure imgf000016_0001
wherein
X is N or CH;
R2 is -C(0)R2a; Cs-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R a;
R2a at each occurrence is independently H, OCFh, CN, NO?., -(CH2)rORb,
-iCH?)rSRb, -(CH?)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb, CH2)rNR! !Rn,
-(CH?)rC(0)NR11R11, -(CH?)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(0)NRnRn, -S(0)pNRnRn, -NRbS(0)pRc, -S(Q)PRC, Ci-e alkyl substituted with 0-3 R3, Ci-6 haloalkyl, C?-6 alkenyl substituted with 0-3 Ra, -(CH?)-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH?)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 R3;
R5 is Ci-4 alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH?)-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P;
R5a is is independently at each occurrence, H, F, Cl, Br, OCFs, CFs, CN,
NO?, -ORe, -(CFi?)rC(0)Rc, -NR¾e, -NReC(0)ORc, Ci-6 alkyl or (CH?)r-phenyl substituted with 0-3 R1;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (Cl I '}·. phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R6a;
Rba is H, Ci-4 alkyl substituted with 0-3 Rf, CFi, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd; RH at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CFs, C3-10 cycloalky] substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd:
Ra at each occurrence is independently H, F. Cl, Br, OCFs, CF3, CHF2, CN,
Figure imgf000017_0001
alkyl substituted with 0-3 R1, C1-6 haloalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-e alkynyl substituted ith 0-3 R3, -(CH2)r-3-14 membered carbocycle or ~(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)f-phenyl substituted with 0-3 Rd;
Rc is Ci-6 alkyl substituted with 0-3 R1, (CH2)r~C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Cue alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CFi2)r-phenyl substituted with 0-3 Rf;
R1 is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3 -6 cycloalkyl, CFs, 0(CJ -6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, l, or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 6th aspect of the invention, there is provided a compound of the formula
Figure imgf000018_0001
wherein
X is N or CH;
R2 is ~C(0)R2a; Ci-6 alkyl, -(CH2)r-3-14 membered carbocyele substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
-(CH2)rSRb, -(CH2)rC(0)Rb, ~(CH2)rC(G)GRb, -(CH2)rOC(0)Rb, CH2)rNR11R11,
-(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(G)NR11R11, -S(0)pNRuR!!, -NRbS(0)pRc, -S(0)PRC, Ci-e alkyl substituted with 0-3 Ra, Ci-e haloaikyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-l4 membered carbocyele substituted with 0-1 Ra or a -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 Ra;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R6a;
R6a is H, Ci -4 alkyl substituted with 0-3 Rf, CF:<, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or ~(CH2)r-5~7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
RH at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CFs, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd:
Ra at each occurrence is independently H, F, Cl, Br, OCFs, CF3, CHF2, CN,
NO'. -(( i l 'fORh. -(CFI2)rSRb, -(CH2)rC(0)Rb, -(CH2) C(0)ORb,
-(CH2)rOC(0)Rb, -(CH^rNR1^11, -(CH2)IC(0)NR11R11, -(CH2)rNRbC(0)Rc, -(CH2)rNRb C(0)ORc, -NRbC(0)NR!!Ri !, -S(0)pNRuR!!, -NRbS(G)PRc, -S(G)RC, -S(G)2RC, Ci-6 alkyl substituted with 0-3 Rf, Ci-6 haioalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted w th 0-3 Ra, -(CH2)r-3-14 membered carbocycle or ~(CH2)r-5-7 memhered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Ry
Rb is H, C i-6 alkyl substituted with 0-3 Rd, Ci-e haioalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1 or (ChbVplienyl substituted with 0-3 Rd;
Rc is Ci-e alkyl substituted with 0-3 Ry (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -ORe, -(CH2)rC(0)Rc, -N R R\ -NReC(0)GRy Ci-e alkyl or (CH2) -phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloalkyl or (CHzfr-phenyl substituted with 0-3 Rf;
R1 is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CFs, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 7th aspect of the invention, there is provided a compound of the formula
Figure imgf000019_0001
wherein R2 is -C(0)R2a; Ci-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH2)rORb,
-(CH2)rSRb, -(CH?)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2) OC(0)Rb, CH2)rNR11Rn,
-ίP ΐ 'K'ίOϊN ΊO 1. -(CH?)rNRbC (0)RC, -(CH?)rNRbC(0)ORc, -NRbC(0)NR11R11, -S(0)pNRnRn, -NRbS(0)PRc, -S(0)PRc, Cm alkyl substituted with 0-3 Ra, Cm haloalkyl, C?-6 alkenyl substituted with 0-3 Ra, -(CH2)t-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH?)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 Ra;
R6 is Ci-4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R6a;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CFb, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycie containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R11 at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2) -5-7 membered heterocycie containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF?, CN,
Figure imgf000020_0001
alkyl substituted with 0-3 Rf, Ci-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH?)r-3-14 membered carbocycle or -(CH?)r-5-7 membered heterocycie containing 1 -4 heteroatoms selected fromN, O, and S(OlP substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, C1-0 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH?)r-5-7 membered heterocycie containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd; Rc is Ci -6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Ci-e alkyl or (CH2)t-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
In an 8th aspect of the invention, there is provided a compound of the formula
Figure imgf000021_0001
wherein
R2 is ~C(0)R2a; C1-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
Figure imgf000021_0002
alkyl C2-6 alkenyl substituted with 0-3 Ra, -(CH2)f-3- 14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra; R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 rnerabered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rba;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CFN, C -jo cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N. O, and S(0)p substituted with 0-3 Rd;
R11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R1, CFh, Cs-io cycloalkyl substituted with 0-1 Rf, (CH) -phenyi substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CFb, CHF2, CN,
NO’. -(CH2)IORb, -(CH2)rSRb, -(CH2)fC(0)Rb, -(CH2)IC(0)ORb,
Figure imgf000022_0001
alkyl substituted with 0-3 Rf, Ci-6 haioalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, ~(CH2)r-3-14 membered carbocycle or ~(CFI2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Ry
Rb is FI, C i-6 alkyl substituted with 0-3 Rd, Ci-e haioalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(Q)P substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci-e alkyl substituted with 0-3 Ry (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO’. -ORe, -(CH2)rC(0)Rc, -NR Ry -NReC(0)ORy Ci-e alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or !( 1 1’f-phens 1 substituted with 0-3 Rf;
1 is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P; p is 0, 1, or 2;
r is 0, 1 , 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 9th aspect of the invention, there is provided a compound of the formula
Figure imgf000023_0001
wherein
R2 is -C(0)R23 or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH?)fORb,
-(CH?)rSRb, -(CH?)rC(0)Rb, -(CH?)rC(0)0Rb, -(CH2)rOC(0)Rb, CH?)rNR11R11,
-(CH?)rC(0)NR11R11, -(CH?)rNRbC (0)RC, -(CH?)rNRbC(0)0Rc, -NRbC(0)NRiiR11, -S(0)pNR!1Rn, -NRbS(0)pRc, -S(0)PRc, CM alkyl substituted with 0-3 Ra, Ci-6 haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R3 or a ~(CH?)r-5~7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 R3;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH?)-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 R6a;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cy cloalkyl substituted with 0-1 R1, (CH)r-phenyl substituted with 0-3 Rd or -(CH?)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R“ at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 Rd; Ra at each occurrence is independently H, F, CL Br, OCF3, CF3, CHF2, CN,
NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb,
-(CH2)IOC (0)Rb, -(CH2)rNR11R1L ~(CH2)rC(0)NR33R3 L ~(CH2)rNRbC(Q)Rc, -(CH2)rNRb C(Q)ORc, -NRbC(0)NRnRn, -S(0)PNR!1R11, -NRbS(0)PRc, -S(0)Rc, -S(0)?Rc, Ci-e alkyl substituted with 0-3 Rf, CI-6 haioalkyl, C2-6 alkenyl substituted with 0-3 R3, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-l4 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rf;
Rb is FI, Ci-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)t-phenyl substituted with 0-3 Rd;
Rc is Ci -6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO¾ -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, Ci-6 alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, Cj-6 alkyl, C3-6 eycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 eycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1 , or 2;
r is 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 10th aspect of the invention, there is provided a compound of the formula
Figure imgf000024_0001
wherein
R2 is -C(0)R23 or a 5-12 membered heierocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
Figure imgf000025_0001
-S(0)pNR!1Rn, -NRbS(0)PRc, -S(0)PRc, C1-6 alkyl substituted with 0-3 Ra, Ci-6 haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R3 or a ~(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R6 is a -(CH2)-5-7 membered heierocy cle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R6a;
R11 at each occurrence is independently H, Cm alkyl substituted with 0-3 R1, CF3, R6a is H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-30 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heierocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R! ! at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd
or ~(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected frornN, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN,
Figure imgf000025_0002
alkyl substituted with 0-3 R1. Ci-6 haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, Ci-6 haloalkyi, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r~5-7 membered heierocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R* or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci -6 alkyl substituted with 0-3 R1, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO'. ~ORe, -(CH2)rC(0)Rc, -N R· R''. -NReC(0)ORc, Ci-e. alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
R1 is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CFs, 0(CJ -6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
In an 11 th aspect of th e invention, there is provided a compound of the formula
Figure imgf000026_0001
wherein
R2 is -C(0)R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCFs, CN, NO2, -(CH2)rORb,
-(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb, CH2)rNRnRn,
-(CH2)rC(0)NR11Rl!, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(0)NR! !Rn, -S(0)pNRnR] ] , -NRbS(0)PRc, -S(0)PRc, Ci-e alkyl substituted with 0-3 R3, Ci-e haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)I-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R6 is a -(CH2)-5 -7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R6a;
R6a is H, Ci -4 alkyl substituted with 0-3 R1. CF:<, C3-10 cycloalkyl substituted with 0-1 Rf, ί(Ί 1). -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
RH at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalky] substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)t-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd:
Ra at each occurrence is independently H, F, Cl, Br, OCFs, CF3, CHF?„ CN,
Figure imgf000027_0001
alkyl substituted with 0-3 R1, C1-6 haloalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-e alkynyl substituted ith 0-3 R3, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, Ci-e. haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)f-phenyl substituted with 0-3 Rd;
Rc is Ci-6 alkyl substituted with 0-3 R1, (CH2)r~C3-6 cycloalkyl substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 R1;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Ci-e alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically-acceptable salt thereof.
In another aspect, there is provided a compound selected from the exemplified examples within the scope of the first aspect, or a pharmaceutically acceptable salt or stereoisomer thereof.
In another aspect, there is provided a compound selected from any subset list of compounds within the scope of any of the above aspects.
In another aspect, there is provided a compound (IUPAC naming convention) selected from
6-cyclopropaneamido-4-{| 3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-
2-yl]amino} -N-(2H3)methy]pyridazine-3-carboxamide,
4-{[3-metboxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N- (2H3)methy 1-6- 1 (pyridin-2-y l)ammo] py ridazine-3 -carboxamide,
6-cy clobutaneamido-4- { [3-methoxy-4-(l-methy 1- 1H- 1 ,2,4-triazol-3-yl)pyridin-2- y]]amino} -N-(2H3)methylpy ri dazine-3-carboxamide,
4- { 13 -methoxy-4-( 1 -methyl- 1 H- 1 ,2,4-triazol- 3-y l)py ndin-2-y 1] amino} -N- (2H3)methyl-6-[2-(morpholin-4-yl)acetamido]pyridazine-3-carboxamide,
0-acetamido~4-{[3-methoxy~4~(l -methyl- 1 H-1, 2, 4~triaz.ol~3-yl)pyridin-2- yl]amino}-N-(2H3)metbylpyridazine-3-carboxamide,
6-[(5-fluoropyridin-2-yl)amino]-4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3- yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
6-butanamido-4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2- yl]amino} -N-(2H3)methylpyri dazine-3-carboxamide,
4- { j 3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino} -N- (2H3)methyl-6-propanamidopyridazine-3-carboxamide,
methyl N-(5-{[3-metboxy-4-(]-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}- 6-[(2H3)methylcarbamoyl]pyridazin-3-yl)carbamate, 6-(2-cyclopropylacetamido)-4- { [ 3-methoxy -4-(l -methyi-lH-1 ,2,4-triazol-3- yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4- { [3-methoxy -4-(l -methyl- 1H- 1 ,2,4~triazol~3-yl)pyridin~2~yl] amino} -N- (2H3)metliy 1-6- j (4-methy ipy ridm-2-y l)amino] py ridazine-3 -carboxamide,
4- { [3-methox -4-(l-methyl-lH-l , 2, 4-triazol-3-yl)pyridin-2-yl]amino}-6- (4- methoxypyridin-2-yl)amino]-N-(2H3)methylpyridazine-3-carboxamide,
6- f (4-cy anopy ridin-2-y l)amino] -4- { [3 -methoxy-4-( 1 -methyl- 1 H- 1 ,2,4-triazol-3 - y l)py ri din-2-y G| amino } -N-(2H3,)methy Ipy ri dazine-3-carboxami de,
0-j (5-fluoropyridin~2-y])amino j~4~{j 3-methoxy ~4~(1 -methyl- 1H-1, 2, 4~iriazol~3~ y!)pyridin-2-yl]amino}-N~(2H3)methy!pyridazine-3-carboxamide,
6-[(4,5-dimethylpyridin-2-yl)amino]-4- {[3-methoxy -4-(l-methyl-lH-l, 2, 4- triazoi-3-yl)pyndin-2-yi]amino}-N-(2iis)methylpyndazine-3-carboxamide,
6- [(5 -fluoro-4-methy ipy ridin-2-y l)amino] -4- { [3 -methoxy -4-( 1 -methyl- GH- 1 ,2,4- triazol-3 -y l)py ridin-2-y 1] ammo } -N-(2H3)methy ipy ridazine-3 -carboxamide,
6-[(4-ethylpyridin-2-yl)amino]-4-{ [3-methoxy -4-(l-methyl-lH-l , 2, 4-triazol -3- yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4- { [3-methoxy -4-(l-methyl-lH-l, 2, 4-triazol-3-yl)pyridin-2-yl]amino} -N- (2H3)methyl-6- { [5-(2-oxopyrrolidin- 1 -yl)pyridin-2-yl] amino} pyridazine-3-carboxamide, 6- [ (4-fluoropy ridin-2-y l)ammo j -4- { [3 -methoxy -4-(l -methyl- 1 H- 1 ,2,4-triazol-3 - y])pyridin-2-yl]amino} -N-(2H3)methylpyridazine-3-earboxamide,
4- { 13-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-†riazol-3-yl)pyndin-2-yl] amino} -N- (2H:s)methyl-6-[(5-methyl-l,3,4-thiadiazoI-2-yl)aminoipyndazine-3-carboxamide,
6- f (4-chloropy ri din-2-y l)amino] -4- { [3-methoxy -4-( 1 -methyl- 1 H- 1 ,2,4-triazol-3 - yl)pyridin-2-yl]amino}-N~(2H3)methylpyridazine-3-carboxamide,
6- [ (5 -chloro-4-methy ipy ridin-2-y l)amino] -4- { [3 -methox -4-( 1 -methy 1- 1H- 1,2,4- triazol-3-yl)pyridin-2-yl]amino}-N-(2iis)methylpyridazine-3-carboxamide,
6- [ (4-chl oro-5 -methy Ipy ridin -2-yl)amino] -4- { [3 -methoxy-4-( 1 -methy 1- 1 H- 1 ,2,4- triazol-3 -y l)py ridin-2-y 1] ammo } -N-(2H3)methy Ipy ridazine-3 -carboxamide,
4- { j 3-methoxy -4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyridin-2-yl] amino} -N- (2H3)methyl-6-({2-oxo-2H-[l ,3'-bipyridine]-6'-yl}amino)pyridazine-3-carboxamide,
6- { [4-(2-hydroxypropan-2-yl)pyridin-2-yl] amino} -4- { [3-methoxy-4-(l -methyl- 1H- 1 ,2,4-triazol-3-y l)pyridin-2-y 1] amino } -N-(2H3)methy ipy ridazine-3 -carboxamide, 4- { 3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino}-N- (2H3)methyl-6-{[2-oxo-3-(trifluoromethyl)-2H-[l,3'-bipyridine]-6'-y]]amino}pyridazine-
3-carboxamide,
4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-6-[(6- methoxypyridin-2-yl)amino]-N-(2H3)methylpyridazine-3-carboxamide,
4- { [3-methoxy-4-(l-methyl- 1H- 1 ,2,4-triazol-3-yl)pyridin-2-yl]amino} -N- (2H3)methyl-6-(phenyiamino)pyridazine-3-earboxamide,
6-[(4-acetylpyridin-2-yl)amino]-4-{[3-methoxy-4-(l-metbyl-lH-l,2,4-triazol-3- yl)pyridin-2-yijamino}-N-(2H3)methylpyridazine-3-carboxamide,
6-({5-chloro-2-oxo-2H-[l ,3'-bipyridine]-6'-yl } amino)-4- {[3-methoxy-4-(l - methy 1- 1H- 1 ,2,4-triazol-3 -y l)py ri din-2 -y 1] amino } -N-(2H3)methy lpyndazine-3 - carboxamide,
4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N- (2H3)methyi-6-({| L3]thiazoio[5,4-b]pyndin-5-yl}amino)pyndazine-3-carboxamide, 4-{ 3-metboxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N- (2H3)methyl-6-{[4-(ttifluoromethyl)pyridin-2-yl]amino}pyridazine-3-carboxamide,
6- { [5-(2-hydroxypropan-2-yl)pyridin-2-yl] amino} -4- { [3-metboxy-4-(l -metbyl- 1H- 1 ,2,4-triazol-3-y l)pyridin-2-y 1] amino } -N-(2H3)metby ipy ridazine-3 -carboxamide, 6-[(4-fluorophenyl)amino]-4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3- y])pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4- { 13 -methoxy-4-( 1 -methyl- 1 H- 1 ,2,4-triazol- 3-y l)py ridin-2-y 1] amino} -N- (2H3)methy 1 -6- [ (pyridin-4-y i )amino | py ridazine-3 -carboxamide,
6-f(6-ethoxypyridazin-3-yl)amino]-4-{ f3-methoxy-4-(l -methyl- iH-l,2,4-triazol- 3-y!)pyridin-2-yl]amino}-N-(2H3)methy!pyridazine-3-carboxaniide,
6-{[5-(3-tert-butyl-2-oxoimidazolidin-l-yl)pyridin-2-yl]amino}-4-{[3-methoxy-4-
(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yi]amino}-N-(2H3)methylpyndazine-3- carboxamide,
4- { 13 -methoxy-4-( 1 -methyl- 1 H- 1 ,2,4-triazol- 3-yl)py ndin-2-y 1] amino} -N-
(2H3)methyl-6-{| 5-(morpholin-4-yl)pyridin-2-yl|amino}pyridazine-3-carboxamide,
6-f(4,5-difluoropyridin-2-yl)aminol-4-{f3-methoxy-4-(l-methyl-lH-l,2,4-triaz.ol-
3-y!)pyridin-2-yl]amino}-N-(2H3)methy!pyridazine-3-carboxamide, 4- { 3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino} -N- (2H3)methyl-6-[(6-methylpyridin-2-yl)amino]pyridazine-3-caTboxamide,
6-cy clopropaneamido-4- { [3-metboxy-4-(5~methy 1- 1 ,2,4-oxadiazol-3-yl)pyridin-2- y 1] amino} -N-(2H3)methy lpy ridine-3 -carboxamide,
4-[(3-methoxy-4- {5-[(morpholin-4-yl)methyl]-l,2,4-oxadiazol-3-yl }pyridin-2- yl)amino]-N-(2H3)methyl-6-[(4-methylpyridin-2-yl)amino]pyridazine-3-carboxamide,
4-{[3-methoxy-4-(5-me†hyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl]amino}-N-
(2H3)methyl-6-propanamidopyridine-3-carboxamide,
6-(2-cy cl opropylacetamido)-4- { [3-methoxy -4-(5-methyl- 1 ,2,4-oxadiazol-3- yl)pyridin-2-yl]amino}-N-(2H3)methylpyridine-3-carboxamide,
6 CycIopropaneamido-4-({3 methoxy-4~|5-(methoxymethyl) l,2,4-oxadiazol-3- yl]pyridin-2-yl}amino)-N-(2H3)methylpyridine-3-carboxamide,
6-cyclopropaneamido-4-({4-[5~(ethoxymeihyl)-i,2,4~oxadiazol-3-yl]-3- methoxy py ridin-2-y 1 } amino)-N-(2H3)metbylpyridine-3 -carboxamide,
6-cyclopropaneamido-4-[(3-methoxy-4-{5-[(propan-2-ylox nietbyl]-l ,2,4- oxadiazol-3-yl}pyri din-2 -yl)amino]-N-(2H3)meihylpyridine-3-carboxarnide,
4-({3-methoxy-4~[5-(methoxymethyl)-i,2,4-oxadiazol-3-yl]pyridin-2-yl} amino)- N -(2H )methy I-6-propanamidopyridine-3 -carboxamide,
4-({4-| 5-(ethoxymethyl)-l,2,4-oxadiazol-3-yl |-3-methoxypyridin-2-yl}amino)-N-
(2H3)methyl-6-propanamidopyridine-3-carboxamide,
6-cyclopropaneamido-4-({3-methoxy-4-[5-(methoxymethyl)-l,2,4-oxadiazol-3- yl |pyridin-2-yl } ammo)-N-(2H3)methylpyridazine-3-carboxamide,
4-[(4-cyano-3-methoxypyridin-2-yl)amino]-6-cyclopropaneamido-N-
(2H3)methylpyridazine-3~carboxamide,
methyl N- {5-[(3-methoxy-4-{5-[(N-methylmethanesulfonamido)methyl]-l,2,4- oxadiazoi-3 -y I } py ridin-2-y l)amino] -6- [(% )methy lcarbamoy 1 j pyridazin-3-y I } carbamate, methyl N-{5-[(3-methoxy-4-{5-[(morpholin-4-yl)methyl]-l,2,4-oxadiazol-3- y 1 } py ridin-2-y l)amino] -6- [(2H3)methy lcarbamoy 1] pyndazin-3 -y 1 } carbamate,
6-cyclopropaneamido-4-[(3-methoxy-4-{5-[(N- methylmethanesulfonamido)methyl]-l,2,4-oxadiazol-3-yl }pyridin-2-y])amino]-N- (2H3)methylpyridazine-3~carboxamide, 6-cyclopropaneamido-4-| (3-methoxy-4-{5-| (morpholin-4-yl)methyr|-l,2,4- oxadiazol-3-yl}pyri din-2 -yl)amino]-N-(2H3)nieihylpyridazine-3-carboxamide,
methyl N-(5-{[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl]amino}- 6-[(2H3)methylcarbamoyl]pyridazin-3-yi)carbamate,
6-cyclopropaneamido-4- (4-{5-[(lS)-l-hydroxyethyl]-l,2,4-oxadiazol-3-yl }-3- methoxy pyridin-2-y l)amino] -N -(2H3)methy lpyridazine-3 -carboxamide,
6-cy clopropaneamido-4- [(4- { 5- [(dimethy lamino)methy 1] - 1 ,2,4-oxadiazol-3 -y 1 } -3 - methoxypyridin-2-yl)amino|-N-(2H: )methylpyridazine-3-carboxamide,
6-cy clopropaneamido-4-[(3-methoxy -4- {5-[(methylamino)methyl]-l, 2,4- ox adi azol-3 ~y 1 } pyridin-2-y l)amino] -N-(2H3)methy ipy ridazine-3-carboxamide,
4-({4-[5-(cyanome†hyl)-l,2,4-oxadiazol-3-yl]-3-methoxypyridin-2-yl}amino)-6- cyclopropaneamido-N-(2H3)methylpyridazine-3-carboxamide,
4-[(3-methoxy-4-{5-[(N-methylmethanesulfonamido)melhyl]-l,2,4-oxadiazol-3- y 1 } py ridin-2-y l)ammo] -N-(2H3)methy 1-6- 1 (4-methy Ipy ridin-2-y l)amino]py ridazine-3 - carboxamide,
4-({3-methoxy-4-[5-(methoxytnethyl)-l ,2,4-oxadiazol-3-yl]pyridin-2-yl} amino)- N-(2H3)methyl-6-[(4-methylpyridin-2-yl)amino]pyridazine-3-carboxamide,
4-((3-methoxy-4-(5-(morpholinomethyl)-l,2,4-oxadiazol-3-yl)pyridin-2- yl)amino)-N-(methyl-d3)-6-((4-methylpyndin-2-yi)amino)pyndazine-3-caiboxamide, methyl N-{5~[(4~{5-[(l,1 -dioxo~l/-6,2~thiazinan-2-yl)methy]]-I,2,4~oxadiazol~3- y 1 } -3 -methoxy pyridin-2-y l)amino] -6- [(2H3)methy lcarbamoy 1] pyridazin- 3-y 1 } carbamate, 4-| (3-methoxj -4-{5-| (morpholin-4-yl)methyl]-l ,2,4-oxadiazol-3-yl}pyridin-2- yl)amino]-N-(2H3)methyl-6-propanamidopyridazine-3-carboxamide,
4-({3-methoxy-4-[5-(methoxymethyl)-l ,2,4-oxadiazol-3-yl]pyridin-2-yl} amino)- N-(2H3)methyl-6-propaiiamidopyridazine-3-carboxamide,
6-(2-cy clopropy lacetamido)-4- [ (3 -methoxy-4- { 5 - [ (N- methylmethanesulfonami do)methyl]-l ,2,4-oxadiazol-3-yl}pyridin-2-yl)aniino]-N- (2H3)methylpyndazine-3-carboxamide,
4-({3-metboxy-4-| 5-(methoxymethyl)-l,2,4-oxadiazoI-3-yl]pyridin-2-yl}amino)- N -(2H3)methy l-6-(3 -niethy lbutanami do)py ridazine-3 -carboxamide,
4-[(3-medioxy-4-{5-[(morpholin-4-yl)methyl]-] ,2,4-oxadiazol-3-yl}pyridin-2- yl)amino]-N-(2H3)methyl-6-(3-methylbutanamido)pyridazine-3-carboxamide, 4-[(3-methoxy-4-{5-[(N-methylmethanesulfbnamido)metbyl]-l,2,4-oxadiazol-3- yl}pyridin-2-yl)amino]-N-(2H3)methyl-6-(3-methylbutanamido)pyridazine-3- carboxamide,
4-[(3-methoxy-4-{5-[(2-oxo-l,3-oxazolidin-3-yl)methyl]-l,2,4-oxadiazol-3- yl}pyridin-2-yl)amino]-N-(2H3)methyl-6-(3-methylbutanamido)pyridazine-3- carboxamide,
6-(2-cy clopropylacetamido)-4-({3-methoxy -4-[5-(methoxymethyl)-l, 2,4- ox adi azoi-3-y 1 j py ridin-2-y 1 } amino)-N-(2H3)methy lpy ridazine-3 -carboxamide,
6-(2-cy cl opropylacetamido)-4-( { 4-[5-(hydroxy methyl)- 1 ,2,4-oxadiazol-3-yl] -3- methoxypyridin-2-yl}amino)-N-(2H3)methylpyridazine-3-carboxamide„
6-cyclopropaneamido-4- {[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2- yl]amino}-N-(2H3)methylpyridazine-3-carboxamide
6-(2-cyclopropylacetamido)-4-{[3-methoxy-4-(5-metbyl-l,2,4-oxadiazol-3- y l)py ridin-2-y 1] amino } -N -(2H3)methy lpyridazine-3-carboxamide,
4-({3-metboxy-4-| 5-(methoxymethyl)-l,2,4-oxadiazol-3-yl]pyridin-2-yl}amino)-
N-(2H3)methyl-6-[2-(oxetan-3-yl)acelamido]pyridazine-3-carboxarnide,
6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-{[3-metboxy-4-(5-methyl-l,2,4- oxadiazol-3-yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4-{[3-methoxy'-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl]amino}-N-
(2H3)methyl-6-f(4-methylpyridin-2-yl)amino]pyridazine-3-carboxamide,
4-{[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl]amino}-N-
(2iis)methyl-6-[(6-methylpyrimidin-4-yi)aminojpyridazme-3-carboxamide,
6- { f 4-(2-hy droxy propan -2-y l)py ridin-2-y 1] amino} -4- { [3 -methoxy -4-(5 -methyl-
1.2.4-oxadiazol-3-yl)pyridin-2-yl]amino}-N-(2H3)meihylpyridazine-3-carboxamide,
4- { [3-methoxy-4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)pyridin-2-yl] amino} -N- (2H3)methyl-6-propanamidopyridazine-3-carboxamide,
6-{[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-{|3-methoxy-4-(5-meihyl-
1.2.4-oxadiazol-3 -y l)py ridin-2-y 1] amino } -N -(2H3)methy lpyndazine-3 -carboxamide
6-cyclopropaneamido-4-({3'-methoxy-[2,4,-bipyridine]-2'-yl } amino)-N- (2H3)methylpyridazine-3-carboxamide„
6-cyclopropaneamido-4-({3'-methoxy-[2,4'-bipyridine]-2'-yl}aimno)-N-
(2H3)methylpyridine-3-carboxamide, 6-cyclopropaneamido-4-({5-cyclopropaneamido-3'-methoxy-|2,4'-bipyridine]-2'- yl}amino)-N-(2H3)methylpyridine-3-carboxarnide,
4-({5-chloro-3'-methoxy-[2,4'-bipyridine]-2'-yl}amino)-6-cyclopropaneamido-N-
(2H3)methylpyridme-3-carboxamide,
6-cy clopr opaneamido-4-( { 4- [ 5 -(dimethy lcarbamoy i)py razin-2-y i] -3- methoxypyridin-2-yl}amino)-N-(2H3)meihylpyridazine-3-carboxamide,
6-cyclopropaneamido-4-[(4-{5-[ethyl(methyl)carbamoyl]pyrazin-2-yl}-3- methoxypyridm-2-yl)amino|-N-(2H: )methylpyridazine-3-carboxamide,
6-(2-cyc]opropylacetairado)-4-({4-[5-(diraethylcarbamoyl)pyrazin-2-yl]-3- methoxypyridin-2-y!} amino)-N-(2H3)methy!pyridazine-3-carboxamide,
4-( {4-[ 5 -(dimethy lcarbamoy l)py razin-2-y 1] -3 -methoxy pyridin-2-y 1 } amino)-N - (2H3)methyl-6-[ (l-methyl-l H-pyrazol-3-yl)amino]pyridazine-3-carboxamide,
6-[(l,5-dimethyl-lH-pyrazol-3-yl)amino]-4-({4-[5-(dimethylcarbamoyl)pyrazin-
2-yl]-3-methoxypyridin-2-yl}amino)-N-(2H3)methylpyridazine-3-carboxamide,
6-[(5-chloro-l-methyl-l H-pyrazol-3-yl)amino]-4-( {4-[5-
(dimethylcarbamoyl)pyrazin-2-yl]-3-methoxypyridin-2-yl}amino)-N-
(2H3)methyipyridazine-3~carboxarnide,
4- { [4-(5 -fluoropy nmidin-2-y l)-3-methoxy py ndin-2-y 1] amino } -6- { | 5-(2- hy dr oxy propan-2 -yi)py ridin-2-y 1 j amino } -N-(2H:>)methy Ipy n dazine-3-carboxarmde,
6-{[5-(2-aminopropan-2-yl)pyridin-2-yl]amino} -4-{[4-(5-f!uoropyrimidin-2-yl)-
3-methoxypyridm-2-yi]amino}-N-(2H3)nietliylpyridazine-3-carboxamide,
4-{|4-(5-fTuofopyrimidm-2-yl)-3-methoxypyridin-2-yljammo}-N-(2H3)methyl-6-
[(5-methy]pyrazin-2-y])amino]pyridazine-3-carboxamide,
6-[(6-ethoxypyridazin-3-yl)amino]-4-{[4-(5-fluoropyrimidin-2-yl)-3- methoxypyndin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4-{[4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-yl]amino}-N-(2H3)methyl-6-
{ [5-(morpholin-4-yl)pyridin-2-yl]amino}pyridazine-3-carboxamide,
6-| (4-fluoiOpyridin-2-yl)amiiio|-4-{|4-(5-fluoropyrimidin-2-yl)-3- methoxypyri dm-2-yi] amino} -N-(2I-i3)methylpyridazine-3-carboxamide,
4-{f4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-yl]amino}-N-(2H3)niethyl-6-
[(4-methylpyridin-2-y!)amino]pyridazine-3-carboxamide, 4- { [ 4-(5-fluoropyrimi din-2-yl)-3-methoxypyri din-2 -y l | amino} -6-[ (6- methoxypyridazin-3-y])amino]-N-(2H3)methylpyridazine-3-carboxamide,
4-{[4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-yl]amino}-N-(2H3)methyl-6-
[(pyridin-2-yl)amino]pyridazine-3-carboxamide,
6-cyclopropaneamido-4-{[4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2- yd]amino}-N~(2¾)methylpyridazine-3-carboxamide,
4- { 13 -methoxy -4-(2-methy 1-2H- 1 ,2, 3 ,4-tetrazol- 5-y l)pyridin-2-y 1] amino } -N- (2H3)methyl-6-[(4-methyJpyridin-2-yl)amino]pyridine-3-carboxamide,
methyl N-(4-{f3-me1hoxy-4-(2-methyl-2H-l,2,3,4-tetrazol-5-y])pyridin-2- yl]amino}-5-[(2H3)methylcarbamoyl]pyridin-2-yl)carbamate,
4-{[3-methoxy-4-(2-methyl-2H-l,2,3,4-tetrazol-5-yl)pyridin-2-yl]amino}-N- (2H3)methyl-6-propanamidopyridine-3-carboxamide, or
6-[(4-cyanopyridin-2-yl)amino]-4-{[3-methox\ -4-(2-methyl-2H-l,2,3,4-tetrazol- 5 -y l)pyri din-2 -y 1] amino } -N-(2H3)methy ipy ridme-3 -carboxamide.
or a stereoisomer or pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula 1 and a pharmaceutically acceptable carrier or diluent.
Hie present invention is also directed to pharmaceutical compositions useful in treating diseases associated with the modulation of IL-12, IL-23 and/or IFNa by acting on Tyk-2 to cause signal transduction inhibition, comprising compounds of formula I, or pharmaceutically-acceptable salts thereof, and pharmaceutically -acceptable carriers or diluents.
The invention further relates to methods of treating diseases associated with the modulation of IL-12, IL-23, and/or IFNa, comprising administering to a patient in need of such treatment a therapeutically -effective amount of a compound according to formula I.
The present invention also provides processes and intermediates for making the compounds of the present invention.
The present invention also provides a method for treating proliferative, metabolic, al lergic, autoimmune and inflammatory diseases (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a host in need of such treatment a therapeutically effecti ve amount of at least one of the compounds of the present invention.
The present invention also provides a method of treating an infl ammatory' or autoimmune disease (or use of the compounds of the present invention for the
manufacture of a medicament for the treatment of these diseases) comprising
administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula 1.
The present invention also provides a method for treating a disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory' bowel disease, psoriasis, Crohn's Disease, psoriatic arthritis, Sjogren's syndrome, systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult onset Stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,
thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyeiinating Polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary' inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyeiinating polyneuropathy.
The present invention also provides a method of treating an inflammatory or autoimmune disease (or use of the compounds of the present invention for the
manufacture of a medicament for the treatment of said diseases), comprising
administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's Disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.
The present invention also provides a method for treating a rheumatoid arthritis (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of rheumatoid arthritis, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I.
In addition, the present invention also provides a method of treating a condition (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these conditions) comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the condition is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neovasculization, and infantile haemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, multiple vaseulitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, Type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evans syndrome, hemolytic uremic syndrome/thrombotic
thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathies, pemphigus vulgaris and asthma.
The present invention also provides a method of treating an IL-12, IL-23, and/or IFNcx mediated disease (or use of the compounds of die present inv ention for the manufacture of a medicament for the treatment of these diseases), comprising
administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula 1.
The present invention also provides a method of treating an IL-12, IL-23 and-'or IFNcx mediated disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising
administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula I, wherein the IL-12, IL-23 and/or IFNcx mediated disease is a disease modulated by IL-12, IL-23 and/or IFNa. The present invention also provides a method of treating diseases, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula I in combination with other therapeutic agents.
The present invention also provides the compounds of the present invention for use therapy.
In another embodiment, compounds of formula I are selected from exemplified compounds or combinations of exemplified compounds or other embodiments herein.
In another embodiment are compounds having an ICso < 1000 nM in at least one of the assays described below'.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
DETAILED DESCRIPTION OF THE INVENTION
The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.
Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and tram- geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds ca be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (e.g, R ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R3, then said group may optionally be substituted with up to two R3 groups and R3 at each occurrence is selected independently from the definition of R3. Also, combinations of substituents and/or variables are permissible only if such combinations result m stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
In cases wherein there are nitrogen atoms (e.g, amines) on compounds of the present invention, these can be converted to N -oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, ail shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its \ -oxide (N-»0) derivative.
ij>
In accordance with a convention used in the art, ^ is used in structural formulas herein to depict the bond that is the poin t of attachment of the moiety' or substituent to the core or backbone structure.
A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.
The term "optionally substituted" in reference to a particular moiety' of the compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.
As used herein, the term "at least one chemical entity" is interchangeable with the term "a compound".
As used herein, the term "alkyl” or "alkyiene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-io alkyl" (or alkyiene), is intended to include Ci, C?., Cy Cy Cs, C6, C?, Cs, (¾, and Cio alkyl groups. Additionally, for example, "Ci-Ce alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alky! groups include, but are not limited to, methyl (Me), ethyl (Et), propyl ( e.g ., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, /-butyl), pentyl (e.g., n-pentyJ, isopentyl, neopentyl), and the like.
"Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene), is intended to include C2, Cy Cy Cs, and Ce alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4- methyl-3-pentenyl, and the like.
"Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkynyl" (or alkynylene), is intended to include C2, Cs, Cy Cs, and Ce alkynyl groups; such as ethynyl, propyny!, butynyl, pentynyl, hexynyl and the like.
One skilled in the field will understand that, when the designation "CO2" is used o
herein, this is intended to refer to the group * O .
When the term "alkyl" is used together with another group, such as in "arylalkyl", this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, "arylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(Co-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(Co)alkyi. The term "heieroarylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.
When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.
The term "alkoxy" refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term "alkoxy" includes the group -O-Ci-eaikyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, feri-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3- methylpentoxy, and the like. "Lower alkoxy" refers to alkoxy groups having one to four carbons.
It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and ammoalkyl, will be made by one skilled in the field to provide stable compounds.
The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo, or keto, (i.e., =0) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cyeloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g. , C=C, C=N, or N=N).
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent it is preferred that the presently recited compounds do not contain a N-halo, S(0)2H, or S(0)H group.
The term '' cycloalky G refers to cyclized alkyl groups, including mono-, bi- or poly cyclic ring systems. C3-7 cycloalkyl is intended to include C3, Cy C.% Cc,, and C? cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norhornyl, and the like. As used herein, "carbocycle" or
"carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cydobutenyl, cyclopentyl, cydopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyi, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g.,
|2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.
Accordingly, in compounds of formula 1, the term "cycloalkyl" includes
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems:
Figure imgf000042_0001
and the like, which optionally may be substituted at any available atoms of the ring(s).
Preferred cycloalkyl groups include cyclopropyl, cydopenty!, cyclohexyl, and
Figure imgf000042_0002
The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.
The term "ha!oalkyi" means a substituted alkyl having one or more halo substituents. For example, "haloalkyi" includes mono, bi, and trifluoromethyl.
The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.
Thus, examples of aryl groups include:
Figure imgf000043_0001
Figure imgf000043_0002
(fluorenyl) and the like, which optionally may be substituted at any available carbon or nitrogen atom. A preferred aryl group is optionally-substituted phenyl.
The terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", or "heterocyclyl" may be used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 1 l-membered bicychc groups, and 10- to 15- membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroato containing ring preferably having 1 , 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. 'The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quatemized. The fused rings completing the bicychc and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein the terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", and "heterocyclyl" include "heteroaryl" groups, as defined below. In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidiny], isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, l-pyndonyl, 4-piperidonyl, tetrahydropyranyl, morphoiinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxoIane and tetrahydro-l,l-dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuciidinyl. Additional
monocyclic heterocyclyl groups include
Figure imgf000044_0001
Figure imgf000044_0002
The term "heteroaryd" refers to substituted and unsubstituted aromatic 5- or 6- membered monocyclic groups, 9- or lO-membered bicyclic groups, and 11- to 14- membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quatemized. Heteroaryd groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =0 (oxo).
Exemplary monocyclic heteroaryd groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, qumoxalinyl, indazolyl, pyrrolopyridyl,
*\ furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
Exemplar}' tricyclic heteroaryl groups include carbazo!yl, benzmdolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
In compounds of formula I, preferred heteroaryl groups include:
Figure imgf000045_0001
, h optionally may be substituted at any available carbon or nitrogen atom.
Unless otherwise indicated, when reference is made to a specifically -named arylo (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e g., pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl) the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from those recited above for the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, as appropriate.
0 Tire term "carbocyclyl" or "carbocyclic" refers to a saturated or unsaturated
monocyclic or bicychc ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and and rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyelic carbocycles have 7 to 12 ring atoms, e.g, arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as5 a bicyclo [5,6] or [6,6] system. Examples of mono- and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, l-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cydohex-3-enyl. phenyl and naphthyl. The carbocyclic ring may be substituted in winch case the substituents are selected from those recited above for cycloalkyl and aryl groups.
The term "heteroatoms" shall include oxygen, sulfur and nitrogen.
When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.
Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and/or intermediate compounds useful in making pharmaceutically-acceptable compounds.
The compounds of formul a I may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof The term "salt(s)" denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, the term "salt(s)" may include zwitterions (inner salts), e.g., when a compound of formula I, contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of the formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifiuoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsuJfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2- hydrox ethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenes ulfonates, nicotinat.es, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as tria!kylamines such as triethylamine, procaine, dibenzyl amine, N-benzyl- b-phenethylamine, 1 -ephenamine, TVpV'-dibenzylethylene-diamine, dehydroabietylamine, N-ethyipiperidine, benzylamine, dicyciohexylamme or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g, dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, !auryi, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically-acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically-acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically-acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanihc, 2-acetoxy benzoic, fumaric, toluenesulfonic,
methanes ulfonic, ethane disu!fonic, oxalic, and isethionic, and the like.
The pharmaceutica!ly-acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th Editi on, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity . The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
Tire present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include l3C and i4C.
Isotopicaily -labeled compounds of the invention can generally be prepared by
conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopicaiiy-labeied reagent in place of the non-labeled reagent otherwise employed.
Prodrugs and solvates of the inventive compounds are also contemplated. The term "prodrug" denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula 1) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula 1 include Ci-6alkylbenzyi, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,
Ci-e.alkanoyloxy-Ci-ealkyl, e.g., acetoxymethyl, piva!oyloxy methyl or
propionyloxymethy!, Ci-6alkoxycarbonyloxy-C i-ealkyl, e.g , methoxycarbonyl-oxymethyl or ethoxy carbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2- oxo-1, 3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K et a , eds .. Methods in Enzymology, 112:309-396, Academic Press (1985):
b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", Krosgaard-Larsen, P. et ak, eds., A Textbook of Drug Design and Development, pp. 113- 191, Harwood Academic Publishers (1991); and
c) Bundgaard, H ., Adv. Drug Deliv. Rev., 8:1-38 (1992),
each of which is incorporated herein by reference. Compounds of the formula I and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged it should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Additionally, inventive compounds may have tram- and eA -isomers.
It should further be understood that solvates (e.g , hydrates) of the compounds of Formula I are also with the scope of the present invention. Methods of solvation are eeneraliy known m the art.
UTILITY
The compounds of the invention modulate IL-23-stimulated and IFNa-stimulated cellular functions, including gene transcription. Other types of cellular functions that may be modulated by the compounds of the instant invention include, but are not limited to, IL-12-stimulated responses.
Accordingly, compounds of formula I have utility in treating conditions associated with the modulation of the function of IL-23 or IFNa, and particularly the selective inhibition of function of IL-23, IL-12 and/or IFNa, by acting on'Tyk2 to mediate signal transduction. Such conditions include IL-23-, IL-12-, or IFNa-associated diseases in winch pathogenic mechanisms are mediated by these cytokines.
As used herein, the terms "treating" or "treatment" encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it;
(b) inhibiting the disease state, i.e., arresting its development; and/or (c) achieving a full or partial reduction of the symptoms or disease state, and/or alleviating, ameliorating, lessening, or curing the disease or disorder and/or its symptoms.
In view of their activity as modulators of IL-23-, IL-12 and IFNa-stimulated cellular responses, compounds of Formula 1 are useful in treating IL-23-, IL-12- or IFNa- associated diseases including, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosis, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onset stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis;
metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis;
neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury', oncologic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS, respectively.
More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis. Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory' reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic b-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty- arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary' sarcoidosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary' to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart atacks, organ hyposia [should this be hypoxia], vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris. Preferred methods of treatment are those wherein the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Alternatively preferred methods of treatment are those wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions inj ury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction. Another preferred method of treatment is one in which the condition is multiple myeloma.
When the terms "1L-23-, IL-12- and/or IFNa-associated condition" or "IL-23-, IL-12- and/or IFNa-associated disease or disorder" are used herein, each is intended to encompass all of the condi tions identified above as if repeated at length, as well as any other condition that is affected by 1L-23, IL-12 and/or IFNa.
The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically -effective amount of at least one compound of Formula I or a salt thereof. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit IL-23, IL-12 and/or IFNa function and/or treat diseases.
The methods of treating 1L-23-, IL-12 and/or IFNa-associated conditions may comprise administering compounds of Formula I alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions. Accordingly, "therapeutically effective amount" is also intended to include an amount of the combination of compounds claimed that is effective to inhibit IL-23, IL-12 and/or IFNa function and/or treat diseases associated with IL-23, IL-12 and/or IFNa.
Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAlDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, eelecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, lef!unomide, FK506 (tacrolimus, PROGRAF®); anti-malarials such as hydroxychloroquine; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-tx inhibitors such as temdap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians ' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the
administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating IL-23-, IL-12- or IFNa-associated conditions by inhibiting Tyk2-mediated signal transduction, including TL-23-, IL-12- and/or IFNa-mediated diseases, as described above.
The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques s uch as those well known m the art of pharmaceutical formulation.
Accordingly, the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.
A "pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purvie of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable
pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington’s Pharmaceutical Sciences , 17th Edition (1985), which is incorporated herein by reference in its entirety .
The compounds of Formula I may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin- related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as m the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrastema! injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release.
Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly m the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcell ulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g. , with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included m such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG): an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g. , GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g. , CARBQPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, winch are solid at ordinary
temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
The therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary' dosage amounts for a mammal of from about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of indi vidual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and wall depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammalian species that are affected by modulation of IL-23, IL-12 and/or IFNa-mediated functions.
METHODS OF PREPARATION
The compounds of the present invention may he synthesized by many methods available to those skilled m the art of organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art.
Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds. Examples of compounds of the present invention prepared by methods described in the general schemes are given in the preparations and examples section set out hereinafter.
EXAMPLES
Preparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (1), can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (1) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature. In the Examples given, the phrase "dried and concentrated" generally refers to drying of a solution in an organic solvent over either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature suitable to the stability of the material being prepared). Column chromatography was performed with pre-packed silica gel cartridges using an Isco medium pressure chromatography apparatus (Teledyne Corporation), eluting with the solvent or solvent mixture indicated. The following abbreviations are used: Abbreviations
Figure imgf000057_0001
Figure imgf000058_0001
Preparations
The preparations set out below are for the synthesis of reagents that were not obtained from commercial sources and were employed for the preparation of compounds of formula 1 of the invention. Ail chiral compounds m the Tables and Schemes are racemic unless specified otherwise.
Reverse-phase preparative high performance liquid chromatography ("HPLC") was performed with Shimadzu 8A liquid chromatographs using YMC S5 ODS columns (20 x 100, 20 x 250, or 30 x 250 millimeter ("mm")). Gradient elution was performed with methanol ("MeOH")/water mixtures in the presence of 0.1 % trifluoroacetic acid ("TFA").
Method A: (analytical)
Column: Waters Acquit BEH Cis 2.0 x 50 mm, 1.7 pm; mobile phase A: water with 0.1% TFA; mobile phase B: MeCN with 0.1% TFA; temperature: 40 °C; flow rate 1 mL/min; gradient: 0-100% B over 1.5 min, then 0.5 min isocratie at 100% B.
Method B: (analytical)
Column: Acquit} UPLC® BEH Cis 2.1 x 50 mm, 1.7 pm (Waters Corp.); mobile phase A: water with 0.05% TFA; mobile phase B: MeCN with 0.05% TFA; temperature: 50 °C; flow rate 0.8 mL/min; gradient: 0-100% B over 1.8 min.
Method C: (analytical)
Column: Aequity UPLC® BEH Cis 2.1 x 50 mm, 1.7 pm (Waters Corp.); mobile phase A: water with 0.1 % TFA; mobile phase B: MeCN with 0.1 % TFA; temperature: 50 °C; flow rate 1 mL/min; gradient: 0-100% B over 3 min, then 0.5 min isoeratic at 100% B.
Method D: (0C-ACN-AA-X6) W aters Acquit} UPLC BEH CI8, 2.1 x 50 mm, 1.7-mih particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 rnM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow7: 1.0 mL/min; Detection: UV at 220 nm.
Example 1
Figure imgf000060_0001
4-Bromopyridin-3-ol (0.98 g, 5.63 mmol) was dissolved in concentrated sulfuric acid (3 mL), nitric· acid (0.378 ml, 8.45 mmol) (fuming) was added under ice-cooling and the mixture was stirred for 20 hours. The reaction mixture was gently poured into ice water (40 mL) with stirring. The mixture was extracted with AcOEt (50 mL), which was washed with brine (30 mL), dried over NaeSCL and concentrated under vacuo to give 4- hromo-2-nitropyridin-3-ol (0.45 g) which was used as is. LCMS rn/z 219.1 (M+H)+; HPLC (R 1 04 min (analytical HPLC Method A); ¾ NMR (400 MHz, METHAN OL-d-r) d 8.01 (d, .7=4 6 Hz, 11 1). 7.95 (d, J=4.6 Hz, 1H).
4-Bromo-2-ni tropyri din-3 -ol (400 mg, 1.827 mmol) was dissolved in DMF (5 ml,). K2CO3 (505 mg, 3.65 mmol) was added and the mixture was stirred at rt for 10 min, then Mel (228 mΐ, 3.65 mmol) was added and the mixture was stirred at rt for o/n. The reaction mixture was diluted with AcOEt (40 mL) and water (20 mL), the organic layer was separated and washed with sat. NaHCOr (2 x 20 mL), brine (20 mL), dried over NazSOi and concentrated under vacuo. The crude product w as purified with ISCO column (12 g, AcOEt/Hexane = 0-60%, gradient time = 16 min) to give 4-bromo-3- methoxy-2-nitropyridine (260 mg) LCMS m/z 233.1 (M+H)+; HPLC /R 1.17 min (analytical HPLC Method A); !H NMR (400 MHz, CHLOROFORM-d) 5 8 10 (d, ./ 5.1 Hz, I I I ). 7.79 (d, ./ 5. ! Hz, H i). 4.06 (s, 31 11.
4-Bromo-3-methoxy-2-nitropyridine (350 mg, 1.502 mmol) was dissolved in AcOH ( ! mL), EtOH (1 mL) and water (0.5 mL), IRON (419 mg, 7 51 mmol) was added. After lh the LC-MS indicated the complete consumption of the sm and the mixture was filtered, the filtrate was diluted with AcOEt (50 mL), winch vras mixed with sat. aHCOs and the organic layer -was washed with brine (30 mL), dried over Na?S()4 and
concentrated under vacuo to give the desired product which was used as is (300 rng). LCMS m/z 205.1 (M+H)+; HPLC fe 0.66 min (analytical HPLC Method A); ¾ NMR (400 MHz, METHANOL-d4) d 7.51 (d, J=5.1 Hz, 1H), 6.81 (d, J=5.5 Hz, 1H), 3.89 - 3.78 (m, 3H).
Step 4:
4-Bromo-3-methoxypyridin-2-amine (100 rng, 0.493 mmol) was mixed with dieyanozme (57.8 mg, 0.493 mmol), Pcb(dba)3 (18.04 mg, 0.020 mmol), DPPF (21.84 mg, 0.039 mmol), Zmc (3.86 mg, 0.059 mmol) in Acetamide (2 mL). The mixture was flushed with NL for a couple m and heated at 135 c€ for o/n. LC-MS indicated the complete consumption of the starting materieal and the mixture was filtered, the filtrate was diluted with AcOEt (40 mL), which was washed with sat. NaHCO? (2 x 20 mL) and brine (20 mL), dried over arSOi and concentrated under vacuo to give 2-amino-3- methoxy i soni cotinonitril e which was purified with isco column (12 g, MeOH/DCM ::: 0- 15%, 12 min gradient) (45 mg of the desired product). LCMS m/z 150.3 (M+H)+; HPLC to 0.34 mm (analytical HPLC Method A); ¾ NMR (400MHz, METHANQL-dr) d 7.80 - 7.67 (m, i l l ). 6.79 - 6.71 (m, I H i.. 4.06 (s, 3H). Step 5:
To 2-amino-3-methoxyisonicotinonitrile (100 mg, 0 670 mmol) and N- methylformohydrazide (174 mg, 2.347 mmol) in 5 i, of THF (55-60 °C) was added potassium tert-butoxide (2682 mΐ, 2.68 mmol). The mixture was stirred at 60 C for Ih. The mixture was mixed with 1 mL of MeOH, concentrated and purified with isco column (12g, MeOH/DCM = 0-10%, gradient time =12min) to give 3-methoxy~4~( 1 -methyl - 1H- 1 ,2,4-triazol-3-yl)pyridin-2-amine (62 mg). LCMS m/z 206.3 (M+H)+; HPLC fe 0.36 min (analytical HPLC Method A); ¾ NMR (400 MHz, METH AN OL-dr) d 8.50 (s, IH), 7.74 (d, J=5.5 Hz, IH), 7.10 (d, .7=5.3 Hz, IH), 4.03 (s, 3H), 3.75 (s, 3H).
Step 6:
To a clear solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (61.1 mg, 0.292 mmol) and 3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-amine (60 mg, 0.292 mmol) in Tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (877 mΐ, 0.877 mmol) dropwise to cause color changing to dark amber, the mixture was stirred at rt for o/n. The reaction was quenched with addition of water (2 mL), and extracted with AcQEt (40 mL) and washed with brine (20 mL), the organic layer was dried over Na?.S04 and concentrated under vacuo and the residue was purified with 1SCO column (12 g, AcOEt/Hexane = 0-100% gradient time =12 min) to give 6-chloro-4-((3-methoxy-4-(l- methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide (50 mg). LCMS m/z 378.4 (M+H)f; HPLC tR 1.01 mm (analytical HPLC Method A); Ti NMR (400 MHz, CHLOROF ORM-d) d 9.41 - 9.36 (m, 1H), 8.22 - 8.16 (m, 21 1). 7.67 - 7.61 (ra, i l l ). 4 05 (d, .7=13.4 Hz, 6H).
Step 7:
A mixture of 6-chloro-4-((3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin- 2-yl)amino)-N-(methyl-d3)pyridaz.ine-3-carboxamide (15 mg, 0 040 mmol),
cyclopropanecarboxamide (6.76 mg, 0.079 mmol), xantphos (4.59 mg, 7.94
pmoi),Cs2C03 (25.9 mg, 0.079 mmol) and Pd2(dba)i (3.64 mg, 3.97 mhioΐ) in dioxane (1 mL) was sparged with nitrogen for 2 min., then it was stirred at 130 °C for 3h. After cooling the mixture was diluted with DMSO and the crude material was purified via preparative LC/MS with the following conditions: Column: XBridge 08, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-rnM ammonium acetate; Gradient: 5- 55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(l -methyl- 1H-1, 2, 4-triazol-3- yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide was 8.6 mg, and its estimated purity by LCMS analysis was 99%. LCMS m/z 427.5 (M+H)+; HPLC ?R 0.89 min (analytical HPLC Method A); Ti NMR (500 MHz, DMSG-de) d 12.43 (s, 1H), 11.46 - 1 1.25 (m, 1H), 9.88 (s, 1H), 9.24 (br s, 1H), 8 75 - 8 60 (m, ITT), 8.14 (d, .7=5 1 Hz, 1H), 7.50 (d, J= 5.2 Hz, i l l ). 3 99 (s, 3H), 3 94 - 3.81 (m, 31 1 ). 2.18 - 2.04 (m, i l l ). 0 96 - 0.80
(m, 4H).
The Examples m Table 1 were prepared using a similar procedure used to prepare Example 1.
Table 1
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0002
Figure imgf000072_0001
Figure imgf000073_0001
Ex
Figure imgf000073_0003
Figure imgf000073_0002
Step 1 :
A solution of 4,6-dichloro-N-(rnethyl-d3 (nicotinamide (430 mg, 2 065 mmol) and 2~amino-3-methoxyisonicotinonitrile (280 mg, 1.877 mmol) m DMF (20 ml) was cooled to 0 °C and NaH (300 mg, 7.51 mmol) was added m a single portion. The reaction mixture was stirred overnight allowing reaction to warm to RT. Reaction was incomplete by LCMS. More 4, 6-dichloro~N-(methyl-d3 (nicotinamide (430 mg, 2.065 mmol) and
NaH (300 mg, 7.51 mmol) were added sequentially. After stirring 4 more hours, quenched with small amount of water. Reaction mixture w as concentrated in vacuo. Resulting solid was triturated in DCM. Solid was collected by filtration and dried to afford 6-chloro-4-((3-methoxy-4-(l-methyJ-lH-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-
(methyl-d3)pyridazine-3-carboxarnide (370 mg, 1.154 mmol, 61.4 % yield). MS (nvH ) ::: 321.0. HPLC Peak RT = 0.86 minutes. (Method I)
Step 2:
A mixture of 6-chloro-4-((4-cyano-3-methoxypyridin-2-yl)amino)-N-(methyl- d3)nicotinamide (40 mg, 0.125 mmol), cyclopropanecarboxamide (21.23 mg, 0.249 mmol), Xantphos (14.43 mg, 0.025 mmol), CszCCh (81 mg, 0.249 mmol) and Pd?.(dba)3 (11.42 mg, 0 012 mmol) in dioxane (0.60 mL) was sparged with nitrogen for 2 min., then sealed and stirred at 130°C for lh. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSOg filtered and concentrated. MS (m+l) ::: 370.0. HPLC Peak RT = 0.67 minutes (method ?). The crude residue was transferred to a vial and Ethanol (5 mL) was added followed by 1M NH2OH in EtOH (0.624 mL, 0.624 mmol). The reaction mixture was heated at 85 °C in a sealed vial overnight. Cooled and filtered away any solids. Filtrate was concentrated and used in the next step without further purification. MS (m+l) = 403.1. HPLC Pea RT ::: 0.50 minutes. (Method I).
Step 3:
To a mixture of (E)~6~(cyclopropanecarboxamido)~4~((4~(N'~
hydroxy carbamimidoyl)-3-methoxypyri din-2 -yl)amino)-N-(methyl-d3)mcotinamide (50 mg, 0.124 mmol) and acetic acid (0.014 mL, 0.248 mmol) in DMF (2 mL) was added DIC (0.039 mL, 0.248 mmol). After 1 hour, LCMS show's coupling is complete. TBAF in THF (0.373 mL, 0.373 mmol) w¾s added. Heated at 80 °C overnight. The reaction mixture was diluted with dichloromethane and washed with H2O and ImL of sat.
NaHCOs. Washed 4 more times with water to remove TBAF. The organic layer was dried with MgSOr, filtered and concentrated. The crude material w'as purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: weter with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15- 55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 6-(cydopropanecarboxamido)-4-((3-methoxy-4 (5-methy 1-1 ,2,4-oxadiazol-3- yl)pyridin-2-yl)araino)-N-(methyl-d3)nicotinamide (6.2 mg, 0.014 mmol, 11.23 % yield). 41 N.Y1R (500MHz, DMSO-d6) d 12.12 (s, 1H), 10.81 (s, 1H), 9.59 (s, 1H), 8.71 (s, 1H), 8.62 (s, illl 8.21 id. J 5.1 Hz, 111}.7.39 (d, J 5.1 Hz, III).3.88 (s, 3H), 2.72 (s, 3H), 2.03 Id.1=46 Hz, If!) 0.97 - 069 (m, 4H); MS (m+1) = 427.3; HPLC Peak RT = 1.14 minutes. (Method qc-acn~tfa-xb-02); HPLC Purity' = 96%
Figure imgf000075_0001
4-((3-raet oxv~4-(5-(morphoIinometisYl)-l,2,4~oxadiazol-3-yI}pyridHi-2-Yl}amiiso)-A7~
Figure imgf000075_0002
E
Figure imgf000076_0002
Figure imgf000076_0001
A solution of 4,6-dichloiO-A-trideuteromethylpyndazine-3-carboxamide (0.420 g, 2.01 mmol) and 2-amino-3-methoxyisonicotinonitrile (0.300 g , 2.01 mmol) in DMF (13.4 niL) was cooled to 0 °C and NaH (0.257 g, 6.44 mmol) was added in a single portion. After 5 minutes, the reaction was allowed to warm to room temp. After 2.5 hours, more NaH (0.050 g, 1.25 mmol) was added. After stirring for 21.5 hours more, NaH (0.050 g, 1.25 mmol) was added, and after 30 minutes, NaH (0.050 g, 1.25 mmol) was added again, at which point the reaction was deemed complete. Reaction was quenched with saturated aqueous ammonium ehoride, water, and DCM, and solids precipitated. Saturated aqueous KH2PO4 was added to bring mixture to -pH 5. The quenched reaction mixture was extracted with a 4/1 mixture of CHCb/VPrOH three times, and the combined organics were washed with water and concentrated without filtration because of suspended solids solids. After concentration of the organic layer, the obtained orange solid was taken up as a slurry' in DCM and filtered through a medium frit. The solid was triturated with DCM and dried to obtain 6-chloro-4~((4~cyano~3~methoxypyridin-2~yl)amino)-/V- trideuteromethylpyridazine-3-carboxamide (0.273 g, 0.849 mmol, 42% yield) as an off- white solid. LCMS RT = 0.89 minutes (TS). MS (m+l) = 322.0. This material was carried fonvard without additional purification.
Step 2:
A mixture of 6-chJoro-4-((4-cyano-3-methoxypyridin-2-yl)amino)-7V- trideuteromethylpyridazine-3-carboxamide (0 100 g, 0.311 mmol), Xantphos (0.036 g, 0.062 mmol), Pd?.(dba)3 (0.028 g, 0.031 mmol), 4-methylpyridin-2-amine (0.067 g, 0.622 mmol) and CszCCh (0.253 g, 0.777 mmol) in dioxane (3.11 mL) was degassed by bubbling nitrogen gas through the mixture for 10 minutes. The reaction vessel was sealed and heated to 130 °C for 1 hour. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a celite pad. The filtrate was washed with water twice, dried over sodium sulfate, filtered, and concentrated to afford a crude yellow solid. This crude yellow solid contained some desired material as well as leftover amine and catalyst. The rest of the product precipitated out and remained in the frit with the celite pad. The solid mixture from the frit was suspended in 20 mL of DMF which was then filtered.
The DMF filtrate was diluted with EtOAc (120 mL) and washed with water. The organic layer was concentrated, suspended in DCM/EtzO and vacuumed dry in a frit. The collected solid was triturated with w¾ter and EtzO to provide 30 mg of brown solid. The crude yellow solid from the initial reaction filtration and w'orkup was triturated with Et?.0 to give 98 mg of solid. Combined total of 128 mg of solid obtained, which was greater than quantitative recovery. The material w¾s considered quantitative conversion to 4-((4- cyano-3-methoxypyridin-2-yl)amino)-7V-trideuteromethyl-6-((4-methylpyri din-2- yl)amino)pyridazine-3-carboxamide (0.122 g, 0.31 1 mmol, 100% yield) LCMS RT =
0.71 minutes (TS). MS (m+l) = 394.1 and was carried fonvard without additional purification. A solution of hydroxylamme hydrochloride (0.216 g, 3.11 mmol) and KOH (0.174 g, 3.1 1 mmol) in ethanol (6.22 mL) was stirred for 1 hour at room temperature and then filtered. The filtrate was added to the material from above 4-((4-cyano-3- methoxypyridm-2~yl)amino)-N-trideuteromethyl-6-((4-methylpyndin-2- yl)amino)pyridazine-3-carboxamide (0.122 g, 0.311 mmol) and the resulting mixture w'as sealed and heated to 85 °C. After 5 hours and 15 min, the reaction has finished. The reaction was cooled to room temperature, concentrated, and carried forward as is without purification. Consider quantitative yield of (Z)-4-((4-(/V'-hydroxycarbamimidoyl)-3- methoxypyridin-2-yl)amino)-7V-trideuteromethyl-6-((4-methylpyridin-2- yl)amino)pyridazine-3~carhoxamide (0.133 g, 3.1 1 mmol, 100% yield). LCMS RT = 0.55 minutes (TS). MS (m+1) = 427.1.
Step 3:
To a solution of (2)-4-((4-(/V-hydroxycarbamimidoyl)-3-methoxypyridin-2- yl)amino)-7V-trideuteromethyl-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (44.4 mg, 0.104 mmol) and 2-morpholinoacetic acid (45.3 mg, 0.312 mmol) in DMF (1 mL) was added DIG (0.065 mL, 0.416 mmol). After 30 minutes, TBAF (0.624 mL, 0.624 mmol) was added m a single portion. After 30 minutes, another aliquot of TBAF (0.624 mL, 0.624 mmol) was added. After 10 minutes more, the reaction was diluted with DCM, water, and ~1.5 mL. ofNaHCOs to keep the solution basic. The organic layer was washed with water five times, dried over sodium sulfate, filtered, and concentrated to afford a crude brown material. This material was taken up in DMF and purified by preparative LC/MS with the following conditions: Column: XBndge CIS, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flows 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 4-((3- methoxy-4-(5-(morpholinomethyl)-I ,2,4-oxadiazol-3-yl)pyridin-2-yl)amino)-N- trideuteromethyl-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide, TFA (11.1 mg, 0.017 mmol, 16.19 % yield), and its estimated purity by LCMS analysis was 98%. TWO analytical LC/MS injections were used to determine the final purity. Injection I conditions: Column: Waters Acquit}' UPLC BEH C18, 2.1 x 50 mm, 1.7-mih particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min;
Detection: UV at 220 nm. Injection 2 conditions: Column: Waters Acquit}' UPLC BEFi C18, 2.1 x 50 mm, 1.7-mih particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow : 1.0 mL/min; Detection: UV at 220 nm. LCMS RT = 1.73 minutes (QC- ACN-AA-XB). MS (nr h = 536.3. !H NMR (500 MHz, DMSO-de) d 12.64 (s, 1H), 9.32 (s, 1H).922 (s, 11 .8.33 (d, ./ 5.1 Hz, III).8.29 (d, .7=5.6 Hz, 1H), 7.94 (s, III}.7.55 (d, .7=51 Hz, 1H), 7.37 (s, 1H), 7.07 (br d, J=5.4 Hz, 1H), 425 (s, 2H), 3.92 (s, 3H), 3.67 (br s, 4H), 2.79 (br s, 4H), 2.41 (s, 3H)
The Examples m Table 2 were prepared using a similar procedure used to prepare
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0003
Example 83 6-(cyclopropanecarboxamido)-4-((3,-methoxy-[2,4,-bipyridin]-2,-yl)amino)-N-
(methyl-d3)pyridazine-3-carboxamide
Figure imgf000089_0001
Step 1. Synthesis of 3'-Methoxy-[2,4'-bipyridin]-2' -amine
Figure imgf000089_0002
A mixture of 4-bromo-3-methoxypyridin-2-amine (90 mg, 0.443 mmol), 2- (tributylstannyl)pyridine (245 mg, 0.665 mmol), and bis(triphenylphosphine) palladium(II) chloride (46.7 mg, 0.066 mmol) in 1,4-dioxane (3.5 mL) was heated at 1 15 °C for 16 h. Upon cooling to rt, the mixrure was diluted with ethyl acetate (15 L) and filtered through Celite. The filtate was concentrated under vacuum. The residue was subjected to flash chromatograph (24 g silica gel, solid loading, 100% ethyl acetate) to provide the desired product, 3'-methoxy-| 2,4'-bipyridin]-2' -amine (64.0 mg, 0.318 mmol, 71.8 % yield), as a white solid. LCMS m/z = 202.1 (M+H)+.
Step 2. Synthesis of 6-ChJoro-4-((3'-methoxy-[2,4'-bipyridin|-2'-yl)amino)-N- (methyl-d3)pyridazine-3-carboxamide
Figure imgf000090_0001
To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide and 3 - methoxy-j2,4'-bipyridin]-2'-amine (63.7 mg, 0.316 mmol) in tetrahydrofuran (4 mL) at rt was added lithium bis(trimethylsiiyl)amide m THF (0.753 mL, 0.753 mmol) over 2 min. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (2 mL). The mixture was adjusted with 1 N HC1 solution to pH 9-10, diluted with ethyl acetate (80 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous MgSOr and concentrated under vacuum. The residue was subjected to flash chromatograph (24 g silica gel, solid loading, 35-80% ethyl acetate/dichloromethane) to provide the desired product, 6-chloro-4-((3'-methoxy-[2,4'- bipyridin]-2'-yJ)amino)-N-trideuteromethylpyridazine-3-carboxamide (47.6 mg, 0.127 mmol, 42,3 % yield), as a white solid. LCMS m/z ::: 373.9 (M+H)+.
Step 3. Synthesis of 6-(Cyclopropanecarboxamido)-4-((3'-methoxy-[2,4'- bipyridin|-2'-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
A mixture of 6-chloro-4-((3'-methoxy-[2,4'-bipyridin]-2'-yl)amino)-N- trideuteromethylpyridazine-3-carboxamide (47.6 mg, 0.127 mmol), cyclopropanecarboxamide (27.1 mg, 0.318 mmol), tris(dibenzylideneacetone) dipalladium(O) (17.49 mg, 0.019 mmol), xantphos (1 1.03 mg, 0.019 mmol), and cesium carbonate (104 mg, 0.318 mmol) in 1,4-dioxane (2.2 mL) and NMP (0.3 mL) was heated under microwave at 145 oC for 1 h. The mixture was diluted with ethyl acetate (8 mL) and filtered through celite. The filtrate was concentrated under vacuum. To the residue was added DMSG (1.5 mL), followed by water (20 mL). The insoluble material was collected as beige solid by suction filtration and dried at 50 °C under vacuum. This material was further purified by flash chromatograph (24 g silica gel, solid loading, 0-6% MeOH/CH2C12) to provide the desired product, 6-(cyclopropanecarboxamido)-4-((3'- methoxy-[2,4'-bipyridin]-2'-yl)amino)-N-trideuteromethylpyridazine-3-carboxamide (21.9 mg, 0.050 mmol, 39.5 % yield), as a pale yellow solid. LCMS rn/z = 423.0 (M+H)+; Ή NMR (400 MHz, DMSO-de) d 12.44 (s, 1H), 11.34 (s, 1H), 9.88 (s, 1H), 9.24 (s, 1H), 8.85 - 8.72 (m, 1H), 8.19 id. ./ 5.3 Hz, 1 1 1). 8 03 - 7.95 (m, 2H), 7.53 - 7.48 (m. 1 1 1). 7 37 {d. J= 5.3 Hz, 1H), 3.63 (s, 3H), 2.19 - 2.10 (m, 1H), 0.96 - 0.84 (m, 4H).
Example 84
6-(Cyclopropanecarboxamido)-4-((3,-methoxy-[2,4,-bipyridin]-2,-yl)amino)-N-
(methyl-d3)nicotinamide
Figure imgf000091_0001
Step 1. Synthesis of 6-Chloro-4-((3,-methoxy-[2,4'-bipyridin]-2,-yl)amino)-N-
(methyl-d3)nicotinamide
Figure imgf000092_0001
To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide and 3'- methoxy-[2,4'-bipyridin]-2'-amine (62.6 mg, 0.311 mmol) in tetrahydrofuran (4 niL) at rt was added lithium his(trimethyisiiyl)amide in THF (0.740 mL, 0.740 mmol) over 2 min. The resulting mixture was stirred at rt for 2 5 h. The reaction was quenched with water (2 mL). The mixture was adjusted with 1 N HC1 solution to pH 9-10, diluted with ethyl acetate (80 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous MgSOr and concentrated under vacuum. The residue was subjected to flash chromatograph (24 g silica gel, solid loading, 50-100% ethyl acetate/dichloromethane) to provided the desired product (37.0 mg, 0.099 mmol, 33.5 % yield) as a white solid. LCMS m/z ------ 372.9 < M 1 1 ) .
Step 2. Synthesis of 6-(Cyclopropanecarboxamido)-4-((3'-methoxy-[2,4'- bipyridin]-2'-yl)amino)-N-(methyl-d3)nicotinamide
A mixture of 6-chloro-4-((3'-meihoxy-[2,4'-bipyridin]-2'-yl)amino)-N~ trideuteromethy lnicotinamide (37 mg, 0.099 mmol), cyclopropanecarboxamide (21.11 mg, 0.248 mmol), tns(dibenzyhdeneaeetone)dipaliadium(G) (13.63 mg, 0.015 mmol), xantphos (8.61 mg, 0.015 mmol), and cesium carbonate (81 mg, 0.248 mmol) in 1,4- dioxane (2.2 mL) and NMP (0 3 mL) was heated under microwave at 145 °C for 1 h. The mixture was diluted with ethyl acetate (8 mL) and filtered through ce!ite. The filtrate was diluted with DMSO and MeOH, and injected to prep. HPLC. The correct practions w¾re combined, concentrated under vacuum, basified with 1.5 M K2HPO4 solution to pH 9-10, and extracted with dichloromethane (3 x 30 mL). The combined extract was dried over anhydrous NaSCfi and concentrated under vacuum. The residue w-as further purified by flash chromatograph (12 g silica gel, solid loading, 1-8% methanol/dichloromethane) to provide the desired product, 6-(cyclopropanecarboxamido)-4-((3'-methoxy-[2,4'- bipyridin]-2'-yl)amino)-N-trideuteromethylnicotinamide (13.2 mg, 0.031 mmol, 30.9 % yield), as a pale solid. LCMS m/z = 422.0 (M+H)+; 'l l NMR (400 MHz, DMSO-de) 6 12.01 (s, 1H), 10.77 (br s, 1H), 9.57 (s, 1H), 8.80 - 8.74 (m, 1H), 8.67 (s, 1H), 8.60 (s, 11 1). 8 14 (d, =5. i Hz, 1H), 8.04 - 7.94 (m, 2H), 7.49 (ddd, .7=6 7, 4.7, 2.1 Hz, 1H), 7.31 (d, =5.3 Hz, i l l). 3.60 (s, 31 1 }. 2.10 - 1.99 (m, 1H), 0.90 - 0.78 (m, 4H).
Figure imgf000093_0001
Step 1. Synthesis of 5-Chloro-3'-methoxy-[2,4'-bipytidin]-2'-amine
Figure imgf000093_0002
A mixture of 4-bromo-3-methoxypyridin-2-amine (180 mg, 0.887 mmol), 5- chloro-2-(tributylstannyl)pyridine (535 mg, 1.330 mmol), and
bis(triphenylphosphine)palladium(II) chloride (93 mg, 0.133 mmol) in 1,4-dioxane (8 mL) was heated at 115 °C for 16 h. The mixrure was diluted with ethyl acetate (15 mL) and filtered through Celite. The filiate was concentrated under vacuum. The residue was subjected to flash chromatograph (24 g silica gel, solid loading, 100% ethyl acetate) to provide the desired product, 5-chloro-3'-methoxy-[2,4'-bipyridin|-2'-aniine (177 mg, 0.751 mmol, 85 % yield), as a white solid LCMS m/z = 236.0 i \! H ) .
Step 2. Synthesis of 6-Chloro-4-((5-chloro-3'-methoxy-[2,4'-bipyridin]-2'- yl)amino)-N-(methyl-d3)nicotinamide
Figure imgf000094_0001
To a solution of 4,6-dichloro-N-tndeuteromethylpyridazme-3-carhoxamide and 5- chloro-3'-methoxy-[2,4'-bipyridin j~2'~amine (88 mg, 0.373 mmol) in tetrahydrofuran (5 mL) at rt was added lithium bis(trimethylsilyl)amide in THF (0.889 mL, 0.889 mmol) over 2 mm. The resulting mixture was stirred at rt for 90 mm. The reaction was quenched with water (2 mL). The mixture was adjusted with 1 N HCl solution to pH 9-10, diluted with ethyl acetate (80 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous MgSOr and concentrated under vacuum. The residue was subjected to flash chromatograph (24 g silica gel, solid loading, 50-100% ethyl acetate/dichloromethane) to provide the desired product (68 mg, 0.167 mmol, 46.9 % yield) as a white solid.
Step 3. Synthesis of 6-(Cyclopropanecarboxamido)-4-((5-
(cye!opropanecarhoxamido)-3'-methoxy-[2,4'-bipyridin]-2'-y!)amino)~N~(methyl- d3)nicotinamide
A mixture of 6-Chloro-4-((5-chloro-3'-methoxy-[2,4'-bipyridin]-2'-yl)amino)-N- (methyl-d3)nicotinamide (40 mg, 0.098 mmol), cyclopropanecarboxamide (20.90 mg, 0.246 mmol), tris(dibenzy!ideneacetone)dipa!!adium(0) (13.49 mg, 0.015 mmol), xantphos (8.52 mg, 0.015 mmol), and cesium carbonate (80 mg, 0.246 mmol) in 1,4- dioxane (2.2 mL) and NMP (0.3 mL) was heated under microwave at 140 °C for 1 h. The mixture was diluted with ethyl acetate (8 mL) and filtered through celite. The filtrate was concentrated under vacuum. The residue was dissolved in DMSG (2 mL) and submitted to SCP group for purification to provide the desired product (20 mg, 37% yield). LCMS mJz = 505.2 { M l ! } . 3H NMR (500 MHz, DMSO-de) d 1 1.98 (br s, 1H), 10.76 (s, I H i. 10.67 (s, 1H), 9.58 (s, 1H), 8.90 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.22 (br d, ./ 8.2 Hz,
H i). 8.11 (ά. .7=5.1 Hz, I I I}- 8.01 (br d, J= 8.6 Hz, 11 1 ). 7.34 (d, .7=5.1 Hz, I I I ). 3.60 (s, 3H), 2.03 (br s, 1H), 1.88 - 1.81 Cm. 1H), 0.93 - 0.76 (m, 8H)
Example 86
4 CC5 ChiorO-3, nieih0xy- 2,4,-b!pyridin| 2,-yi)imi!no)-6-(cydopropai!3eca5'boxamido}
~N-(met yI-d3)nicotinamide
Figure imgf000095_0001
A mixture of 6-chloro-4-((5-chioro-3'-methoxy-[2,4'-bipyridin -2'-yi)amino)-N- trideuteromethylnicotinamide (53 rng, 0.130 mmol), cyclopropanecarboxarnide ( 1 1.30 mg, 0.133 mmol), tris(dibenz) lideneacetone)dipailadium(O) (17.88 mg, 0.020 mmol), xantphos (11.29 mg, 0.020 mmol), and cesium carbonate (106 mg, 0.325 mmol) in 1,4- dioxane (2.5 mL) and NMP (0.3 mL) was heated under microwave at 135 °C for 1 h. The mixture was diluted with ethyl acetate (8 ml,) and filtered through celite. The filtrate was concentrated under vacuum. The residue was dissolved in DMSO and MeOH, and injected to prep. HPLC. The correct fractions were combined, concentrated under vacuum, basified with 1.5 M K2HPO4 solution to pH 9-10, and extrcted with
dichloromethane (3 x 35 mL). The combined extract was dried over anhydrous MgSOr. Removal of solvent under vacuum provided the desired product, 4-((5-chloro-3'-methoxy- [2,4'-bipyridin]-2 -yl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethyl nicotinamide (4.6 mg, 9.38 pmol, 7.21 % yield), as a yellow solid. LCMS m/z = 455.9 (M il) ; T-I NMR (400 MHz, DMSO-cU) d 12.05 (s, 1H), 10.93 - 10.72 (m, 1H), 9.55 (s, ill).882 (dd, J= 2.5, 0.7 Hz, 111).8.72 - 8.67 (ra, ill).860 (s.111).818 - 809 (m, 211). 8.07 - 802 (m, 1H), 7.31 (d, J=5.3 Hz, III).3.61 (s, 3H), 2.09 - 1.99 (m, ill).090 - 0.81 (m, 4H)
Example 87
6-(Cyclopropanecarboxamido)-4-((4-(5-(dimethylcai*bamoyl)pyrazin-2-yl)-3- methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure imgf000096_0001
Step 1. Synthesis of 5-Chloro-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000096_0002
To a suspension of 5-chloropyrazine-2-carboxylic acid (1.00 g, 631 mmol) in dichloromethane (12 mL) and DMF (0.015 mL) at rt was added oxalyl chloride (0.804 mL, 7.25 mmol) drop wise over 10 min. The mixture was stirred at rt for 2 h before it was concentrated under vacuum to dryness. Tire residue was dissolved in dichloromethan (15 mL). Dimethylamine in THF (3.94 mL, 7.88 mmol) was added at rt over 10 min, followed by triethylamine (1.934 mL, 13.88 mmol). The mixture was stirred at rt for 2 h. The mixture was diluted with ethyl acetate (50 mL) and filtered through Cehte. The filtrate was concentrated under vacuum to dryness, and the residue was applied to flash chromatograph (80 g silica gel, solid loading, 65-100% ethyl acetate) to provide the desired product, 5-chloro-N,N-dimethylpyrazine-2-carboxamide (1.07 g, 5.76 mmol, 91 % yield), as a white solid. LCMS m z 186.1 (M+H)+.
Synthesis of N,N-Dimethyl-5-(trimethylstannyl)pyrazine-2-carboxamide
Figure imgf000097_0001
A mixture of 5-chloro-N,N-dimethylpyrazine-2-carboxamide (300 mg, 1.616 mmol) tetrabutylammonium iodide (657 mg, 1.778 mmol), 1,1 , 1,2, 2, 2- hexamethyldistannane (0.402 mL, 1.940 mmol), and
tetrakis(triphenyiphosphine)palladium(0) (112 mg, 0.097 mmol) in toluene (8 mL) was degassed and heated at 105 °C for 16 h. Upon cooling to rt, the mixture was diluted with ethyl acetate (15 mL) and filtered through C elite. The filtrate was concentrated under vacuum, and the residue was subjected to flash chromatograph (80 g silica gel, solid loading, 35-85% ethyl acetate/hexane) to provide the desired product, N,N-dimethyl-5- (trimeihylstannyl)pyrazine-2-carboxamide (96 mg, 0.306 mmol, 18.92 % yield), as a light yellow solid. LCMS m/z = 315.9 (Vl - Hj . Step 3. Synthesis of 5-(2-Amino-3-methoxypyridin-4-yl)-N,N-dimethylpyrazine·
2-carboxamide
Figure imgf000098_0001
A mixture of 4-bromo-3-methoxypyridin-2-amine (133 mg, 0.655 mmol), N,N- dimeihyl-5-(trimethylstannyi)pyrazine-2-carboxamide (226 mg, 0.721 mmol), and bis(triphenylphosphine)palladium(II) chloride (69.0 mg, 0.098 mmol) in 1,4-dioxane (6 mL) was heated at 115 °C for 16 h. The mixrure was diluted with ethyl acetate (15 mL) and filtered through Celite. The filiate was concentrated under vacuum. The residue was subjected to flash chromatograph (24 g silica gel, solid loading, 0-6% MeOH/CH2C12) to provide the desired product, 5-(2-amino-3-methoxypyridin-4-yl)-N,N-dimethylpyrazine- 2-carhoxamide (88 mg, 0.322 mmol, 49.2 % yield), as a white solid. LCMS m/z = 274.0 ·; M i l )
Step 4. Synthesis of 6-Chloro-4-((4-(5-(dimethylcarbamoyl)pyrazin-2-yl)-3- methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure imgf000098_0002
To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide and 5-
(2-amino-3 -methoxy pyridin-4-y l)-N,N-dimethy 1 py razine-2-carboxami de ( 109 mg, 0.400 mmol) in tetrahydrofuran (6 mL) at rt was added lithium bis(tnmethylsiiyl)amide in THF (0.981 mL, 0.981 mmol) over 2 min. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (60 mL). The mixture was adjusted with 1 N HC1 solution to pH 9-10. The insoluble product, 6-chloro-4-((4-(5-(dimethylcarbamoyl) pyrazin-2-yl)-3-methoxypyridin-2-yl)amino)-N-trideuteromethylpyridazine-3- carboxamide (91 mg, 0.204 mmol, 52.0 % yield), was collected as a beige solid by suction filtration and dried at 50 °C under vacuum. LCMS m/z = 445.9 (M+H)f
Step 5. Synthesis of 6-(Cyclopropanecarboxamido)-4-((4-(5-
(dimethylcarbamoyl)pyrazin-2-yl)~3-methoxypyridin-2-yl)amino)-N-(methyl~ d3)pyridazine-3-carboxamide
A mixture of Reactant 1 (45 mg, 0.101 mmol), cyclopropanecarboxamide (21.47 mg, 0.252 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.86 mg, 0.015 mmol), xantphos (8.76 mg, 0.015 mmol), and cesium carbonate (82 mg, 0.252 mmol) in 1,4- dioxane (2.6 mL) and NMP (0.4 mL) was heated under microwave at 145 °C for 1 h. The mixture was diluted with ethyl acetate (8 ml.) and filtered through celite. The filtrate was concentrated under vacuum. The residue was dissolved m DMSO and MeOH, and injected to prep. HPLC. The correct fractions were combined, concentrated under vacuum, hasified with 1.5 M K2HPO4 solution to pH 9, and extracted with
dichloromethane (3 x 35 mL). The combined extract was dried over anhydrous NarSOr, and concentrated under vacuum. The residue was further purified by flash chromatograph (24 g silica gel, solid loading, 0-7% MeOH/dichloromethane) to give the desired product, 6-(cyclopropanecarboxamido)-4-((4-(5-(dimethylcarbamoyl)pyrazin-2-yl)-3- methoxypyridin-2-y!)amino)~N~trideuteromethy!pyridazine-3~carboxamide (10.4 mg, 0.021 mmol, 20.63 % yield), as a yellow solid. LCMS m/z = 495.0 (M+H) 1: Ή NMR (400 MHz, DMSO-do) d 12.50 (s, 1H), 11.36 (s, 1H), 9.88 (s, 1H), 9.26 (s, 1H), 9.21 (d,
J 1.5 Hz, i l l ). 9.02 (d. ./ 1.5 Hz, 11 1). 8.26 (d, .7=5.3 Hz, i l l). 7.44 (d, ,7=5.3 Hz, I f !) 3.71 (s, 3H), 3.08 (s, 3H), 3.06 (s, 3H), 2.19 - 2.11 (m, 1H), 0.95 - 0.86 (m, 4H).
Figure imgf000099_0001
methoxy py rid in-
Figure imgf000099_0003
ine-3
Figure imgf000099_0002
Figure imgf000100_0001
This compound was prepared using a similar procedure used to prepare Example 87. LCMS m/z = 509.0 (VI 11) ; !11 NMR (400 MHz, DMSO-tk) d 12.52 (s, ill).11.40 (s, HI).989 (d, ,/ 2.4 Hz, HI).9.29 (s, 111).9.21 (dd, .7=5.0, 1.5 Hz, ill).9.02 (dd,
.7=29, 15 Hz, 1H), 826 (d, .7=5.3 Hz, HI).7.44 (d, 7=5.1 Hz, 1H), 3.70 (s, 3H), 3.55 (q, 7=7.1 Hz, 1H), 3.41 - 3.35 (m, 1H), 3.04 (d, 7=8.3 Hz, 3H), 2.20 - 2.07 (m, 1H), 1.23 - 1.12 (m, 3H), 0.96 - 0.82 (m, 4H). Example 89
6-(2-Cyclopropylacetamido)-4-((4-(5-(dimethylcarbamoyl)pyrazin-2-yl)-3- methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure imgf000100_0002
This compound was prepared using a similar procedure used to prepare Example
87. LCMS m/z = 509.1 (M+H)+;‘HNMR (400 MHz, DMSG-de) 612.51 (s, 111).10.95 (s, 1H), 9.93 (s, 1H), 9.26 (s, 1H), 9.22 (d, .7=1.5 Hz, i l l ). 9.03 (d. -/ 1.5 Hz, ! ! ! ). 8.30 (d, .7=5.3 Hz, 1H), 7.46 (d, .7=5 3 Hz, 1H), 3.72 (s, 3H), 3.09 (s, 3H), 3.06 (s, 3H), 2.40 (d, .7=7 0 Hz, 2.1 1). 1.17 - 1.05 (m, 1H), 0 55 - 0.48 (m, 2H), 0.26 - 0.20 (m, 2H)
Example 90
4-((4-(5-(Dimethylcarbamoyl)pyrazin-2-yI)-3-methoxypyridm-2-yl)amino)-N-
(methyl-d3)-6-((l-methyl-lH-pyrazol-3-yl)amino)pyridazine-3-carboxamide
Figure imgf000101_0001
A mixture of 6-chloro-4-((4-(5-(dimethylcarbamoyl)pyrazin-2-yl)-3- meihoxypyridin-2-y4)amino)~N~irideuteromeihylpyridazine~3~carboxarmde (30 mg, 0.067 mmol), 1 -methyl-lH-pyrazol-3-amine (13.07 mg, 0.135 mmol), and 4- methylbenzenesulfonic acid monohtdrate (19.20 mg, 0.101 mmol) in THF (2.0 mL) was heated in a closed vial at 100 oC for 20 h. The mixture was then concentrated under vacuum to dryness. The residue was dissolved in DMSO and MeOH, and injected to prep. HPLC. The correct fractions were combined, concentrated under vacuum, basified with 1.5 M K2HPO4 solution to pH 9-10, and extracted with dichloromethane (3 x 35 mL). The combined extract was dried over anhydrous NarSC Removal of solvent under vacuum provided the desired product, 4-((4-(5-(dimethylcarbamoyl)pyrazin-2-yl)-3- methoxypyndin-2-yl)amino)-N-tndeuterometliyl-6-((l-metliyl-iH-pyrazol-3- y])amino)pyridazine-3-carboxamide (14 3 mg, 0.027 mmol, 40.7 % yield), as a yellow' solid. LCMS m/z = 507 2 (M+H)+; ¾ NMR (400 MHz, DMSO-de) d 12 39 (s, 1H), 9.91
- OO - (s, 111).9.28 (s, 111).9.22 (d, ,/ 1.6 Hz, ill).9.15 (s, ill).9.02 (d, .7=1.5 Hz, 111).8.28 (d, .7=5.1 Hz, ill), 7.60 (d, .7=21 Hz, 1H), 7.42 (d, .7=53 Hz, 1H), 630 (d, .7=2.1 Hz, 1H), 382 (s, 311).371 (s, 311).309 (s, 311).306 (s, 311).
Example 91
6-((l,5-Dimethyl-lH-pyrazol-3-yl)aimno)-4-((4-(5-(dimethylcarbamoyl)pyrazin-2- yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure imgf000102_0001
This compound was prepared using a similar procedure used to prepare Example 90. LCMS m/z = 521.2 (Vl l!) : ¾ NMR (400 MHz, DMSO-ds) d 12.38 (s, III).9.80 (s, Ml).9.31 (s, ill).9.22 (d, .7=1.5 Hz, 1H), 9.13 (s, 1H), 9.02 (d, .7=1.6 Hz, 1H), 8.28 (d,
./ 5.3 Hz, ill).7.42 (d, .7=5.1 Hz, 111).6.11 (s, 111).3.71 (s, 3H), 3.70 (s, 3H), 3.09 (s, 3H), 3.06 (s, 3H), 2.26 (s, 3H).
Example 92
6-((5-Chloro~l-methyl~lH-pyrazol-3-yl)ammo)-4-((4-(5~
(dimethykarbamoyl)pyrazin~2~yl)-3--methoxypyridiii-2--yl)ammo)-N-(methyl~ d3)pyridazme-3-earboxamide
Figure imgf000103_0001
This compound was prepared using a similar procedure used to prepare Example 90. LCMS m/z = 5411 (M+H)+; *H NMR (400 MHz, DMSO-de) d 1241 (s 1H), 1006 (s.111).924 - 9.20 (m, 2H), 9.17 (s, ill).9.02 (d, .7=15 Hz, 111).8.29 (d, ./ 5.1 Hz, 111). 743 (d, ,7=5.1 Hz, 1H), 648 (s, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.08 (s, 3H), 3.06 (s, 3H).
Figure imgf000103_0002
4-((4-(5-fluoropyrimidin-2-yl)-3-methoxjpyridin-2-yl)amino)-6-((5-(2-hydiOxypropan-2 yI)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure imgf000103_0003
Figure imgf000104_0001
Step 1:
4-bromo-3-methoxypyridin-2-amine (500 mg, 2.463 mmol),
bis(pinacolato)diboron (1376 mg, 5.42 mmol), l,r-bis(diphenylphosphino)ferrocene- pal!adium(II)dich!oiide dichloromethane complex (201 mg, 0.246 mmol) and potassium acetate (725 mg, 7.39 mmol) were mixed in dioxane (20 mL) , degassed with nitrogen for 5 min then healed at 100 °C for o/n. After cooling to rt, the reaction mixture was filtered and !,r-bis(diphenylphosphino)ferrocene-paliadium(II)dichloride dichloromethane complex (201 mg, 0.246 mmol) and 2-chloro-5-fluoropynmidine (424 mg, 3.20 mmol) were added, then Na2C03 (3694 mΐ, 7.39 mmol) (2 M) solution, the mixture was degassed with nitrogen and heated at 105 °C for 4.5h. LC-MS indicated the completion of the reaction. The mixture was diluted with MeOH (15 mL), and was fdtered through a pad of celite and the filtrate was concentrated, the residue w'as mixed v ith DCM, and purified with ISCO column (12 g, AcOEt/Hexane ::: 0-100%, gradient time ::: 15 min) to provide 4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-amine. Yield 260 mg (47.9%). LCMS mlz 221.2 (M+H)+; HPLC tR 0.726 min (analytical HPLC Method A); 1H MMR (400 MHz, METHANOL-d4) d 9.00 - 8.72 (m, 2H), 7.78 (d, j 5.5 Hz, i l l ). 7.00 (d,
.1 5.3 Hz, 11 1 ). 3.73 (s, 3H). Step 2:
To a clear solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (195 mg, 0.931 mmol) and 4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-amine (205mg, 0.931 mmol) in THF (6 ml) was added lithium bis(trimethylsiiyl)amide (2327 mΐ, 2.327 mmol) dropwise at 0°C slowly, the mixture was stirred at 0-rt for 2 5h.The mixture was added vrater (lml) at 0°C with stirring, then with IN HC1 (3ml), the mixture was stirred at 0°C for 30min and the solid was collected with filtration and w ashed with w¾ter (2x), dried to give the desired compound as off wiiite solid: 6-chloro-4-((4-(5-fluoropyrimidin- 2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. Yield 170 mg (46.5%). LCMS m/z 221.2 (M+H)+; HPLC tR 1.13 mm (analytical HPLC Method A); 1H NMR (400MHz, DMSO-d6) d 12.60 (s, 11 1). 9.58 - 9.45 (m, i l l :·. 9.26 (s, i l l ). 9.13 (d, .1 0.9 Hz, 2H), 8.30 (d, j 5.3 Hz, 1H), 7 45 (d, 1=5.3 Hz, i l l ). 3 82 (s, 31 1 )
Step 3:
To a clear solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (195 mg, 0.931 mmol) and 4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-amine (205mg, 0.931 mmol) in THF (6 ml) was added lithium bis(trimethyisilyl)amide (2327 mΐ, 2.327 mmol) dropwise at 0°C slowly, the mixture was stirred at 0-rt for 2.5h.The mixture w¾s added water (1ml) at 0°C with stirring, then with IN HC1 (3ml), the mixture was stirred at 0°C for 30min and the solid was collected with filtration and washed with w-ater (2x), dried to give the desired compound as off wiiite solid: 6-chloro-4-((4-(5-fluoropyrimidin- 2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. Yield 170 mg (46.5%). LCMS m/z 221.2 (M+H)+; HPLC tR 1.13 min (analytical HPLC Method A); 1H NMR (400MHz, DMSO-d6) d 12.60 (s, i l l). 9.58 - 9.45 (m, 1H), 9.26 (s, 1H), 9.13 (d, J=0.9 Hz, 2H), 8.30 (d, j 5.3 Hz, 1H), 7.45 (d, 1=5.3 Hz, 1H), 3.82 (s, 31 i )
The Examples in Table 3 w?ere prepared using a similar procedure used to prepare Example 93.
Table 3
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0003
Figure imgf000108_0001
4-((3-methoxy-4-(2-methyl-2H-tetrazol-5-yl)pyridin-2- l)amino)-N-(methyl-cl3)-6-((4-
Figure imgf000108_0002
Figure imgf000109_0001
Step 1 :
To the mixture of 2~armno-3-rnethoxyisonicotinonitrile (200 mg, 1.341 mmol), Boc- Anhydride (934 mΐ, 4.02 mmol) in DCM (10ml) was added TEA (561 mΐ, 4.02 mmol) and DMAP (164 mg, 1.341 mmol), the mixture was stirred at rt for o/n, and the mixture was quenched with water (5ml) at 0°C and diluted with DCM (50ml), which w¾s washed with sat. NaHC03 (40ml), dried (Na2S04) and concentrated under vacuo and the residue was purified with iseo column (25g, AcOEt/Hexane = 0-100%, gradient time =12min), peakl (tl 1, out@35% AcOEt) w¾s the desired product. Yield 320 mg (68.3%). LCMS ra/z 350.3 (M+H)+; HPLC tR 1.26 min (analytical HPLC Method A); I I I N.Y1R (400 MHz, CHLOROFORM-d) d 8.46 - 8 16 (m, 1H), 7.47 id. .1 5. 1 Hz, 1 1 1). 4.15 (s, 3H),
1.46 (s, 18H)
The product of step one (320 mg, 0.916 mmol) in anisole (2ml), TEA (51 1 mΐ,
3.66 mmol) were added at 60°C, then AcOH (210 mΐ, 3.66 mmol) and NaN3 (208 mg,
3.2! mmol), heated at 130°C (N2) for 4.5h. The mixture was cooled, then mixed with AcOEt (30ml) and water (15ml), shaked and the aqueous layer was extracted one more time with AcOEt (10ml), the aqueous layer was acidified with IN HC1 to pH = 4-5 and extracted with AcOEt (2x20ml), this organic layer was washed with brine, dried (Na2S04) and concentrated under vacuo to get the desired product which was used to the next step without further purification. Crude yield 150 mg (41.7%). LCMS m/z 393.4 (M+H)+; HPLC tR 1.06 min (analytical HPLC Method A); 1H NMR (400 MHz, METHANOL-d4) d 8.59 - 8 30 (m, 1H), 8.04 (d, j 5. 1 Hz, 1 1 1). 3 85 (s, 3H), 1.45 (s, 1 81 1 )
Steps 3 and 4:
To the product of step 2 (l50mg, 0 382 mmol) in DMF (2 rnL) was added K2CO3 (106 mg, 0 765 mmol) and Mel (47 8 mΐ, 0.765 mmol), the mixtre was stirred at rt for o/n. The mixture was diluted with AcOEt (50ml) and water (20ml), the org. layer was washed with NaHC03 (2x20ml), brine (20ml), dried (Na2S04) and concentrated under reduced pressure, the residue was purified with isco column (12g, AcOEt/Hexane =0-100%, 30ml/mm, gradient 15min) to get the 2 regioisomers. The less polar one (peakl) is the desired product (out at 50% AcOEt). The product was used to next step. The above product was mixed with DCM (4ml) and 2 ml of TFA was added and the mixture was stirred at rt for 1.5h., concentrated under vacuo and the residue was dissolved in DCM (30ml), which was wushed with sat. NaHC03 (15ml), the aqueous layer was extracted with DCM (20ml) and the organic layers were combined and dried (Na2S04) and concentrated under vacuo to give the desired product. Yield 40 mg (50.7%); LCMS m/z 207.3 I’vf H) : HPLC tR 0.52 min (analytical HPLC Method A); 1H NMR (400MHz, CHLOROFORM-d) d 7.95 (d, j 5.3 Hz, 1H), 7.39 - 7.16 (m, 1H), 4.97 (hr. s., 2H), 4.47 (s, 3H), 3.86 (s, 3H)
Step 5:
A solution of 3-meihoxy-4-(2-me†hyl-2H-tetrazol-5-yl)pyridin-2-amine (38 mg, 0.184 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (38 3 mg, 0.184 mmol) in DMF (3 ml) wns cooled to 0 °C and NaH (29.5 mg, 0.737 mmol) was added in a single portion, after 15 minutes the reaction was taken up to room temp. The reaction was monitored by LCMS. The solution was slowly turned darker and yellowish brown.
Quenched after o/n by stirring with saturated aqueous ammonium choride (2ml) and water (0.5ml) at 0°C. Brown precipitate was formed, the mixture was stirred for 30mm. The solid was collected with filtration, washed w'ith water and dried under vacuo to give the desired product which was used as is. Yield 46mg (66.1%). LCMS m/z 378.0
(M+H)+; HPLC tR 0.83 min (analytical HPLC Method A); 1H NMR (400MHz, DMSO- d6) d 12.34 - 12.05 (m, 11 1 }. 9.01 (s, i l l }. 8.96 - 8.84 (m, 11 1 ). 8.67 (s, 11 1 ). 8.30 (d, J 5. 1 Hz, 1H), 7.55 (d, .1 5 3 Hz, 1H), 4.51 (s, 3H), 3.90 (s, 3H)
Step 6:
A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-tetrazol-5-yl)pyridm-2- yl)amino)-N-(methyl-d3)nicotinamide (12 mg, 0.032 mmol), 4-methyl pyrudine amine (6.87mg, 0.064mmol), xantphos (3.68 mg, 6.35 pmol), Cs2CQ3 (20.70 mg, 0.064 mmol) and Pd2(dha)3 (2.91 mg, 3.18 mhioΐ) m dioxane (0.5 mL) was sparged with nitrogen for 2 min., then it was stirred at 130°C for 3h. After cooling the mixture was concentrated and diluted with DMSG and purified with preparative HIM (
Yield 4.4mg (30.6%). LCMS m/z 450.4 (M+H)+; HPLC tR 0.96 mm (analytical HPLC Method A); 1H NMR (500 MHz, DMSO-d6) d 12.12 (s, 1H), 9.77 (br s, 1H), 9.36 (s,
1H), 8.58 (s, 2H), 8.24 (d, 1=5.1 Hz, 1H), 8.16 (d, 1=5.0 Hz, 1 1 1 ). 7.53 (s, 1 1 1 ). 7.47 (d, 1=5.1 Hz, I I I ). 6.77 (br d, 1=5.0 Hz, 1H), 4.51 (s, 3H), 3.45 - 3.42 (m, 3H), 2.29 (s, 3H) The Examples in Table 4 were prepared using a similar procedure used to prepare
Figure imgf000111_0001
Figure imgf000112_0002
The Examples m Table 5 were prepared using a similar procedure used to prepare the preceding examples.
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
BIOLOGICAL ASSAYS
The following assay is used to show the activity for compounds of the invention.
IFNa-Induced STAT Phosphorylation in Human Whole Blood After an hour long incubation with compound, human whole blood (drawn with either EDTA or ACD-A as anti-coagulant) was stimulated with 1000 U/mL recombinant human IFNa A/D (R&D Systems 11200-2) for 15 min. The stimulation was stopped by adding Fix/Lyse buffer (BD 558049). Cells were stained with a CD3 FITC antibody (BD 555916), washed, and permeabilized on ice using Perm III buffer (BD 558050). Cells were then stained with an Alexa-Fluor 647 pSTA'15 (pY694) antibody (BD 612599) for 30 mm prior to analysis on the FACS Canto II. The amount of pSTATS expression was quantitated by median fluorescence intensity after gating on the CD3 positive population. IFNa-Induced STAT Phosphorylation in Human Whole Blood Inhibition Data
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
ND - no data available

Claims

WE CLAIM:
1. A compound of formula I:
Figure imgf000122_0001
wherein
X is N or CH;
R1 is selected from H, CD3, C1-3 alkyl or C3-6 cycloalkyl;
R2 is -C(0)R2a; C1-6 alkyl, -(CH?.)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH?)rORb,
-(CH2)rSRb, -(CH2) C(0)Rb, -(CH2)rC(0)ORb, -(CH2 OC(0)Rb, CHrlrNR^R11,
-(CH2)rC (0)NR'! 1 R11 , ~(CH2)rNRbC(0)Rc, ~(CH2)rNRbC(0)QRc, -NRhC{())\ R! ! RM. -S OipNR1^11, -NRbS(0)pRc, -S(0)PRc, Ci-6 alkyl substituted with 0-3 R3, Cue haloalkyl, C2-6 alkenyl substituted with 0-3 R3, -(CH2)f-3-l4 membered carbocycle substituted with 0-1 R3 or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 R3;
R3 is H, Ci-3 alkyl or C3-6 cycloalkykR4 is H, C1-3 alkyl or C3-6 cycloalkyl;
R5 is Ci -4 alkyl substituted with 0-1 R5a, C1-4 alkoxy substituted with 0-1 R53, (CH2)r..phenyl substituted with 0-3 R5a or a ~(CH2)~5~7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
R5,3 is is independently at each occurrence, H, F, Cl, Br, OCF3, CFs, CN,
NO?, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, C1-6 alkyl or (CH )r-phenyl substituted with 0-3 Rf; R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 rnerabered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rba;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CFN, C ?3-J O cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N. O, and S(0)p substituted with 0-3 Rd;
R7 is H, Ci-3 alkyl or Ci-6 cycloalkyl;
RH at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CFy C3-10 cycloalky] substituted with 0-1 Rf, (CH)r-pheny] substituted with 0-3 Rd or -(CH2)r~5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd:
Ra at each occurrence is independently H, F. Cl, Br, OCFs, CF3, CHF2, CN,
Figure imgf000123_0001
alkyl substituted with 0-3 R1, C1-6 haloalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-e alkynyl substituted ith 0-3 R3, -(CH2)r-3-14 membered carbocycle or ~(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, Ci-e. haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci-6 alkyl substituted with 0-3 R1, (CH2)r~C3-6 cycloalkyl substituted with 0-3 R1 or (CH2)r-phenyI substituted with 0-3 R1;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Ci-e alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
The compound according to claim 1 of the formula
Figure imgf000124_0001
wherein
X is N or CH;
R1 is selected from H, CDs, CM alkyl or C3-6 cycloalkyl;
R2 is -C(0)R a; Cue alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH2)rORb,
-(CH?)rSRb, -(CH?)rC(0)Rb, -(CH?)rC(0)0Rb, -(CH?)rOC(0)Rb, CH2)rNR11R11,
-(( i l ' 'CO)\ : : Rn. -(CH?)rNRbC (0)RC, -(CH2)rNRbC(0)0Rc, -NRbC(0)NRiiR11, -S(0)pNR!1R11, -NRbS(0)pRc, -S(0)PRc, CM alkyl substituted with 0-3 Ra, C1 -6 haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-I4 membered carbocycle substituted with 0-1 R3 or a ~(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 R3;
RJ is H, Ci-3 alkyl or C3-6 cycloaikykR4 is H, C1-3 alkyl or C3-6 cycloalkyl; R5 is Ci -4 alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
R3a is is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN,
NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Ci-e alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
R6 is Ci-4 alkyl substituted with 0-1 Rba, (CFh)r-phenyl substituted with 0-3 Rba or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 RM;
R6a is H, Ci-4 alkyl substituted with 0-3 R1, CFs, C3-10 cyc!oalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, Cs-io cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN,
NO2, -(CH2)rORb, -{C! I OrSR!l. -(CH2)rC(0)Rb, -(CH2)rC(0)ORb,
-(CH2)rOC(0)Rb, -( ( 1 !’ }:N R‘‘ R1 -(CH2)IC(0)NR11R11, -(CH2)rNRbC(0)R£, -(CH2)rNRb C(0)ORc, -NRbC(0)NR11R11, -S^pNR1^11, ~NRbS(0)PRc, -S(0)Rc, -S(0)2Rc, Ci-e alkyl substituted with 0-3 Rf, Cue haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)i-3-14 membered carbocycie or -(CFb) -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1;
Rb is H, C -6 alkyl substituted with 0-3 Rd, C1-6 haloalkyi, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2.) -5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci -6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)0Rc, C1-6 alkyl or (CH2) -phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 eycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a ··{('! 1 · },·'· -7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1 , or 2;
r is 0, 1,
2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 of the formula
Figure imgf000126_0001
wherein
X is N or CH;
R2 is ~C(0)R2a; C1-6 alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
Figure imgf000126_0002
0-1 Ra or a -(CH2)I-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R3 is H, Ci-3 alkyl or C3-6 cycloalkykR4 is H, C1-3 alkyl or C3-6 cycloalkyl;
R' is C1-4 alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
Rsa is is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN,
NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, C1-6 alkyl or (CH2)r-phenyi substituted with 0-3 R1;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (Ci I '}·. phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R6a;
R6a is H, Ci -4 alkyl substituted with 0-3 Rf, CF3, C3 -10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CFh)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, Cf !!·' ·. CN,
Figure imgf000127_0001
alkyl substituted with 0-3 R1, Ci-6 haloa!kyi, C2-6 alkenyl substituted with 0-3 Ra, C2-e alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(G)P substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyd, C3-6 cycloalkyd substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)f-phenyl substituted with 0-3 Rd; Rc is Ci -6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCFs, CF3, CN, NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)0Rc, Ci-e alkyl or (CHaVphenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloalkyd or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 of the formula
Figure imgf000128_0001
wherein
X is N or CH;
R2 is -C(0)R2a; C--6 alkyl, -(CFl2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 3;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
··(( l l’PSRk -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2) OC(0)Rb, CH2)fNR! !R11,
-(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(0)NR! !R11, -S(0)pNRnRn, -NRbS(0)pRc, -S(0)PRc, Ci-e alkyl substituted with 0-3 R3, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH?)r-3-14 membered carbocycle substituted with 0-1 Ra or a ~(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 R3;
R3 is H, Ci-3 alkyl or C3-6 cycloalkyliR5 is Ci-4 alkyl substituted with 0-1 R5a, Cm alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
Rsa is is independently at each occurrence, H, F, Cl, Br, OCFs, CF3, CN,
NO2, -ORe, -(CH2)IC(0)Rc, -NReRe, -NReC(())()Rc, C1-6 alkyl or (CH2)r-phenyi substituted with 0-3 R1;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2.)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 R6a;
R6a is H, Ci -4 alkyl substituted with 0-3 Rf, CF3, C3 -10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2.)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CFIF2, CN,
Figure imgf000129_0001
alkyl substituted with 0-3 R1, Ci-6 haloalkyi, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CFbVS-M membered carbocycle or -(CH2.)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(G)P substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyi, C3-6 cycloalkyi substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CFbVphenyi substituted with 0-3 Rd; Rc is Ci -6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCFs, CF3, CN, NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)0Rc, Ci-e alkyl or (CHaVphenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloalkyd or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 of the formula
Figure imgf000130_0001
wherein
X is N or CH;
R2 is -C(0)R2a; C --6 alkyl, -(CFl2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 3;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
Figure imgf000130_0002
-S(0)pNRnRn, -NRbS(0)pRc, -S(0)PRc, Ci-e alkyl substituted with 0-3 R3, C1-6 haloalkyl,
C2-6 alkenyl substituted with 0-3 Ra, -(CH2)t-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)I-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R5 is Ci -4 alkyl substituted with 0-1 R5a, Ci-4 alkoxy substituted with 0-1 R5a, (CH2)r-phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(G)P;
R3a is is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN,
NO?., -ORe, (CH?)rC(0)Rc, -NReRe, -NReC(0)ORc, C1-6 alkyl or (CH?)r-plienyl substituted with 0-3 Rf;
R6 is Ci - alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH?)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R6a;
R6a is H, Ci -4 alkyl substituted with 0-3 Rf, CF:<, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
RH at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalky] substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd:
Ra at each occurrence is independently H, F, Cl, Br, OCFs, CF3, CHF?, CN,
NO?, -(CH?)rORb, -(CFI?)rSRb, -(CH?)rC(0)Rb, -(CH?)rC(0)ORb,
Figure imgf000131_0001
alkyl substituted with 0-3 R1, C1-6 haloalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 R3, ~(CH?)r-3-14 membered carbocycle or -(CH?)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, Ci-e. haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH?)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci-6 alkyl substituted with 0-3 R1, (CH2)r~C3-6 cycloalkyl substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 R1; Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a --{ l 1 · },·'· -7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1 , or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
6 The compound according to claim 5 of the formula
Figure imgf000132_0001
wherein
X is N or CH;
R2 is ~C(0)R2a; Ci-6 alkyl, -(CH2)r-3-14 membered carbocyele substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
Figure imgf000132_0002
aikyl C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocyele substituted with 0-1 Ra or a -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra; R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 rnerabered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rba;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CFN, C -jo cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N. O, and S(0)p substituted with 0-3 Rd;
R11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R1, CFs, Cs-io cycloalkyl substituted with 0-1 Rf, (CH)f-phenyi substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CFs, CHF2, CN,
NO’. -(CH2)IORb, -(CH2)rSRb, -(CH2)fC(0)Rb, -(CH2)IC(0)ORb,
Figure imgf000133_0001
alkyl substituted with 0-3 Rf, Ci-6 haioalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, ~(CH2)r-3-I4 membered carbocycle or ~(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Ry
Rb is FI, Ci-6 alkyl substituted with 0-3 Rd, Ci-e haioalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocyele containing 1 -4 heteroatoms selected from N, O, and S(Q)P substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci-e alkyl substituted with 0-3 Ry (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO’. -ORe, -(CH2)rC(0)Rc, -NR Ry -NReC(0)ORy Ci-e alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CFI2)r -phenyl substituted with 0-3 Rf;
1 is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocyele containing 1-4 heteroatoms selected from N, O, and S(0)P; p is 0, 1, or 2;
r is 0, 1 , 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 of the formula
Figure imgf000134_0001
wherein
R2 is -C(0)R2a; Ci-6 alkyl, -(CH2)r-3-14 membered earbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)iORb,
-(CH?.)rSRb, -(CH2)rC(0)Rb, -(CH2>C(0)0Rb, -(CH2)rOC(0)Rb, CHrfNR^R11,
-(CTy CCC NR1 ¾u, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(0)NRnRn, -S(0)pNRi lR11, ~NRbS(0)pRc, -S(0)pRc, Ci-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-14 membered earbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(OlP substituted with 0-2 R3;
R6 is C1-4 alkyl substituted with 0-1 Rba, (CH2)r-phenyl substituted with 0-3 R63 or a -(CH2)-5-7 membered heterocycle containing 1 -4 heteroatoms selected fromN, O, and Rba is H, C la alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R! ! at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0- 1 R1, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rd; Ra at each occurrence is independently H, F, CL Br, OCFy CF3, CHF2, CN,
NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb,
-(CH2)IOC (0)Rb, -(CH2)rNR11R1L ~(CH2)rC(0)NR33R3 L ~(CH2)rNRbC(Q)Rc, -(CH2)rNRb C(Q)ORc, -NRbC(0)NRnRn, -S(0)PNR!1R11, -NRbS(0)PRc, -S(0)Rc, -S(0)?Rc, Cue alkyl substituted with 0-3 Rf, CI-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R3, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-l4 membered carbocyc!e or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rf;
Rb is H, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)t-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO¾ -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, C1-6 alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, Cj-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1 , or 2;
r is 0, 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
8 The compound according to claim 7 of the formula
Figure imgf000136_0001
wherein
R2 is -C(0)R2a; Ci-6 alkyl, -(CH?.)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH?)rORb,
-(CH2)rSRb, -(CH2) C(0)Rb, -(CH2) C(0)ORb, -(CH2 OC(0)Rb, CI-fclrNR^R11,
-(CH2)rC(0)NR11R11, ~(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC{0)\ R! ! RM. -S OipNR1^11, -NRbS(0)pRc, -S(0)PRc, Ci-6 alkyl substituted with 0-3 R3, Cue haloalkyl, C2-6 alkenyl substituted with 0-3 R3, -(CH2)f-3-14 membered carbocycle substituted with 0-1 R3 or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 R3;
R6 is Cj-4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R53;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C l3-io cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R1, CF3, Cs-io cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF?, CN,
NO’. -(CH2) ORb, -(CH2)rSRb, -(CH2)fC(0)Rb, -(CH2)fC(0)ORb,
-(CH2)rOC(0)Rb, -(CH2) NRi f R! !, -(CH2)IC(0)NR11R11, -(CH2)rNRbC(0)Rc, -(CH2)rNRb C(0)ORc, -NRbC (O)NR 1 ¾ 11 , -S(0)PNRilR11, -NRbS(0)PRc, -S(0)Rc, ~S(0)2Rc, Ci-e alkyl substituted with 0-3 Rf, Ci-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1;
Rb is H, C -6 alkyl substituted with 0-3 Rd, Ci-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci -6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyi substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Ci-e alkyl or (CH2)t-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)I-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2;
r is 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
9. The compound according to claim 8 of the formula
Figure imgf000137_0001
wherein
R2 is -C(0)R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a; R2a at each occurrence is independently H, OCFs, CN, NC , -(CH2)iORb,
Figure imgf000138_0001
-S(0)pNRuR!!, -NRbS(0)PRc, -S(0)PRc, Ci-6 alkyl substituted with 0-3 Ra, Ci-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)f-3-l4 membered carbocycie substituted with 0-1 R3 or a -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-2 Ra;
R6 is Ci -4 alkyl substituted with 0-1 R6a, (CH2)r-phenyl substituted with 0-3 R6a or a -(CH2)-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rba;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CFi, C hao cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rd;
R11 at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 R1, CFs, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)f-phenyi substituted with 0-3 Rd
or -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CFs, CHF2, CN,
NO’. -(CH2) ORb, -(CH2)rSRb, -(CH2)fC(0)Rb, -(CH2)fC(0)ORb,
Figure imgf000138_0002
alkyl substituted with 0-3 Rf, Ci-6 haloalkyl, C2-e alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted w th 0-3 Ra, ~(CH2)r-3-14 membered carbocycie or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(Q)P substituted with 0-3 R1;
Rb is H, Ci-6 alkyl substituted with 0-3 Rd, Ci-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1 or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci-6 alkyl substituted with 0-3 R% (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(0)Rc, -NReRe, ~NReC(0)0R£, C1-6 alkyl or (CH2) -phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, CJ -6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, 0(Ci-6 alkyl) or a ··{('! 1 · },·'· -7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1 , or 2;
r is 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
10 The compound according to claim 9 of the formula
Figure imgf000139_0001
where
R2 is ~C(0)R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO?., -(CH?.)rORb,
-(CH2)rSRb, ~(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2 OC(0)Rb, CIHlrNR^R11,
-(CH2)rC(0)NR11R11, ~(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRhC{())\ R! ! RM. -S OlpNR1^11, -NRbS(0)pRc, -S(0)PRc, Cue, alkyl substituted with 0-3 R3, Cue haloalkyl,
C2-6 alkenyl substituted with 0-3 R3, -(CH2)r-3-l4 membered carbocyde substituted with
0-1 Ra or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from
N, O, and S(0)P substituted with 0-2 Ra; R6 is a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R63;
R6a is H, Ci -4 alkyl substituted with 0-3 R1, CFs, C3-10 cycloaikyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R!! at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CFb, Cs-io cycloaikyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rd;
Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN,
NO2, - (C l 10:(>Rh. -{C! l OrSRk -(CH2 C(G)Rb, -(CH2)rC(0)GRb,
-(CH2)rOC(0)Rb, -(CFl2) NRi iR! !, -(CFI2)1C(0)NR11Rii, -(CH2)rNRbC(0)R£, -(CH2)rNRb C(0)ORc, -NRbC (O)NR 1 ¾.11 , -S(0)PNR11R11, -NRbS(0)PRc, -S(G)R\ -SCO) K . Cue alkyl substituted with 0-3 Rf, Ci-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)I-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1;
Rb is H, C 1 -6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloaikyl substituted with 0-2 Rd, or -(CH2)f-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R1 or (CHy!r-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloaikyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN,
N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, Cw alkyl or (CH2)t-phenyl substituted with 0-3 Rf;
Re is independently at each occurrence, hydrogen, Ci-e alkyl, C3-6 cycloaikyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-6 cycloaikyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1, or 2; r is 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
11. The compound according to claim 6 of the formula
Figure imgf000141_0001
wherein
R2 is -C(0)R2a or a 5-12 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;
R2a at each occurrence is independently H, OCF3, CN, NO2, -(CH2)rORb,
Figure imgf000141_0002
(CH2)IC(0)NR! !Ru 5 -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(0)NR11R11,
-S(0)pNRnRn, -NRbS(0)pRc, ~S(0)PRc, C1-6 alkyl substituted wilh 0-3 Ra, Cue haloalkyl,
C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r-3-l4 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(G)P substituted with 0-2 Ra;
R6 is a -(CH2)-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 R63;
R6a is H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 R1, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rd;
R“ at each occurrence is independently H, Ci-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd
or -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected fromN, O, and S(0)p substituted with 0-3 Rd; Ra at each occurrence is independently H, F, CL Br, OCF3, CF3, CHF2, CN,
N02J -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb,
~(CH2)rQC (0)Rb, -(CH2)rNR11R1L ~(CH2)rC(0)NR33R3 L ~(CH2)rNRbC(Q)Rc, -(CH2)rNRb C(Q)ORc, -NRbC(0)NRnRn, -S(0)PNR!1R11, -NRbS(0)PRc, -S(0)Rc, -S(0)?Rc, Cue alkyl substituted with 0-3 Rf, CI-6 haloalky!, C2-6 alkenyl substituted with 0-3 R3, C2-6 alkynyl substituted with 0-3 R3, -(CH2)r-3-l4 membered carbocyc!e or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected fromN, O, and S(0)P substituted with 0-3 Rf;
Rb is H, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r~5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P substituted with 0-3 Rf or (CH2)t-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 R% (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, N02, -ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)OR£, C1-6 alkyl or (CH2)f-phenyl substituted with 0-3 R1;
Re is independently at each occurrence, hydrogen, Cj-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-e cycloalkyl, CF3, 0(Ci-6 alkyl) or a -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(0)P;
p is 0, 1 , or 2;
r is 0, 1, 2, 3, or 4;
12. A compound which is
6-cy clopropan eamido-4- { [ 3-methoxy -4-( 1 -methyl- 1 H- 1 ,2,4-triazol-3 -y l)py ridin- 2-y 1] amino } -N-(2H3)methy Ipy ridazme-3 -carboxamide,
4- {[3-methoxy -4-(l-methyl-lH-l, 2, 4-triazol-3-y l)pyridin-2-yl]amino} -N- (2H3)methyl-6-[(pyridin-2-yl)amino]pyridazine-3-carboxamide,
6-cy clobutaneamido-4-{ [3-methoxy ~4~(1 -methyl-lH- 1,2, 4~triazol~3-yi)pyri din-2- yl]amino}-N-(2H3)methylpyridazine-3-carboxamide, 4- { 3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino}-N- (2H3)methyl-6-[2-(morpholin-4-yl)acetamido]pyridazine-3-carboxamide,
6-acetamido-4-{[3-methox>'-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2- yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
6- [ (5 -fluoropy ridin-2-y l)amino j -4- { [3 -methoxy-4-(l -methyl- 1 H- 1 ,2,4-triazol-3 - yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
6-butanamido-4- {[3-methoxy-4-(l-methyl-lH-L2,4-triazol-3-yl)pyridin-2- yllamino} -N-(2H3)methylpyridazine-3-carboxamide,
4-{[3-methoxy-4-(l -methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N- (2H3)methy 1 -6-propanami dopy ridazine-3 -carboxamide,
methyl N-(5-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yi)pyridm-2-yijamino}- 6- 1 (2H3)methy icarbamoy 1 jpyridazin-3-y l)carbamate,
6-(2-cyclopropylacetamido)-4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3- y l)py ridin-2-y 1] amino } -N -(2H3)methy lpyridazine-3-earboxamide,
4-{ 3-methoxy-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N-
(2H3)methyl-6-[(4-methylpyridin-2-yi)amino]pyridazine-3-ca.rboxarnide,
4-{[3-methoxy~4-(l-metbyl~lH-l,2,4-triazol-3-yl)pyridin-2-yl]ammo}-6~[(4- methoxypyndin-2-yl)amino]-N-(2H3)methylpyridazme-3-carboxamide,
6-[(4-cyanopyridin-2-yl)amino]-4-{[3-methoxy-4-(l-methyl-lH-l,2,4-triazoI-3- y])pyridin-2-yllamino}-N-(2H3)methylpyridazine-3-carboxarnide,
6- 1 (5 -fluoropy ridin-2-yl)amino | -4- { 13 -methoxy-4-(l -methy 1- 1H- 1 ,2,4-triazol- 3 - y l)py ri din-2-y G| amino } -N-(2H3,)methy Ipy ri dazine-3-carboxami de,
0H (4,5~dimethylpyridin-2-y])aminoj-4-{[3-methoxy~4~(1 -meihyl~! H-l,2,4- triazol-3-yl)pyridin-2-yl]amino}-N-(2H3)metbylpyridazine-3-carboxamide,
6- [ (5 -fluoro-4-methy ipy ridin-2-y l)amino] -4- { [ 3 -methoxy -4-(l -methyl- lH-1,2,4- triazoi-3-yl)pyndin-2-yi]amino}-N-(2H3)methylpyndazine-3-carboxamide,
6-[(4-ethylpyridin-2-yl)amino]-4-{ [3-methoxy-4-(l -methyl-lH-l,2,4-triazol-3- y l)py ridin-2-y 1] amino } -N -(2H3)methy lpyridazine-3-carboxamide,
4- { 3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino}-N- (2H3)methyl-6-{ [5-(2-oxopyrrolidin-l -y])pyri din-2 -yl]amino}pyridazine-3-carboxamide, 6-[(4-fluoropyridm~2-yl)amino]~4~{[3-methoxy-4-(l~methyl-lH-l,2,4-triazol~3~ yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide, 4- { [3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino} -N- (2H3)methyl-6-[(5-methy]-l,3,4-thiadiazol-2-yl)amino]pyridazine-3-carboxamide,
6- [(4-chloropy ridin-2-y l)amino] -4- { [3-methoxy -4-( 1 -methyl- 1 H- 1 ,2,4-triazoS -3 - yl)pyndin-2-yl] amino} -M-(2H:5)methylpyndazine-3-caiboxamide,
6- [ (5 -chi oro-4-methy lpy ridin-2-y l)amino ] -4- { [3 -methoxy -4-( 1 -methy 1- 1H- 1,2,4- triazol-3-yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
6- j (4-ehloro-5 -methyipy ridm-2-y I)amino] -4- { f 3 -methoxy -4-( 1 -methy 1- 1H- 1,2,4- iriazol-3-yi)pyridm-2-yr|ammo}-N-(2H3)methylpyridazine-3-carboxamide,
4- { [3-methoxy -4-(l -methyl-lH-l, 2, 4-triaz.ol-3-y])pyridin-2-yl]amino} -N- (2H3)methy]-6-({2-oxo-2H-[l ,3'-bipyridine]-6'-yl}amino)pyridazine~3~carboxamide,
6- { [4-(2-hydroxypropan-2-yl)pyridin-2-yl] amino} -4- { [3-methoxy-4-(l -methyl- 1 H- 1 ,2,4-triazol-3-y i)py ridin-2-y 1 ] amino } -N-(2H3)methy lpy ridazine-3 -carboxamide,
4- { [3-methoxy -4-(l-methyl- 1H- 1 ,2,4-triazol-3-yl)pyridin-2-yl]amino} -N- (2H3)methyl-6-{[2-oxo-3-(trifluoromethyl)-2H-[l,3'-bipyndine]-6'-yl]amino}pyridazine- 3-carboxamide,
4-{[3-methoxy-4-(l -methyl- iH-l,2,4-triazol-3-y])pyridin-2-yl]amino} -6-[(6- methoxypyridin-2-yl)amino]-N-(2H3)methylpyridazine-3-carboxamide,
4-{[3-methox\,-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N-
(2H3)methyl-6-(phenylamino)pyridazine-3-carboxamide,
6-[(4-acetylpyridin-2-yl)amino]-4- {[3-methoxy -4-(l-methyl-lH-l, 2, 4-triazol-3- y l)py ridin-2-y 1] amino } -N -(2H3)methy lpyridazine-3-carboxamide,
6-({5-chioro-2-oxo-2H-[ l,3'-bipyridine]-6'-yl }amino)-4- {[3-methoxy-4-(l- methyl-lH-l ,2,4-triazol-3-yl)pyridin-2-yllamino}-N-(2H3)methylpyridazine-3- carboxamide,
4- { [3-methoxy -4-(l-methyl-lH-l, 2, 4-triazol-3-yl)pyridin-2-yl]amino}-N- (2H3)methyi-6-( { [ 1 ,3]thiazolo[5,4-b]pyridin-5-yl } amino)pyridazine-3-carboxamide,
4- { [3-methoxy-4-( 1 -methyl- 1 H- 1 ,2,4-triazol -3-yl)py ridin-2-y 1] amino} -N~ (2H3)methy 1-6- { [4-(trifluoromethy l)py ridin-2-y 1] ammo } py ridazine-3 -carboxamide,
6- { 15-(2 -hydroxy propan-2 -yi)pyridin-2-yi |ammo} -4- {[3-methoxy -4-(l -methyi- lH-l,2,4-triazol-3-yr)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide, 6-[(4-fluorophenyl)amino]-4-{[3-meihoxy-4-(i-methyl-lH-] ,2,4-triazol-3- yl)pyndin-2-yl] amino} -M-(2H3)methylpyndazine-3-caiboxamide, 4- { 3-methoxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino} -N- (2H3)methyl-6-[(pyridin-4-yl)amino]pyridazine-3-carboxamide,
6-[(6-ethoxypyridazin-3-yl)amino] -4- { [3-methoxy-4~(l -meth l- 1H- 1,2,4-triazol- 3-yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
6- { [ 5 -(3 -tert-buty l-2-oxoimidazolidin- 1 -y l)py ridin-2-y lj ammo } -4- { [3-methoxy-4- (l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N-(2H3)methylpyridazine-3- earboxamide,
4- { 3-metboxy-4-( 1 -methyl- 1H- 1 ,2,4-triazol-3-y l)pyndin-2-yl] amino}-N- (2H3)methyl-6-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyridazine-3-carboxamide,
6-[(4,5-difluoropyridin-2-yl)amino] -4- { [3-medioxy-4-(l -methyl- 1H- 1 ,2,4-triazol- 3-yl)pyridiii-2-yl]amino}-N-(2H:5)methylpyndazine-3-carboxamide,
4-{[3-methoxy'-4-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-yl]amino}-N- (2H3)metby 1-6- [(6-methy lpy ri din-2-y l)amino] py ri d azine-3 -carboxami de,
6-cyclopropaneamido-4-{[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2- yllamino} -N-(2H3)methylpyridine-3-carboxamide,
4-f(3-methox -4-{5-f(morpholin-4-yl)methyl]-l ,2,4-oxadiazo]-3-yl}pyridin-2- y!)amino]-N-(2H3)methyl-6-[(4-methylpyridin-2-y!)amino]pyridazine-3-carboxamide,
4- { [3-methoxy-4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)pyridin-2-yl] ammo} -N- (2H3)methyl-6-propanamidopyridme-3-carboxamide,
6-(2-cydopropylaceiamido)-4-{[3-meihoxy-4-(5-methyl-l,2,4-oxadiaz.ol-3- y l)py ridm-2-y 1] amino } -N-(2H3)methy lpy ridine-3 -carboxamide,
6-cy clopropaneami do-4-( { 3 -methoxy-4- [ 5-(methoxy methyl)- 1 ,2,4-oxadiazol-3- yl]pyridin-2-yl } amino)-N-(2H3)methylpyridine-3-carboxamide,
6-cyclopropaneamido-4~({4-[5-(ethoxymethyl)-l,2,4-oxadiazol-3-yl]-3- methoxypyndin-2-yl}amino)-N-(2H3)methylpyridine-3-carboxamide,
6-cyclopropaneamido-4-[(3-methoxy-4-{5-[(propan-2-yloxy)methyl]-l,2,4- oxadiazol-3-yl }pyridin-2-y])amino]-N-(2H3)methylpyridine-3-carboxamide,
4-({3-methoxy-4-[5-(methoxymethyl)-l,2,4-oxadiazol-3-yl]pyridin-2-yl}amino)-
N-(2H3)methyl-6-propanamidopyridine-3-carboxamide,
4-({4-[5-(ethoxymethyl)-l ,2,4-oxadiazol-3-yl]-3-methoxypyridin-2-y]} amino)-N-
(2H3)methy]-6-propanamidopyridine-3-carboxamide, 6-cyclopropaneamido-4-({3-methoxy-4-[5-(methoxymethyl)-l ,2,4-oxadiazoJ-3- yl]pyridin-2-yl }amino)-N-(2H3)methylpyridazine-3-carboxamide,
4-[(4-cyano-3-methoxypyridm~2~yl)amino]-6~cyclopropaneamido-N-
(2H3)methylpyridazine-3-carboxamide,
methyl N- {5-[(3-methoxy-4-{5-[(N-methylmethanesulfonamido)methyl]-l,2,4- oxadiazol-3-yl}pyridin-2-yl)amino]-6-[(2H3)methylcarbamoyl]pyridazin-3-yl} carbamate, methyl N-{5-[(3-methoxy-4-{5-[(morpholin-4-yl)methyl]-l,2,4-oxadiazol-3- y 1 } py ridin-2-y l)amino] -6- [ (2H3)methy lcarbamoy i] pyridazin-3 -y 1 } carbamate,
6-cyclopropaneamido-4-[(3-methoxy-4-{5-[(N- methylmethanesulfonamido)methyl]-l,2,4-oxadiazol-3-yl}pyiidin-2-yl)amino]-N- (2H3)methylpyridazine-3-carboxamide,
6-cyclopropaneamido-4-[(3-methoxy-4-{5-[(morpholin-4-yl)methyl]-l,2,4- oxadiazol-3-yl}pyridin-2-yl)amino]-N-(2H3)methylpyridazine-3-carboxamide,
methyl N-(5-{[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl]amino}- 6-[(2H: )methylcarbamoyr|pyridazin-3-yi)carbamate,
6-cyclopropaneamido-4-[(4-{5-[(l S)-l -hydroxyethyl]-l ,2,4-oxadiazol-3-yl}-3- methoxypyridin-2-y!)amino]~N-(2H3)methylpyridazine-3-carhoxamide,
6-cy clopropaneamido-4- [(4- { 5 - [(dimethy lamino)methy 1] - 1 ,2,4-oxadiazol-3 -y 1 } -3 - methoxypyridin-2-yl)amino]-N-(2H3)methylpyridazine-3-carboxamide,
6-cy clopropaneamido-4-[(3-methoxy -4- {5-[(methylamino)niethyl]- 1 ,2,4- oxadi azol-3-yl}pyri din-2 -yl)amino]-N~(2H3)methylpyridazine-3-carboxamide,
4-({4-[5-(cyanomethyl)-l,2,4-oxadiazol-3-yl]-3-methoxypyridin-2-yl} amino)-6- cyclopropanearnido-N-(2H3)methylpyridazine-3-carboxamide,
4-[(3-medioxy-4-{5-[(N-methylmethanesulfonamido)methyl]-l,2,4-oxadiazol-3- yl}pyridin-2-yl)amino]-N-(2H3)methyl-6-[(4-methylpyridin-2-yl)amino]pyridazine-3- carboxamide,
4-({3-methoxy-4-[5-(methoxymethyl)-l,2,4-oxadiazol-3-yl]pyridin-2-y] } amino)-
N-(2H3)methyl-6-[(4-methylpyridin-2-yl)ammo]pyridazme-3-carboxamide,
4-((3-methoxy-4-(5-(morpholinomethyl)-l,2,4-oxadiazol-3-yl)pyridin-2- yl)amino)-N-(methyl-d3)-6-((4-methylpyridin-2-yl)arnino)pyridazine-3-carboxamide, methyl N~{5-[(4-{5-[(l, l-dioxo-lA6,2-thiazinan-2-yl)methyl]~] ,2,4-oxadiazol-3- yl } -3-methoxy pyridin-2-y l)ammo] -6- [(2H3)methy lcarbamoy 1] pyndazin-3-y 1 } carbamate, 4-| (3-methoxy-4-{5-| (morpholin-4-yl)methyll-l ,2,4-oxadiazol-3-yl}pyridin-2- yl)amino]-N-(2H3)niethyl-6-propanarmdopyridazine-3-carboxamide,
4-({3-methoxy-4-[5-(methoxymethyl)-l,2,4-oxadiazol-3-yl]pyridin-2-yl}amino)-
N-(2H3)methyl-6-propaiiamidopyridazine-3-carboxamide,
6-(2-cy clopropy lacetamido)-4- [ (3 -methoxy-4- { 5 - [ (N- methylmethanesulfbnamido)methyl]-l,2,4-oxadiazol-3-yl}pyridin-2-yl)amino]-N- (2H3)methyipyndazine-3-carboxamide,
4-({3-methoxy-4-| 5-(methoxymethyl)-l,2,4-oxadiazol-3-yl]pyridin-2-yl}amino)-
N-(2H3)methyl-6-(3-niethylbutanamido)pyridazine-3-carboxamide,
4-[(3-methoxy-4-{5-[(morpholin-4-yl)methyl]-l ,2,4-oxadiazol-3-yl}pyridin-2- yl)amino]-N-(2H3)methyi-6-(3-methyibutanamido)pyridazine-3-carboxamide,
4-[(3-methoxy-4-{5-[(N-meth}dmethanesulfonamido)methyl]-l,2,4-oxadiazol-3- y]}pyridin-2-yl)amino]-N-(2H3)methyl-6-(3-meihylbuianamido)pyridazine~3- carboxamide,
4-[(3-methoxy-4-{5-[(2-oxo-l,3-oxazolidin-3-yl)methyl]-l,2,4-oxadiazol-3- yl}pyridin-2-yl)amino]-N-(2H3)methyl-6-(3-methylbutanamido)pyridazine-3- carboxamide,
0-(2-cyclopropyiacetamido)-4-({3-methoxy-4-[5-(methoxymethyi)-L2,4- oxadiazol-3-y i ] py ridin-2-y 1 } amino)-N-(2H:>)methy ipy ridazine-3 -carboxamide,
6-(2-cyclopropylacetamido)-4-({4-[5-(hydroxymethyl)-l,2,4-oxadiazol-3-yl]-3- methoxypyridin-2-yl}amino)-N-(2H3)methy Ipy ridazine-3 -carboxamide,,
6-cyclopropaneamido-4-{[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2- yl]amino} -N-(2H3)methylpyridazine-3-carboxamide
6-(2-cyclopropylacetamido)-4-{[3-methoxy~4-(5-methyl~l,2,4-oxadiazoS-3- yl)pyndin-2-yl] amino} -M-(2H3)methylpyndazine-3-caiboxamide,
4-( {3 -methoxy-4- [ 5-(methoxy methy I)- 1 ,2,4-oxadiazoi-3 -y i | pyridin-2-y 1 } amino)- N -(2H3)methy 1-6- [2-(oxetan -3 -y l)acetamido] py ri dazine-3 -carboxami de,
6- 1 (5 -chloro-4-methy ipy ridm-2-y l)amino] -4- { f 3 -methoxy-4-(5-methy i- 1,2,4- oxadiazo{-3-yl)pyridin-2-yr|amino}-N-(2H3)metliylpyridazme-3-carboxamide,
4-{|3-methoxy-4-(5-methyl- i ,2,4-oxadiazol-3-yl)pyridin-2-y]]amino}-N-
(2H3)methyl-6-[(4~methylpyridin-2-yl)amino]pyridazine-3-carboxamide, 4-{|3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl]amino}-N-
(2H3)melhyl-6-[(6-methylpyriraidin-4-yl)arnino]pyridazine-3-carboxairade,
6- { [4-(2-hy droxy propan -2-y l)py ridin-2-y 1] amino} -4- { [3 -methoxy-4-(5 -metby 1-
1.2.4-oxadiazol-3 -y l)py ridin-2-y 1] ammo } -N-(2H3)methy lpyridazine-3 -carboxamide,
4-{[3-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yr|amino}-N-
(2H3)methyl-6-propanamidopyridazine-3-carboxamide,
6-{[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4- {[3-methoxy-4-(5-methyl-
1.2.4-oxadiazol-3-yl)pyndin-2-yi]amino}-N-(2H:s)meihylpyndazine-3-caiboxamide
6-cyclopropaneamido-4-({3'-methoxy-[2,4'-bipyridine]-2'-yl}amino)-N-
(2H3)methylpyridazine-3~carboxamide,,
6-cyclopropaneamido-4-({3'-methoxy-[2,4'-bipyridine]-2'-yl}amino)-N-
(2H3)methylpyridine-3-carboxamide,
6-cydopropaneamido-4-({5-cyclopropaneamido-3'-methox ,-[2,4'-bipyridine]-2'- yl}amino)-N-(2H3)methylpyridine-3-carboxamide,
4-({5-chloro-3'-methoxy-|2,4'-bipyridine]-2'-yl}amino)-6-cyclopropaneamido-N-
(2H3)methylpyridine-3-carboxamide,
6-cyclopropaneamido-4~({4-[5-(dimeihylcarbamoyl)pyrazin-2-yl]-3~ methoxypyndin-2-yl}amino)-N-(2H3)methylpyridazine-3-carboxamide,
6-cyciopropaneamido-4-[(4-{5-[ethyi(methyi)carbamoyl]pyrazin-2-yl}-3- methoxypyridin-2-yl)amino]-N-(2H3)methylpyridazine-3-carboxamide,
6-(2-cyclopropylacetamido)-4-({4-[5-(dimethylcarbamoyl)pyrazin-2-yl]-3- methoxypyridin-2-yl}amino)-N-(2H3)methylpyridazine-3-carboxamide,
4-({4-[5-(dimethylcarbamoyl)pyrazin-2-yl]-3-methoxypyridin-2-yl}amino)-N-
(2H3)metliyl-6-[(l~methy!-lH-pyrazo!-3~yl)amino]pyridazine~3-carboxamide,
6-[(l,5-dimethyl-lH-pyrazol-3-yl)amino]-4-({4-[5-(dimethylcarbamoyl)pyrazin-
2-yl]-3-methoxypyridin-2-yl}annno)-N-(2H3)methyipyridazine-3-carboxamide,
6-[(5-cbloro-l-methyl-lH-pyrazol-3-yl)amino]-4-({4-[5- (dimethyicarbamoyl)pyrazin-2 -yi]-3-methoxypyri din-2 -yl}amino)-N- (2ii3)methylpyndazine-3-carboxamide,
4-{f4-(5-fluoropyrimidin-2-yl)-3-methoxypyridin-2-yllaniino}-6-{[5-(2- hydroxypropan-2~yl)pyridm-2-yl]airdno}-N-(23¾)methylpyridazme-3-carboxamide, 0-{[5-(2-aminopropan-2-yl)pyridm-2-yljamino}-4-{[4-(5-iluQropyrimidin-2-yi)-
3-methoxypyridin-2-yl]amino}-N-(2H3)niethylpyridazine-3-carboxamide,
4-{[4-(5-fliioropyrimidin-2-yl)-3-meihoxypyridin-2-yi]amino}-N-(2H3)methyl-6- j(5-methylpyrazin-2-yl)amino]pyridazme-3-earboxamide,
6-[(6-ethoxypyridazin-3-yl)amino]-4-{[4-(5-fluoiOpyrimidin-2-yi)-3- methoxypyridin-2-yl]amino}-N-(2H3)meihylpyridazine-3-carboxamide,
4-{j4-(5~fiuoropyrimidm-2-yl)-3-methoxypyridin-2-yijamino}-N-(2H3)metliyi-6-
{[5-(morpholin-4-yl)pyridm-2-yr amino}pyridazme-3-carboxamide,
0-j (4-fluoropyridin~2~yl)aminoj~4~{j4-(5-fluoropyrimidin~2-yl)-3~
niethoxypyridin-2-yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4 {[4-(5-fluoiOpyrimidin 2-yl)~3-methoxypyridiii-2-yl]amino}-N (2H3)methyl 6- j(4-methylpyridm-2-yl)aminojpyridazine-3-carboxamide,
4-{[4-(5~fluoropyrimidin-2-yl)-3-methoxypyridin-2-yl]ammo}-6-[(6- methoxy pyridazin- 3 -y l)amino] -N -(2H3)methy lpyridazine-3 -carboxamide,
4-{|4-(5-fluoropyrimidin-2-yJ)-3-methoxypyridin-2-yr|amino}-N-(2H3)methyl-6-
[(pyridin-2-yl)amino]pyridazine-3-carboxamide,
6-cyclopropaneaniido-4-{[4-(5-fluoropyrimidin-2~yl)-3-methoxypyri din-2- yl]amino}-N-(2H3)methylpyridazine-3-carboxamide,
4-{[3-methox '-4-(2-methyl-2H-l,2,3,4-tetrazol-5-yl)pyridin-2-yl]amino}-N-
(2H3)methyl-6-f(4-methylpyridin-2-yl)aniino]pyridine-3-carboxamide,
methyl N-(4- { f 3 -methoxy-4-(2-methy 1-2H- 1,2,3 ,4-tetrazol-5-yl)pyridin-2- yl|amino} -5-[(2H:)methylcarbamoyr|pyridin-2-yl)carbamaie,
4-{|3-rnethoxy-4-(2-methyl-2H-l,2,3,4~tetrazol-5-y])pyridin~2-yl]amino}-N- (2H3)methyl-6-propanamidopyridine-3-carboxamide, or
6-[(4-cyanopyridin-2-yl)amino]-4-{[3-methoxy-4-(2-methyl-2H-l,2,3,4-tetrazol-
5-yl)pyridin-2-yl]amino}-N-(2H3)methylpyndine-3-carboxamide.
or a stereoisomer or pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-12 and a pharmaceutically acceptable carrier or diluent.
14. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to any one of claims 1-12, wherein the disease is an inflammatory or autoimmune disease.
15. The method of claim 14 wherein the inflammatory or autoimmune disease is multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s Disease, Sjogren’s syndrome or scleroderma.
PCT/US2019/023111 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine useful as modulators of il-12, il-23 and/or ifn alpha responses WO2019183186A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
KR1020207029906A KR20200135425A (en) 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine useful as modulators of IL-12, IL-23 and/or IFN alpha reactions
EP19715330.7A EP3768667B1 (en) 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine useful as modulators of il-12, il-23 and/or ifn alpha responses
CN201980020946.5A CN111936486B (en) 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine as modulators of IL-12, IL-23 and/or IFN alpha responses
US16/982,937 US11597721B2 (en) 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine useful as modulators of IL-12, IL-23 and/or IFNα responses
JP2020550632A JP2021518389A (en) 2018-03-22 2019-03-20 Pyridine-containing heterocyclic compounds useful as modulators of IL-12, IL-23 and / or IFNα responses
ES19715330T ES2944733T3 (en) 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine, useful as modulators of responses to IL-12, IL-23 and/or IFN alpha

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862646432P 2018-03-22 2018-03-22
US62/646,432 2018-03-22

Publications (1)

Publication Number Publication Date
WO2019183186A1 true WO2019183186A1 (en) 2019-09-26

Family

ID=66001366

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/023111 WO2019183186A1 (en) 2018-03-22 2019-03-20 Heterocyclic compounds comprising pyridine useful as modulators of il-12, il-23 and/or ifn alpha responses

Country Status (7)

Country Link
US (1) US11597721B2 (en)
EP (1) EP3768667B1 (en)
JP (1) JP2021518389A (en)
KR (1) KR20200135425A (en)
CN (1) CN111936486B (en)
ES (1) ES2944733T3 (en)
WO (1) WO2019183186A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021211741A1 (en) 2020-04-14 2021-10-21 Gossamer Bio Services, Inc. Substituted pyridines for the treatment of inflammatory diseases
WO2022268119A1 (en) * 2021-06-22 2022-12-29 南京明德新药研发有限公司 Sulfoximine compound and use thereof
WO2023027948A1 (en) * 2021-08-21 2023-03-02 Relay Therapeutics, Inc. Jak2 inhibitors and methods of use thereof
WO2023064223A1 (en) 2021-10-11 2023-04-20 Gossamer Bio Services, Inc. Tri-substituted pyridines
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
EP4206196A1 (en) 2021-12-29 2023-07-05 Almirall S.A. Pyrimidine substituted derivatives as tyk2 inhibitors
WO2024020221A1 (en) * 2022-07-21 2024-01-25 Arvinas Operations, Inc. Modulators of tyk2 proteolysis and associated methods of use

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3170773A1 (en) * 2020-03-11 2021-09-16 Xiangyang Chen Heterocyclic compounds for inhibiting tyk2 activities
TWI804266B (en) * 2021-04-07 2023-06-01 大陸商上海齊魯製藥研究中心有限公司 Tyk2 inhibitors and use thereof
JP2024517453A (en) * 2021-05-04 2024-04-22 シャンハイ ゼイ バイオテクノロジー カンパニー リミテッド Nitrogen-containing heterocyclic pyridine compounds
WO2023284869A1 (en) * 2021-07-15 2023-01-19 南京明德新药研发有限公司 Sulfur/phosphorus-containing aryl compound and application thereof
WO2023109954A1 (en) * 2021-12-16 2023-06-22 Lynk Pharmaceuticals Co. Ltd. Tyk2 inhibitors and compositions and methods thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013052393A1 (en) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. 3-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS
US20130178478A1 (en) * 2012-01-10 2013-07-11 Hoffman-La Roche Inc. Pyridazine amide compounds
US20150299183A1 (en) * 2012-11-08 2015-10-22 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013052393A1 (en) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. 3-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS
US20130178478A1 (en) * 2012-01-10 2013-07-11 Hoffman-La Roche Inc. Pyridazine amide compounds
US20150299183A1 (en) * 2012-11-08 2015-10-22 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses

Non-Patent Citations (42)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
"Methods in Enzymology", vol. 112, 1985, ACADEMIC PRESS, pages: 309 - 396
"Remington's Pharmaceutical Sciences", 1985
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
BAVE, U. ET AL.: "Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenic mechanism", ARTHRITIS RHEUM., vol. 52, 2005, pages 1185 - 1195
BENGTSSON, A.A. ET AL.: "Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies", LUPUS, vol. 9, 2000, pages 664 - 671
BENNETT, L. ET AL.: "Interferon and granulopoiesis signatures in systemic lupus eηthematosus blood", J. EXP. MED., vol. 197, 2003, pages 711 - 723
BUNDGAARD, H. ET AL.: "A Textbook of Drug Design and Development", 1991, HARWOOD ACADEMIC PUBLISHERS, article "Design and Application of Prodrugs", pages: 113 - 191
BUNDGAARD, H., ADV. DRUG DELIV. REV., vol. 8, 1992, pages 1 - 38
CHO, J.H. ET AL.: "Recent insights into the genetics of inflammatory bowel disease", GASTROENTEROLOGY, vol. 140, 2011, pages 1704 - 1712
COUTURIER, N ET AL.: "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility", BRAIN, vol. 134, 2011, pages 693 - 703
CUA, D.J. ET AL.: "Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain", NATURE, vol. 421, 2003, pages 744 - 748, XP002971969, DOI: doi:10.1038/nature01355
DENG, Y. ET AL.: "Genetic susceptibility to systemic lupus erythematosus in the genomic era", NAT. REV. RHEUMATOL., vol. 6, 2010, pages 683 - 692
ELLINGHAUS. D. ET AL.: "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci", AM../. HUM. GENET., vol. 90, 2012, pages 636 - 647
EYRE, S. ET AL.: "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis", NAT. GENET.,, vol. 44, 2012, pages 1336 - 1340
GOTTLIEB, A. ET AL.: "Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind. placebo-controlled, crossover trial", LANCET, vol. 373, 2009, pages 633 - 640
GRACIE, J.A. ET AL.: "Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass", F UR. .1. IMMUNOL., vol. 26, 1996, pages 1217 - 1221
GRAHAM, D. ET AL.: "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families", RHEUMATOLOGY, vol. 46, 2007, pages 927 - 930
HALL, J.C. ET AL.: "Type I interferons: crucial participants in disease amplification in autoimmunity", NAT. REV. RHEUMATOL., vol. 6, 2010, pages 40 - 49, XP055541331, DOI: doi:10.1038/nrrheum.2009.237
HONG, K. ET AL.: "IL-12. independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder", J. IMMUNOL., vol. 162, 1999, pages 7480 - 7491, XP002188301
HUANG, X. ET AL.: "Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients", MOD. RHEUMATOL., vol. 17, 2007, pages 220 - 223, XP019495284
HUE, S. ET AL.: "Interleukin-23 drives innate and T cell-mediated intestinal inflammation", J. EXP. MED., vol. 203, 2006, pages 2473 - 2483, XP055111922, DOI: doi:10.1084/jem.20061099
ISHIZAKI, M. ET AL.: "Involvement of Tyrosine Kinase-2 in Both the IL-12:Thl and IL-23;Thl7 Axes In vivo", J. IMMUNOL., vol. 187, 2011, pages 181 - 189
KIM, D. ET AL.: "Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase 1: association of higher interferon-alpha activity with lung fibrosis", ARTHRITIS RHEUM., vol. 58, 2008, pages 2163 - 2173
KYTTARIS, V.C. ET AL.: "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL6/-1pr/1pr mice", J. IMMUNOL., vol. 184, 2010, pages 4605 - 4609
LEE, E. ET AL.: "Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris", J. EXP. MED., vol. 199, 2004, pages 125 - 130
LEES, C.W. ET AL.: "New IBD genetics: common pathways with other diseases", GUT, vol. 60, 2011, pages 1739 - 1753
LEONARDI, C.L. ET AL.: "PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)", LANCET, vol. 371, 2008, pages 1665 - 1674
LSHIZAKI, M. ET AL.: "Involvement of Tyrosine Kinase-2 in Both the IL-12 Thl and IL-23/Th l7 Axes In vivo", J. IMMUNOL., vol. 187, 2011, pages 181 - 189
MCGEACHY, M.J. ET AL.: "The link between IL-23 and Thl7 cell-mediated immune pathologies", SEMIN. IMMUNOL., vol. 19, 2007, pages 372 - 376, XP022495318, DOI: doi:10.1016/j.smim.2007.10.012
MINEGISHI, Y. ET AL.: "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity", IMMUNITY, vol. 25, 2006, pages 745 - 755, XP055573304, DOI: doi:10.1016/j.immuni.2006.09.009
MURPHY, C.A. ET AL.: "Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation", J. EXP. MED., vol. 198, 2003, pages 1951 - 1957
OYAMADA. A. ET AL.: "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis", J. IMMUNOL., vol. 183, 2009, pages 7539 - 7546
PETERSON, K.S. ET AL.: "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli", J. CLIN. INVEST., vol. 113, 2004, pages 1722 - 1733
PRCHAL-MURPHY, M. ET AL.: "TYK2 kinase activity is required for functional type I interferon responses in vivo", PLOS ONE, vol. 7, 2012, pages e39141
SANDBOM, W.J. ET AL.: "Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12!23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease", GASTROENTEROLOGY, vol. 135, 2008, pages 1130 - 1141
SANDLING. J.K. ET AL.: "A candidate gene study of the type 1 interferon pathway implicates IKBKE and IL8 as risk loci for SLE", EUR. J. HUM. GENET., vol. 19, 2011, pages 479 - 484
SANTIAGO-RABER, M.L. ET AL.: "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice", J EXP. MED., vol. 197, 2003, pages 777 - 788
SCHRODER. K. ET AL.: "Interferon-gamma: an overview of signals, mechanisms and functions", J. LEUKOC. BIOL., vol. 75, no. 2, 2004, pages 163 - 189, XP009031305, DOI: doi:10.1189/jlb.0603252
TAO. J.H. ET AL.: "Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases", A/O/. BIOL. REP., vol. 38, 2011, pages 4663 - 4672, XP019945210, DOI: doi:10.1007/s11033-010-0601-5
TUCCI, M. ET AL.: "Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis", CLIN. EXP. IMMUNOL., vol. 154, 2008, pages 247 - 254
TZARTOS, J.S. ET AL.: "Interleukin-17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis", AM. J. PATHOL., vol. 172, 2008, pages 146 - 155

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021211741A1 (en) 2020-04-14 2021-10-21 Gossamer Bio Services, Inc. Substituted pyridines for the treatment of inflammatory diseases
WO2022268119A1 (en) * 2021-06-22 2022-12-29 南京明德新药研发有限公司 Sulfoximine compound and use thereof
TWI825800B (en) * 2021-06-22 2023-12-11 大陸商南京明德新藥研發有限公司 Sulfinimine compounds and their applications
WO2023027948A1 (en) * 2021-08-21 2023-03-02 Relay Therapeutics, Inc. Jak2 inhibitors and methods of use thereof
WO2023064223A1 (en) 2021-10-11 2023-04-20 Gossamer Bio Services, Inc. Tri-substituted pyridines
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
EP4206196A1 (en) 2021-12-29 2023-07-05 Almirall S.A. Pyrimidine substituted derivatives as tyk2 inhibitors
WO2024020221A1 (en) * 2022-07-21 2024-01-25 Arvinas Operations, Inc. Modulators of tyk2 proteolysis and associated methods of use

Also Published As

Publication number Publication date
ES2944733T3 (en) 2023-06-23
CN111936486A (en) 2020-11-13
US20210032220A1 (en) 2021-02-04
JP2021518389A (en) 2021-08-02
EP3768667B1 (en) 2023-04-12
EP3768667A1 (en) 2021-01-27
CN111936486B (en) 2023-09-22
KR20200135425A (en) 2020-12-02
US11597721B2 (en) 2023-03-07

Similar Documents

Publication Publication Date Title
WO2019183186A1 (en) Heterocyclic compounds comprising pyridine useful as modulators of il-12, il-23 and/or ifn alpha responses
JP6458038B2 (en) Imidazopyridazine compounds useful as modulators of IL-12, IL-23 and / or IFNα responses
EP3523305B1 (en) Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
TWI582077B (en) Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnα responses
AU2022228101B2 (en) Sulfone pyridine alkyl amide-substituted heteroaryl compounds
EP4143180A1 (en) Substituted n-(methyl-d3)pyridazine-3-carboxamide or n-(methyl-d3)-nicotinamide compounds as il-12, il-23 and/or ifnalpha modulators
AU2020216914A1 (en) Amide-disubstituted pyridine or pyridazine compounds
WO2022241172A1 (en) Substituted heterocyclic compounds
EP3935058A1 (en) Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
EA041710B1 (en) SULPHONE-, PYRIDINE-, ALKYL-, AMIDE-SUBSTITUTED HETEROARYL COMPOUNDS

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19715330

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020550632

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20207029906

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2019715330

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2019715330

Country of ref document: EP

Effective date: 20201022