WO2023001794A1 - Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer - Google Patents

Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer Download PDF

Info

Publication number
WO2023001794A1
WO2023001794A1 PCT/EP2022/070137 EP2022070137W WO2023001794A1 WO 2023001794 A1 WO2023001794 A1 WO 2023001794A1 EP 2022070137 W EP2022070137 W EP 2022070137W WO 2023001794 A1 WO2023001794 A1 WO 2023001794A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrazine
carboxamide
pyridin
methylimidazo
methylamino
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2022/070137
Other languages
English (en)
French (fr)
Inventor
Sten NILSSON LILL
Kathryn GIBLIN
Jason Grant Kettle
Frederick Woolf Goldberg
Neil Patrick Grimster
Lucas MORRILL
Randolph ESCOBAR
Anthony METRANO
Kun SONG
James Sheppeck
Robert Evans ZIEGLER
Ye Wu
Li Sha
Dedong Wu
Tyler GREBE
Adelphe MFUH
Amber BALAZS
Jason Shields
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Priority to US18/580,664 priority Critical patent/US20240374606A1/en
Priority to JP2024502652A priority patent/JP7851393B2/ja
Priority to EP22754791.6A priority patent/EP4373817B1/en
Priority to CN202280049292.0A priority patent/CN117693503A/zh
Priority to ES22754791T priority patent/ES3036245T3/es
Publication of WO2023001794A1 publication Critical patent/WO2023001794A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the technical field relates to certain substituted pyrazine 2-carboxamides of Formula (I), and pharmaceutically acceptable salts thereof, together with compositions containing them and their use in therapy.
  • the compounds of Formula (I) are inhibitors of hematopoietic progenitor kinase 1 (HPK1) and are thereby particularly useful in the treatment or amelioration of abnormal cell proliferative disorders such as cancer.
  • T cells are critical in the cancer immunity cycle (Nature, 541 (2017), 321-330; Nature Reviews Immunology, 20, (2020), 651-668); they are the effector cells which recognize and kill tumour cells.
  • T cells are driven to exhaustion in the tumour microenvironment by chronic exposure to antigen and become non -functional. Additionally, suppressive signals in the tumour such as PGE2, TGF ⁇ , adenosine, etc. hamper the function of these cells. Therapies that enhance T cell function and rescue the function of exhausted T cells therefore result in improved tumour control.
  • HPKl hematopoietic progenitor kinase 1
  • mitogen activated protein kinase 1 MAP4K1 a Ste20-related serine/threonine kinase that is expressed only in hematopoietic cells acts as a negative regulator of T cell signalling and tumouricidal cytokine production.
  • HPKl phosphorylates its target SLP76 at Ser376 causing SLP76 to associate with 14-3-3 which results in disassociation of the LAT signalosome (J. Cell Biol., 195 (2011), 839-853; Nat. Immunol., 8 (2007), 84-91) and thus restricts T cell activation (J. Exp.
  • HPKl Loss of HPKl or inactive kinase (kinase dead) causes enhanced activation of T cells resulting in increased cytokine secretion and proliferation (Nat Immunol., 8. (2007), 84-91; Cell Reports, 25 (2016), 80-94).
  • HPKl can also inhibit T cell signalling in response to immunosuppressive prostaglandin E2 (PGE2) through protein kinase A (PKA) (Blood, 101 (2003), 3687-89; J. Biol. Chem., 282 (2007), 34693-99; Cancer Immunol. Immunother., 59 (2010), 419-29).
  • PGE2 immunosuppressive prostaglandin E2
  • PKA protein kinase A
  • HPK1 protein contains an N-terminal kinase domain, which is the regulatory domain containing the ATP binding site amino acids 23-46 (EMBO J., 15, 1996, 7013-25).
  • the intermediate domain has proline-rich motifs with binding sites for SH3- containing proteins such as Crkl, Grb2 and HIP-55 which suggests a scaffolding function.
  • the Citron homology domain is at the C-terminal which may act as a regulatory domain in molecular interactions including T cell adhesion.
  • LCK and ZAP70 induce HPK1 Tyr-379 phosphorylation and kinase activation (Oncogene, 20 (2001), 1703-14; Immunity, 12 (2000), 399-408; J. Biol. Chem., 276 (2001), 45207-16.
  • Essential adapters for T cell (SLP76) and B cell (BLNK) signalling have been reported to bind to activated HPK1 aiding in blockade of downstream signalling in both T and B cells (J. Biol. Chem., 276 (2001), 18908-14).
  • An HPK1 inhibitor can be used alone or in combination with other therapeutic agents for the treatment of cancer.
  • An HPK1 inhibitor could be used in combination with check point blockade PD-(L)1 axis or with CTLA4 in efforts to expand response rates to check point blockade.
  • Primary or secondary resistance to check point blockade may be potential indications for an HPK1 inhibitor. Additional combinations may include radiation, chemotherapy, surgery, tumour targeted agents or other immune targeted agents.
  • HPK1 inhibitor could be used as a therapeutic in multiple cancer indications.
  • a number of small molecule inhibitors of HPK1 have been disclosed in patent applications, for example as summarized in Expert Opinion on Therapeutic Patents, DOI: 10.1080/13543776.2021.1924671.
  • WO2016/205942 HPK1 inhibitors and methods of using same WO2018/167147 Azaindoles as inhibitors of HPK1 W02020/061377 Spirocyclic 2,3-dihydro-7-azaindoles and uses there of WO2018/183964 Isoquinolines as inhibitors of HPK1 W02020/023551 Naphthyridine compounds and uses thereof W02020/023560 Isoquinoline compounds and uses thereof
  • W02020/072627 Isoquinoline compounds for the treatment of cancer W02020/072695 8-Aminoisoquinoline compounds and uses thereof W02018/081531 Methods for Human T-cell activation
  • WO2018/102366 Anilinopyrimidines as Haematopoietic progenitor kinase 1 (HPK1) inhibitors
  • HPK1 inhibitors preparation method and application thereof WO2020/227325 Heterobifunctional Compounds as Degraders of HPK1 WO 2019/090198 Isofuranone compounds useful as HPK1 inhibitors in the treatment of cancer and viral infections and their preparation
  • HPK1 hematopoietic progenitor kinase 1
  • X 1 , X 2 and X 3 are independently selected from CR 5 or N, with the provisos that when X 1 is N, X 3 is CR 5 and when X 3 is N, X 1 is CR 5 ;
  • R 1 is cyclopropyl or C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F;
  • R 2 is H, NH 2 or C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F;
  • R 3 is selected from H, R 6 , OR 6 , NHR 6 , Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl,
  • R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R 6 , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH3) 2 R8 CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 5 is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1 - 2 alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0( C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 )2 and (4- to 5-membered)heterocycloalkyl containing one O;
  • R 7 is selected from NH-cyclopropyl, [di methyl (oxo)- ⁇ 6 -sulfanylidene]ami no, (C 1 -
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R 6 and OR 6 , and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2 ;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalky
  • R 10 is independently selected from H and C 1-2 alkyl , wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl; and
  • R 11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) are inhibitors of HPK1.
  • the compounds of Formula (I) can be used as a medicament, in particular for disorders, disease or conditions responsive to inhibition of HPK1, and more specifically cancer.
  • a pharmaceutical formulation comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
  • a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in the treatment of a condition where inhibition of HPK1 would be beneficial.
  • administration of a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) results in a reduction in levels of activity of HPK1 in a mammal, particularly a human.
  • HPK1 in enzymatic activity assays The compounds of Formula (I) also display promising pharmacological profiles by separating desired and undesired effects in vivo.
  • Figure 1 shows the X-ray powder diffraction pattern for Example 8, form A: 5-
  • Figure 2 shows a DSC/TGA thermogram of Example 8, form A: 5-(Methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide.
  • Figure 3 shows the X-ray powder diffraction pattern for Example 8, form F: 5-
  • Figure 4 shows a DSC/TGA thermogram of Example 8, form F: 5-(Methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide.
  • Figure 5 shows the molecular structure of Example 8, form F: 5-(Methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide.
  • Figure 6 shows the X-ray powder diffraction pattern for Example 8, form G: 5-
  • Figure 7 shows a DSC/TGA thermogram of Example 8, form G: 5-(Methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide.
  • Figure 8 shows the X-ray powder diffraction pattern for Example 8, form I: 5-
  • Figure 9 shows a DSC/TGA thermogram of Example 8, form I: 5-(Methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide.
  • Figure 10 shows the molecular structure of Example 8, form I: 5-(Methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide.
  • Figure 11 shows the X-ray powder diffraction pattern for Example 213, form A: 5-
  • Figure 12 shows a DSC/TGA thermogram of Example 213, form A: 5-Cyclopropyl-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4- yl]amino]pyrazine-2-carboxamide.
  • Figure 13 shows the X-ray powder diffraction pattern for Example 213, form B: 5-
  • Figure 14 shows a DSC/TGA thermogram of Example 213, form B: 5-Cyclopropyl-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4- yl]amino]pyrazine-2-carboxamide.
  • Figure 15 shows the X-ray powder diffraction pattern for Example 213, form C: 5-
  • Figure 16 shows a DSC/TGA thermogram of Example 213, form C: 5-Cyclopropyl-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4- yl]amino]pyrazine-2-carboxamide.
  • Figure 17 shows the X-ray powder diffraction pattern for Example 213, form D: 5-
  • Figure 18 shows the X-ray powder diffraction pattern for Example 213, form A, HC1 salt: 5-
  • Figure 19 shows a DSC/TGA thermogram of Example 213, form A, HC1 salt: 5-
  • Figure 20 shows the X-ray powder diffraction pattern for Example 213, form B, HC1 salt: 5-
  • FIG. 21 shows a DSC/TGA thermogram of Example 213, form B, HC1 salt: 5-
  • Figure 22 shows the X-ray powder diffraction pattern for Example 213, form A, methane sulfonic acid salt: 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l- (2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide.
  • Figure 23 shows a DSC/TGA thermogram of Example 213, form A, methane sulfonic acid salt: 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide.
  • Figure 24 shows the X-ray powder diffraction pattern for Example 213, form B, methane sulfonic acid salt: 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l- (2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide.
  • Figure 25 shows a DSC/TGA thermogram of Example 213, form B, methane sulfonic acid salt: 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide.
  • Figure 26 shows a DSC/TGA thermogram of Example 213, form C, methane sulfonic acid salt: 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide.
  • C 1-3 means a carbon group having 1, 2 or 3 carbon atoms.
  • C 1-2 means a carbon group having 1 or 2 carbon atoms.
  • alkyl includes both straight and branched chain alkyl groups and may be, but is not limited to, methyl, ethyl, n- propyl, /-propyl, //-butyl, sec-butyl, /so-butyl or tert- butyl.
  • aryl means an aromatic or partially aromatic group having 6 to 10 carbon atoms such as for example phenyl or naphtyl.
  • heteroaryl means a mono- or bicyclic aromatic or partially aromatic ring with 5 to 10 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.
  • (5- to 6- membered)heteroaryl means an aromatic ring with 5 to 6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.
  • (6-membered)heteroaryl means an aromatic ring with 6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.
  • (6-membered)heteroaryl means for example 2-pyridone.
  • (5-membered)heteroaryl means an aromatic ring with 5 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.
  • heterocycloalkyl means a partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system with 4 to 10 atoms and wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulphur.
  • (5- to 8- membered)heterocycloalkyl means a partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 5 or 6 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulphur.
  • (5- to 6- membered)heterocycloalkyl means a partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 5 or 6 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulphur.
  • (7- membered)heterocycloalkyl means a partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 7 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulphur.
  • (6- membered)heterocycloalkyl means a partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 6 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulphur.
  • heterocycloalkyl substituent may be attached via a nitrogen atom having the appropriate valences, or via any ring carbon atom.
  • a pharmaceutically acceptable moiety e.g. a salt, dosage form, or excipient
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • X1, and X3 are independently selected from CR5 or N, with the provisos that when X1 is N, X3 is CR5 and when X3 is N, X1 is CR5.
  • X1, X2 and X3 are CR 5
  • X2 is N
  • X1 and X3 are CR 5
  • X1 and X2 are N, X2 is CR5.
  • X2 and X3 are N
  • X1 is CR 5
  • R 5 is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1 -
  • O C 1-2 alkyl wherein said O C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl.
  • R1 is cyclopropyl or C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by
  • R1 is cyclopropyl or C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F.
  • R1 is cyclopropyl or CH 3 .
  • R1 is cyclopropyl
  • R1 is CH 3 .
  • R1 is CH 2 F.
  • R1 is CHF 2 .
  • R1 is CF 3 .
  • R2 is H, NH 2 or C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1,
  • R2 is NH 2 .
  • R2 is C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F.
  • R2 is CH 3 .
  • R2 is CH 2 F. In still a further embodiment is CHF2.
  • R2 is H.
  • R3 is selected from H, R6, OR6, NHR6, Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH(C 1 - 2alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl.
  • R3 is selected from R6, OR6, NHR6 and cyclopropyl.
  • R3 is selected from R6, NHR6 and cyclopropyl.
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O.
  • R3 is selected from C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F.
  • R3 is selected from C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F.
  • R3 is CH3.
  • R3 is CH2F.
  • R3 is CHF2.
  • R3 is CF3.
  • R3 is cyclopropyl
  • R3 is NHC 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F.
  • R3 is NHC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F.
  • R3 is NHCH3.
  • R3 is HCH2F.
  • R3 is HCHF2. In still a further embodiment is NHCF3.
  • aryl or heteroaryl wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6 ⁇ , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6 ⁇ , R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 ) 2 and (4- to 5- membered)heterocycloalkyl containing one O.
  • R7 is selected from NH-cyclopropyl, [di methyl (oxo)- ⁇ 6 -sulfanylidene]ami no, (C 1 -
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH 2 OH, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2.
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R11 and azetinyl substituted by 0 or 1 substituents selected from N(CH 3 ) 2 and C(O)CH 3 ;
  • R10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1- 2alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl; and
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl.
  • R4 is selected from aryl, wherein said aryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R 6 , and 0, 1 or 2 substituents independently selected from NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R 6 , and 0, 1 or 2 substituents independently selected from NH2, CN, OR
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl and R 6 , and 0, 1 or 2 substituents independently selected from NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 .
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 , and 0, 1 or 2 substituents independently selected from NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R8 and CH 2 R 8 .
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 .
  • phenyl wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from NH 2 , CN,
  • R4 is selected from phenyl, wherein said phenyl is substituted by a substituent selected from NH 2 , CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 .
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH 2 R 8 , OR 8 , OCH 2 R 8 and CH 2 R 8
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R 6 and OR 6 , and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH 3 and C(O)N(CH 3 ) 2.
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from (6- membered)heterocycloalkyl, wherein said (6-membered)heterocycloalkyl is substituted by 0,
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from (6- membered)heterocycloalkyl, wherein said (6-membered)heterocycloalkyl is substituted by 0,
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from (6- membered)heterocycloalkyl, wherein said (6-membered)heterocycloalkyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R 6 and OR 6 , and 0 or 1 substituent selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2.
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from morpholinyl, wherein said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from morpholinyl, wherein said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from CH2heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R 6 and OR 6 , and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2 ⁇
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from CH2(5- to 8- membered)heterocycloalkyl, wherein said (5- to 8-membered)heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R 6 and OR 6 , and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2 ⁇
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from CH 2 (6- membered)heterocycloalkyl, wherein said (6-membered)heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R 6 and OR 6 , and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2 ⁇
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 , and a substituent selected from CH 2 (6- membered)heterocycloalkyl, wherein said (6-membered)heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, and OR6.
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R6, and a substituent selected from CH 2 (6- membered)heterocycloalkyl, wherein said (6-membered)heterocycloalkyl is substituted by 0,
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R6, and a substituent selected from CH 2 (7- membered)heterocycloalkyl, wherein said (7-membered)heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH3 and C(O)N(CH3) 2.
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R6, and a substituent selected from CH 2 (7- membered)heterocycloalkyl, wherein said (7-membered)heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6.
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R6, and a substituent selected from CH 2 (7- membered)heterocycloalkyl, wherein said (7-membered)heterocycloalkyl is substituted by 0,
  • R4 is selected from heteroaryl, wherein said heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8
  • R ⁇ is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from
  • R4 is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR 6 ⁇ , R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 .
  • R4 is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0 or 1 substituent selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8
  • R4 is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 and
  • R4 is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from R 8 and CH 2 R 8 .
  • R4 is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH 2 (5- to 8-membered)heterocycloalkyl.
  • R4 is selected from (6-membered)heteroaryl, wherein said (6- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from (6-membered)heterocycloalkyl and CH 2 (6- membered)heterocycloalkyl .
  • R4 is selected from (6-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6, R7, R 8 , R 9 ,
  • OR 8 OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 .
  • R4 is selected from (5-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0 or 1 substituent selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8
  • R4 is selected from (5-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 and CH 2 R 8
  • R4 is selected from (5-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from R 8 and CH 2 R 8 .
  • R4 is selected from (5-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH 2 (5- to 8-membered)heterocycloalkyl.
  • R4 is selected from (5-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from (6-membered)heterocycloalkyl and CH 2 (6- membered)heterocycloalkyl.
  • R4 is selected from (5-membered)heteroaryl, wherein said (5- membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from R7.
  • pyrazolyl wherein said pyrazolyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from
  • R4 is 1H-pyrazol-4-yl, wherein said 1H-pyrazol-4-yl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from R 7 .
  • R4 is 1H-pyrazol-4-yl, wherein said 1H-pyrazol-4-yl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6.
  • R4 is 1H-pyrazol-4-yl, wherein said 1H-pyrazol-4-yl is substituted by 0, 1 or 2 substituents independently selected from R6
  • R 5 is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1-2 alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl.
  • R 5 is H.
  • R 5 is C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and O C 1-2 alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl.
  • R 5 is C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F.
  • R 5 is CH3.
  • R 5 is CH2F.
  • R 5 is CHF2.
  • R 5 is CF3.
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O( C 1-2 alkyl ) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O.
  • C 1-4 alkyl wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3
  • C 1-4 alkyl wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 substituents selected from OH, CN and N(CH3)2-
  • R6 is C 1-4 alkyl , wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F.
  • R6 is C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F.
  • R7 is selected from NH-cyclopropyl, [dim ethyl (oxo)- ⁇ 6 - sulfanylidene)amino, ( C 1-4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2S02CH3, SO2NHCH3, S02N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3, cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH, and imidazolyl, wherein said imidazolyl is substituted by
  • R7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3, and cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH.
  • R7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3.
  • R7 is selected from cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH.
  • R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F,
  • R 8 is selected from (5- to 8-membered)heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R and OR 6 ⁇ , and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2 ⁇
  • R 8 is selected from (5- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR 6 ⁇ , and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4-methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2-
  • R 8 is selected from (5- to 8-membered)heterocycloalkyl, where
  • R 8 is selected from (6-membered)heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F,
  • R 8 is selected from (5-membered)heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR 6 ⁇ , and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2-
  • R 9 is selected from OR 10 , N(R 10 )2, NR11(CH2)2N(CH3)2, -(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3.
  • R 9 is selected from -(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 .
  • R 9 is selected from -O(CH2)2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3.
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1- 2alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl.
  • R 10 is H.
  • R 10 is independently selected from C j. 2 alkyl, wherein said C 1 - 2alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, H2 and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl.
  • R 10 is independently selected from C j. 2 alkyl, wherein said C 1 - 2alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, and NH2. In still a further embodiment R 10 is independently selected from C j. 2 alkyl, wherein said C 1 - 2alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F.
  • a compound of Formula (IA), x1, and X3 are independently selected from CR 5 ;
  • R is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1- 2alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl;
  • R3 is selected from H, R6, OR6, NHR6, Cl, CN, CCH, H2, SCH3, cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH( C 1-2 alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or
  • R4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH2, CN, OR6, R7, R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R7 is selected from NH-cyclopropyl, [di methyl
  • R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH2)2N(CH 3 )2, -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H
  • R 3 is selected from H, R6, OR 6 ⁇ , NHR 6 , Cl, CN, CCH, NH 2 , SCH 3 , cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH( C 1-2 alkyl)N(CH 3 )2, oxetan-3-yl,
  • R is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH2, CN, OR6, R7, R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 )2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R7 is selected from cyclopropyl, wherein said cycl
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 )2;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 )2N(CH 3 ) 2 , -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substitute
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are CR 5 ; R is H;
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 )2N(CH 3 ) 2 , -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1- 2alkyl, wherein said C
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H;
  • R 3 is selected from R 6 ⁇ , NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from aryl, wherein said aryl is substituted by 0 or 1 substituent selected from F, Cl and R 6 ⁇ , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 )2N(CH 3 ) 2 , -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1 - 2alkyl, wherein said
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 ⁇ , and 0, 1 or 2 substituents independently selected from NH2, CN, OR6,
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 ) 2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R 7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO 2 CH 3 , NH-cyclopropyl, [dimethyl(oxo)- ⁇ 6 - sulfanylidene)amino, (C 1-4 alkyl)sulfonimidoyl, SO 2 CH 3 , 0SO 2 CH 3 , C(CH 3 ) 2 SO 2 CH 3 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH 3 and cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH;
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH 2 OH, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2 ;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH 3 ) 2 and C(O)CH 3 ;
  • R10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and O C 1- 2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl; and R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H
  • R 3 is selected from R 6 ⁇ , NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R6, and a substituent selected from morpholinyl, wherein said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R6 and OR6, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; or
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H;
  • R 3 is selected from R 6 ⁇ , NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 ⁇ , and a substituent selected from morpholinyl, wherein said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R6 and OR6, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2; and
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F; or a pharmaceutically acceptable salt thereof.
  • R 5 is H
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH 2 OH, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2 ;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R11 and azetinyl substituted by 0 or 1 substituents selected from N(CH 3 ) 2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1- 2alkyl, wherein said
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H
  • R 3 is selected from R 6 , NHR 6 and cyclopropyl
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 , and 0 or 1 substituent selected from NH 2 , CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 )2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3, NH-cyclopropyl, [dimethyl(oxo)- ⁇ 6 - sulfanylidene)amino, (C 1-4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2S02CH3, SO2NHCH3, S02N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3 and cycl
  • R is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , N R 11 (CH2)2N(CH 3 )2, -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substitu
  • X 1 , X 2 and X 3 are CR 5 ;
  • R 5 is H;
  • R 3 is selected from R 6 ⁇ , NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from OR 6 ⁇ , R7, R 8 , R 9 , OR 8 , OCH2R8, C(O)R 8 and CH2R8;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R7 is selected from
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are CR 5 ; R 5 is H;
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from R 8 and CH2R 8 ;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O( C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; and
  • R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected
  • R 5 is H
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH2(5- to 8- membered)heterocycloalkyl; and
  • R is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; or a pharmaceutically acceptable salt thereof.
  • R 5 is H
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0 or 1 substituent selected from R7;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F; and
  • R7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3; or a pharmaceutically acceptable salt thereof.
  • X1 and are independently selected from CR 5 ; is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1- 2alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl;
  • R 3 is selected from H, R6, OR6, NHR6, Cl, CN, CCH, H2, SCH3, cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH(C 1-2 alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH2, CN, OR6, R7, R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R is selected from NH-cyclopropyl, [dim
  • R is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH 2 OH, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2 ;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH 3 ) 2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1- 2 alkyl, wherein said
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • X1 and are independently selected from CR 5 ;
  • R 5 is H;
  • R3 is selected from H, R6, OR 6 ⁇ , NHR 6 ⁇ Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH(C 1-2 alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R6, and
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH2)2N(CH 3 )2, -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1- 2alkyl wherein said C 1-2 alkyl is
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • R 5 is H
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R 6 ⁇ , and 0, 1 or 2 substituents independently selected from NH2, CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R8 and CH 2 R 8 ;
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 ) 2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R7 is selected from cyclopropyl, where
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH 2 OH, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2 ;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R11 and azetinyl substituted by 0 or 1 substituents selected from N(CH 3 ) 2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1- 2alkyl, wherein said
  • R 5 is H
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from aryl, wherein said aryl is substituted by 0 or 1 substituent selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH 2 CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 )2
  • R is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH2)2N(CH 3 )2, -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substitu
  • x1 and are independently selected from CR 5 ;
  • R 5 is H;
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 ⁇ is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 ⁇ , and 0, 1 or 2 substituents independently selected from NH2, CN, OR 6 ⁇ , R 7 , R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 ) 2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R 7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO 2 CH 3 , NH-cyclopropyl, [dimethyl(oxo)- ⁇ 6 - sulfanylidene)amino, (C 1-4 alkyl)sulfonimidoyl, SO 2 CH 3 , 0SO 2 CH 3 , C(CH 3 ) 2 SO 2 CH 3 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH 3 and cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH;
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH20H, 4- methylpiperazinyl, C(O)CH3 and C(O)N(CH3)2;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 )2N(CH 3 ) 2 , -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1- 2alkyl, wherein said C
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R 6 ⁇ , and a substituent selected from morpholinyl, wherein said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R6 and OR6, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, O(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; or a pharmaceutical
  • R 5 is H;
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from phenyl, wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R6, and a substituent selected from morpholinyl, wherein said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R6 and OR6, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F; or a pharmaceutically acceptable salt thereof.
  • R 5 is H
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0, 1 or 2 substituents independently selected from NH 2 , CN, OR6, R7, R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or
  • X * and are independently selected from CR 5 ; R 5 is H;
  • R3 is selected from R 6 , NHR 6 and cyclopropyl
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 , and 0 or 1 substituent selected from NH 2 , CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH 2 R 8 , C(O)R 8 , C(O)CH 3 , C(O)NHCH 3 , CH 2 C(O)NHCH 3 , C(CH 3 ) 2 R 8 , CH(CH 3 )R 8 and CH 2 R 8 ;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH 3 ) 2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R 7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO 2 CH 3 , NH-cyclopropyl, [dimethyl(oxo)- ⁇ 6 - sulfanylidene)amino, (C 1-4 alkyl)sulfonimidoyl, SO 2 CH 3 , 0SO 2 CH 3 , C(CH 3 ) 2 SO 2 CH 3 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH 3 and cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH;
  • R 8 is selected from SO 2 CH 3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R 6 and OR 6 , and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CH 2 OH, 4- methylpiperazinyl, C(O)CH 3 and C(O)N(CH 3 ) 2 ;
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 (5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH 2 ) 2 (5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloal
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0 or 1 substituent selected from OR6, R7, R 8 , R 9 , OR 8 , OCH2R , C(O)R 8 and CH2R ;
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R ⁇ is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3, NH-cyclopropyl, [dimethyl(oxo)- ⁇ 6 - sulfanylidene)amino, (C 1-4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2 HCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3 and cyclobutyl, wherein said cyclobutyl is substituted by 0 or 1 OH; R is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, and OR6, and 0, 1 or 2 substituents independently selected from
  • R 9 is selected from OR 10 , N(R 10 ) 2 , NR 11 (CH2)2N(CH 3 )2, -(CH 2 )2(5- to 6- membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 , -O(CH2)2(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is substituted by 0 or 1 substituents selected from R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH 3 ;
  • R 10 is independently selected from H and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1- 2alkyl wherein said C 1-2 alkyl is
  • R11 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (IB) wherein x1 and are independently selected from CR 5 ; R 5 is H;
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from R 8 and CH2R 8 ;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O;
  • R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, R6 and OR6, and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2; or a pharmaceutically acceptable salt thereof.
  • R 5 is H
  • R 3 is selected from R6, NHR6 and cyclopropyl;
  • R is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R 6 ⁇ , and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH2(5- to 8- membered)heterocycloalkyl; and R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; or a pharmaceutically acceptable salt thereof
  • a compound of Formula (IB) wherein x1 and are independently selected from CR 5 ;
  • R 5 is H;
  • R3 is selected from R6, NHR6 and cyclopropyl;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F;
  • R4 is selected from (5-membered)heteroaryl, wherein said (5-membered)heteroaryl is substituted by 0, 1 or 2 substituents independently selected from F, Cl and R6, and 0 or 1 substituent selected from R7;
  • R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F; and
  • R is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituents selected from F, CN, OH or SO2CH3; or a pharmaceutically acceptable salt thereof.
  • R 5 is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, H2 and OC 1- 2alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl;
  • R1 is cyclopropyl or C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F;
  • R3 is selected from H, R6, OR6, MIR 6 ⁇ , Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH(C 1-2 alkyl)N(CH3)2, oxetan-3-yl,
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; or a pharmaceutically acceptable salt thereof.
  • R is independently selected from H, F, Cl and C 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH 2 and OC 1- 2alkyl, wherein said OC 1-2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl;
  • R1 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F;
  • R 3 is selected from H, R6, OR6, NHR6, Cl, CN, CCH, NH 2 , SCH3, cyclopropyl, cyclobutyl, NH((5- to 6-membered)heteroaryl containing 1 or 2 N), NH(C 1-2 alkyl)N(CH3)2, oxetan-3-yl,
  • R6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F, 0(C 1-2 alkyl) and 0 or 1 substituents selected from OH, CN, N(CH3)2 and (4- to 5- membered)heterocycloalkyl containing one O; or a pharmaceutically acceptable salt thereof.
  • x1 and are independently selected from CR 5 ;
  • R 5 is H;
  • R1 is C 1-3 alkyl, wherein said C 1-3 alkyl is substituted by 0, 1, 2 or 3 F;
  • R 3 is selected from R 6 ⁇ , NHR6 and cyclopropyl; R 6 is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F; or a pharmaceutically acceptable salt thereof.
  • R 1 is CH 3 ;
  • R 3 is cyclopropyl; R is C 1-4 alkyl, wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 F; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is selected from: 6-(l-Methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,
  • Another embodiment is a product obtainable by any of the processes or examples disclosed herein.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts are useful because they possess pharmacological activity as inhibitors of hematopoietic progenitor kinase 1 (HPK1) and are thereby particularly useful in the treatment or amelioration of abnormal cell proliferative disorders such as cancer.
  • the compounds of Formula (I) are inhibitors of HPK1.
  • the compounds of Formula (I) can be used as a medicament, in particular for disorders, disease or conditions responsive to inhibition of HPK1, and more specifically cancer.
  • a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in the treatment of a condition where inhibition of HPK1 would be beneficial.
  • administration of a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) results in a reduction in levels of activity of HPK1 in a mammal, particularly a human.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day.
  • the compounds of Formula (I), and pharmaceutically acceptable derivatives thereof may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition comprising a novel compound of Formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, inhalation, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs , M. E. Aulton, Churchill
  • the pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof are believed to be useful in the prevention or treatment of disorders, disease or conditions responsive to inhibition of HPK1, and more specifically cancer.
  • treatment includes therapeutic and/or prophylactic treatment.
  • a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse.
  • the compounds described herein have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds known in the prior art.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • a combination therapy wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above.
  • a combination may be used in combination with one or more further active ingredients.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof could be used in combination with check point blockade PD-(L)1 axis or with CTLA4 in efforts to expand response rates to check point blockade.
  • Primary or secondary resistance to check point blockade may be potential indications for a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Additional combinations may include radiation, chemotherapy, surgery, tumour targeted agents or other immune targeted agents.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately.
  • the particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • a method of treatment of a condition where inhibition of HPK1 is required comprises administration of a therapeutically effective amount of a compound of Formula (I) to a person suffering from, or susceptible to, such a condition.
  • the compounds of Formula (I) will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The
  • Suitable daily doses of the compounds of Formula (I) in therapeutical treatment of humans are about 0.0001-100 mg/kg body weight, preferably 0.01-10 mg/kg body weight.
  • Oral formulations are preferred, particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.007 mg to 700 mg.
  • the optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art.
  • a pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable derivatives thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • the compounds of Formula (I) may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation.
  • a further embodiment encompasses pharmaceutically acceptable salts of the compounds of Formula (I).
  • a salt of a compound of Formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent.
  • a salt may be used to aid in the isolation or purification of the compound.
  • the salt is pharmaceutically acceptable.
  • a pharmaceutically acceptable moiety e.g. a salt, dosage form, or excipient
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.
  • an acid co-former is a solid at r.t. and there is no or only partial proton transfer between the compound of Formula (I) and such an acid co-former, a co-crystal of the co- former and compound of Formula (I) may result rather than a salt. All such co-crystal forms of the compound of Formula (I) are encompassed herein.
  • certain compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures.
  • Certain compounds of Formula (I) may also contain linkages (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring bond or double bond.
  • linkages e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds
  • Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis.
  • the compounds of Formula (I) encompass any isotopically-labelled (or “radio-labelled”) derivatives of a compound of Formula (I).
  • a derivative is a derivative of a compound of Formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be incorporated include 3 ⁇ 4 (also written as “D” for deuterium).
  • the compounds of Formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula (I).
  • prodrug derivatives see: Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein.
  • HPK1, GLK, and LCK IC50 assays Activity of purified N-terminal GST-tagged, recombinant, human HPK1, GLK, and LCK enzymes expressed in insect cells (HPK1: amino acids 1-346, ThermoFisher Scientific, #PV6356, Carlsbad, CA; GLK: amino acids 1-380, ThermoFisher Scientific, #PV6351, Carlsbad, CA; LCK: full length, Abeam, #ab79626, Cambridge, MA) was determined in-vitro using ADP-Glo Max Assay (Promega, #V7002, Madison, WI), a luminescent ADP detection assay, by quantifying the amount of ADP produced in a kinase reaction.
  • HPK1 amino acids 1-346, ThermoFisher Scientific, #PV6356, Carlsbad, CA
  • GLK amino acids 1-380, ThermoFisher Scientific, #PV6351, Carlsbad, CA
  • LCK
  • the luminescent signal generated is proportional to the ADP concentration produced in a kinase assay in the presence and absence of the compound(s) and is correlated with the kinase activity.
  • Two microlitres (m ⁇ ) of enzyme mix consisting of 10 nM HPK1, 30 nM GLK, or 2 nM LCK in lx reaction buffer (50 mM HEPES (pH7.2), 1 mM DL-Dithiothreitol (DTT), 0.005% (vol/vol) Brij35, 20 mM MgC12) was spotted into Greiner 384-well low volume plate with 0.1 pi of compound, which was dosed at 100, 31.25, 12.5, 3.19, 1, 0.32, 0.1, 0.032, 0.01 and 0.003 mM of final test concentrations and preincubated for 30 minutes at room temperature.
  • Enzymatic reactions were initiated with 2 m ⁇ of peptide substrate/ ATP mix (for HPK1: 10 mM LRRKtide (RLGRDKYKTLRQIRQ-amide; Cambridge Research Biochemicals, Billingham, UK), 30 mM ATP; for GLK: 14 mM LRRKtide, 60 mM ATP; for LCK: 100 ⁇ MLCKtide (EQEDEDEPEGIY GVLE-amide; Intonation, Boston, MA), 50 mM ATP) in lx reaction buffer and incubated at room temperature for 60 minutes. 4 m ⁇ ADP-Glo Reagent was added to terminate the reactions and deplete the remaining ATP and incubated at room temperature for 60 minutes.
  • ADP-Glo Max Detection Reagent 8 m ⁇ ADP-Glo Max Detection Reagent was added to simultaneously convert ADP to ATP and incubated at room temperature for 60 minutes. The newly synthesized ATP is converted to light using a luciferase/luciferin reaction. Luminescence was read by PHERAstar FSX plate reader (BMG LAB TECH, Cary, NC) and the data was captured by PHERAstar FSX MARS data analysis software. IC50 values were processed using GeneData Screener (GeneData AG, Basel, Switzerland).
  • Cryo-preserved human CD3+ T cells are recovered in warm T cell media overnight. Recovered T cells are seeded at 70000 cells per well in a 384-well Black/Clear Round Bottom Ultra-Low Attachment Spheroid Microplate (Corning 3830). Compounds in a assay ready 384-well plate (Greiner 781280) are added to the seeded T cells using a Bravo liquid handler. T cells are then left in a humidified incubator at 37°C for 1 hour. At the end of incubation, the cells are transferred to a 384-well flat bottom plate (Greiner 781090) coated with anti-CD3 antibody (5ug/mL anti-CD3 in PBS, overnight incubation at 4 °C).
  • Anti-CD28 antibody in T cell media is also added to the cells by Bravo liquid handler at 5ug/mL or lug/mL in a donor dependent manner. T cells are then incubated in a humidified incubator at 37°C for 4 hours. Cell culture supernatant is collected using a Bravo liquid handler in a v-bottom 384 well plate (Greiner 781280) after the 4-hour incubation. IL2 is detected using a IL2 MultiCyt® QBeads® kit on an iQue Screener flow cytometer (Sartorius). Briefly, capture beads are diluted by 50x in the supplied capture bead diluent.
  • lOul per well diluted capture beads is added to each well of a v- bottom 384 well plate (Greiner 781280) using a ThermoFisher multichannel pipette.
  • a ThermoFisher multichannel pipette Using a Bravo liquid handler, lOul cell culture supernatant is transferred to the v-bottom plate with diluted capture beads. The plate is then sealed in foil and incubate at room temperature on a plate shaker set to 900rpm for 1 hour. At the end of incubation, 10 ⁇ L per well of the supplied detection reagent is added to the wells using a ThermoFisher multichannel pipette.
  • iQue Screener flow cytometer uses pre-configured analysis template supplied with the IL2 MultiCyt® QBeads® kit to detect IL2 in each sample wells.
  • BINAP (2, 2'-bis(diphenylphosphino)- 1,1 '-binaphthyl), also known as [l-(2- diphenylphosphanyl-l-naphthyl)-2-naphthyl]-diphenyl-phosphane
  • Pd G3 [(dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane)-2-(2'-amino-l, 1 biphenyl)]palladium(II) methanesulfonate cataCXium A bis(l-adamantyl)-butyl-phosphane cataCXium A Pd G2 chloro[(bis(l-
  • DIPEA DCM dichloromethane DIPEA N,N-diisopropylethylamine, also known as N-ethyl-N-isopropyl- propan-2-amine
  • DIAD diisopropyl azodi carboxyl ate also known as isopropyl (NE)-N- isopropoxycarbonyliminocarbamate
  • DMA N,N-dimethylacetamide
  • DMAP N,N-dimethylaminopyridine, also known as N,N-dimethylpyridin-4- amine
  • DTBAD di-tert-butyl azodi carboxyl ate also known as tert-butyl (NE)-N-tert- butoxycarbonyliminocarbamate
  • EPhos Pd G4 [(dicyclohexyl-[2-isopropoxy-6-(2,4,6- triisopropylphenyl)phenyl]phosphane)-2-(2'-methylamino-l, 1 biphenyl)]palladium(II) methanesulfonate
  • IPA isopropanol, also known as propan-2-ol Ir(dFCF3ppy)2(dtbbpy) [4, 4'-bis(l,l -dimethyl ethyl)-2,2'-bipyridine-N1,N1']bis[3, 5- difl uoro-2-[5-(tri fluorom ethyl )-2-pyridinyl-A']phenyl- C]Iridium(III) hexafluorophosphate
  • PCy 3 Pd G3 [(tricyclohexylphosphane)-2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate
  • Pd-PEPP SI-IP ent [(di(l-adamantyl)-butylphosphine)-2-(2'-amino-l, 1 '- biphenyl)]palladium(II) methanesulfonate sC0 2 supercritical carbon dioxide
  • operations are carried out at room temperature, that is, in a range of 18 to 25 degrees Celsius.
  • Evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 - 30 mmHg) with a bath temperature of up to 60 degrees Celsius.
  • Biotage SNAP Agela Claricep, RediSep Rf Gold Silica, or Buchi FlashPure columns, in sizes ranging from 5 g to 300 g as appropriate.
  • Reverse phase chromatography was performed on Biotage Selekt, Biotage Isolera, Teledyne ISCO Combiflash Companion, or Agela Technologies automated purification instruments, using Biotage Sfar C18 Duo, RediSep Rf C18, or RediSep Rf Gold C18 columns, in sizes ranging from 5 g to 300 g as appropriate.
  • MDAP purification was carried out on an Agilent 1260 Infinity II (autosampler, DAD, quaternary pump, and isocratic pumps) and Agilent 1290 Infinity II (preparative pump and fraction collector) with an Agilent InfmityLab LC/MSD. Columns and gradients are specified in the examples.
  • Preparative HPLC purification was carried out on a Waters FractionLynx system fitted with an Acquity QDa Mass Detector, or an instrument comprising a Waters 2545, 2767, and 2489, fitted with QDa or SQ Detector 2 ESCi mass spectrometers. Columns and gradients are specified in the examples.
  • Ion exchange chromatography was performed using Waters PoraPak Rxn CX cartridges.
  • the column used was Waters Acquity HSS T3, 1.8 micron, 2.1 mm x 30 mm; for base analysis the column used was Waters Acquity BEH Cl 8, 1.7 micron, 2.1 mm x 30mm; or 2) Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA detector and LCMS 2020 MS detector, using one of three conditions: a) Halo C18 column (2.0 micron, 3 mm x30 mm) in combination with a gradient (5-100% B in 1.2 minutes) of water and formic acid (0.1%) (A) and acetonitrile and formic acid (0.1%) (B) at a flow rate of 1.5 mL/min; b) Halo C18 column (2.0 micron, 3 mm x 30 mm) in combination with a gradient (5-100% B in 1.2 minutes) of water and trifluoro
  • Photoredox chemistry was carried out using a 34 W Kessil HI 50 blue LED lamp (440 nm) as light source, in a HepatoChem EvoluChemTM PhotoRedOx reaction apparatus.
  • Optical rotation data were taken on a Jasco P-2000 polarimeter, using a 100 mm path length, 0.40 w/v% solutions of compound in DMSO, with the sodium D line (589 nm), at 25 degrees Celsius.
  • Samples were mounted on single silicon crystal (SSC) wafer mounts and powder X-ray diffraction was recorded with a PANalytical X’Pert PRO (reflection geometry, wavelength of X-rays 1.5418 A nickel-filtered Cu radiation, Voltage 45 kV, filament emission 40 mA). Automatic variable divergence and anti scatter slits were used and the samples were rotated during measurement. Samples were scanned from 2 - 50 °2Theta or 2 - 40 °2Theta using a 0.013° step width and between 44 and 233 seconds count time using a PIXCEL detector (active length 3.35 °2Theta).
  • SSC single silicon crystal
  • an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
  • the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • a measurement error of a diffraction angle in an X-ray powder diffractogram may be approximately plus or minus 0.1° 2-theta, and such a degree of a measurement error should be taken into account when considering the X-ray powder diffraction data.
  • intensities might fluctuate depending on experimental conditions and sample preparation (e.g. preferred orientation).
  • the following definitions have been used for the relative intensity (%): 81 - 100%, vs (very strong); 41 - 80%, str (strong); 21 - 40%, med (medium); 10 - 20%, w (weak); 1 - 9%, vw (very weak).
  • Chemical IUPAC names were generated by BioviaDraw using OpenEye Metachem 1.5.0 software.
  • Iron powder (61.3 g, 1.10 mol) was added to a solution of 3-bromo-N-methyl-2-nitro-aniline (25.4 g, 110 mmol) and ammonium chloride (58.8 g, 1.10 mol) in methanol (146 mL). The resulting suspension was stirred at 60 °C for 2 hours. The reaction mixture was then concentrated. The resulting residue was partitioned between ethyl acetate and a saturated aqueous potassium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated.
  • Dichlorobis(tricyclohexylphosphine)palladium(II) (418 mg, 0.570 mmol) was added to a suspension of 7-bromo-3-methyl-3H-imidazo[4,5-c]pyridine (600 mg, 2.83 mmol), bis(pinacolato)diboron (2.16 g, 8.49 mmol), and potassium acetate (833 mg, 8.49 mmol) in toluene (2 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours. The reaction was then concentrated.
  • N-Bromosuccinimide (209.0 g, 1175 mmol) was added to 3-amino-5-methyl-pyrazine-2- carboxylic acid (180.0 g, 1175 mmol) in acetonitrile (1.4 L). The resulting mixture was stirred at 82 °C for 30 minutes. The reaction was then cooled to 0 °C. The resulting precipitate was isolated by filtration, washed with acetonitrile, and dried under vacuum to afford 3-amino-6- bromo-5-methyl-pyrazine-2-carboxylic acid (248 g, 91% yield) as a beige solid.
  • 1,4-dioxane (10 mL) was added to a mixture of (l-methylbenzimidazol-4-yl)boronic acid (480 mg, 2.73 mmol), methyl 3-amino-6-chloro-5-[2-(dimethylamino)ethoxy]pyrazine-2- carboxylate (500 mg, 1.82 mmol), CsF (829 mg, 5.46 mmol), and PdC12(dppf)-DCM adduct (223 mg, 0.27 mmol). The resulting mixture was stirred at 100 °C for 2 hours. The solvent was then removed under reduced pressure.
  • Triethylamine (0.061 mL, 0.43 mmol) was added to a suspension of 5-[2- (dimethylamino)ethoxy]-6-(l-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2- carboxylic acid (75 mg, 0.14 mmol), ammonium chloride (47 mg, 0.87 mmol), and HATU (72 mg, 0.19 mmol) in DMF (5 mL). The resulting mixture was stirred at 25 °C for 2 hours. The solvent was then removed under reduced pressure.
  • 4-(4-Bromophenyl)morpholine (313 mg, 1.29 mmol) was added to a suspension of methyl 3- amino-5-cyclopropyl-6-(l-methylbenzimidazol-4-yl)pyrazine-2-carboxylate (380 mg, 1.18 mmol), cesium carbonate (766 mg, 2.35 mmol) and Brettphos Pd G3 (107 mg, 0.120 mmol) in 1,4-dioxane (4 mL). The resulting mixture was stirred at 100 °C for 12 hours. The solvent was then removed under reduced pressure.
  • Methyl 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate (280 mg, 0.94 mmol) was added to a suspension of 4-(4-bromophenyl)morpholine (227 mg, 0.940 mmol), cesium carbonate (612 mg, 1.88 mmol) and Brettphos Pd G3 (170 mg, 0.19 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was removed under reduced pressure.
  • the layers were separated and the aqueous layer was extracted three times with DCM (50 mL each).
  • the combined organic layers were washed with saturated aqueous ammonium chloride (50 mL).
  • the combined aqueous layers were extracted a final time with DCM (50 mL).
  • Methyl 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (1.50 g, 3.97 mmol)
  • l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzimidazole (1.63 g, 69 wt%, 4.37 mmol)
  • Pd(dppf)Ch (0.29 g, 0.40 mmol)
  • cesium fluoride (1.81 g, 11.9 mmol) were combined in a microwave vial, which was then evacuated and backfilled three times with nitrogen.
  • MeOH (15 mL) was added and the reaction was stirred at 100 °C for 8 hours in a Biotage microwave reactor. The reaction was then concentrated, loaded onto Celite, and purified by silica gel chromatography, using 0-10% MeOH-DCM as eluent and 0-1% ammonia as modifier, to afford a yellow-brown solid. This material was suspended in MeOH (40 mL), stirred at 40 °C for 30 minutes, and left to stand for 1 hour.
  • Lithium hydroxide monohydrate (2.64 g, 63.0 mmol) was added to a suspension of methyl 5- (methylamino)-6-(l-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2- carboxylate (2.98 g, 6.30 mmol) in water (16 mL) and MeOH (16 mL). The resulting mixture was stirred at 100 °C for 90 minutes in a Biotage microwave reactor. The reaction was allowed to cool to room temperature, diluted with water (70 mL), and concentrated to a volume of 40 mL, then filtered and rinsed with water.
  • DIPEA (7.00 mL, 40.1 mmol) was added to a suspension of 5-(methylamino)-6-(l- methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid, ditrifluoroacetate (5.52 g, 8.05 mmol), ammonium chloride (5.16 g, 96.6 mmol), and HATU (4.59 g, 12.1 mmol) in DMF (60 mL). The resulting mixture was stirred at 25 °C for 3 hours. The reaction was then diluted with saturated aqueous sodium bicarbonate (60 mL) and water (200 mL).
  • the resulting mixture was stirred at 80 °C for 2 h. The reaction was then allowed to cool to room temperature, diluted with water (500 mL), and filtered. The filter cake was dried under vacuum. The resulting solid was used in the next step without further purification.
  • DIPEA (69.4 mL, 397 mmol) was added to a mixture of 5-(methylamino)-6-(3- methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (30.5 g, 66.2 mmol), ammonium chloride (14.17 g, 264.9 mmol), and HATU (50.40 g, 132.5 mmol) in DMF (400 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was then concentrated.
  • Form A was further analyzed by thermal techniques. DSC analysis indicated that Form A starts to de-solvate with an onset at 29 °C and a peak at 54 °C, followed by a several thermal events from 190 °C to 290 °C. TGA indicated that Form A exhibits a mass loss of about 1.3 % upon heating from about 25 °C to about 100 °C. A representative DSC/TGA thermogram of Form A is shown in Figure 2.
  • the filter cake consisting of form A was suspended in 99.5% EtOH (750 mL) and treated with 20 mg seed crystals of Form F 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)- 3-(4-morpholinoanilino)pyrazine-2-carboxamide (obtainable by placing 3-5 mg of form A in a TGA or DSC pan, heating to 300°C at a rate of 10°C/minute and then cooled down to the room temperature.) The resulting suspension was stirred at room temperature for 16 hours, then filtered.
  • Form F was further analyzed by thermal techniques. DSC analysis indicated that Form F has a melting/decomposition temperature with an onset at 334 °C and a peak at 338 °C. TGA indicated that Form F exhibits a mass loss of about 0.5 % upon heating from about 25 °C to about 100 °C. A representative DSC/TGA thermogram of Form F is shown in Figure 4.
  • Example 8 - Form F Single crystals of Form F were obtained from evaporation of the EtOH solution. Single crystal structure analysis confirmed that Form F is an anhydrous form.
  • Form G was further analyzed by thermal techniques. DSC analysis indicated that Form G has a melting/decomposition temperature with an onset at 344 °C and a peak at 345 °C. TGA indicated that Form G exhibits a mass loss of about 0.1 % upon heating from about 25 °C to about 100 °C. A representative DSC/TGA thermogram of Form G is shown in Figure 7.
  • Form I was further analyzed by thermal techniques. DSC analysis indicated that Form I starts to de-solvate with an onset at 66 °C and a peak at 73 °C, followed by has a melting/decomposition temperature with an onset at 344 °C and a peak at 245 °C. TGA indicated that Form I exhibits a mass loss of about 3.7 % upon heating from about 25 °C to about 100 °C. A representative DSC/TGA thermogram of Form I is shown in Figure 9.
  • DIPEA 0.253 mL, 1.45 mmol
  • 6-(l-methylbenzimidazol-4-yl)- 5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid 115 mg, 0.24 mmol
  • ammonium chloride 51.6 mg, 0.97 mmol
  • HATU 184 mg, 0.48 mmol
  • the resulting mixture was stirred at 0 °C for 30 minutes and then at 25 °C for 90 minutes.
  • the reaction was then quenched with saturated aqueous sodium bicarbonate and extracted with 3 : 1 DCM/IPA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • (2S)-l-Aminopropan-2-ol (77 mg, 1.02 mmol) was added to a suspension of 6-(l- methylbenzimidazol-4-yl)-5-methylsulfmyl-3-[4-(4-oxidomorpholin-4-ium-4- yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140 °C for 20 minutes in a Biotage microwave reactor. The reaction was then concentrated. The resulting residue was partitioned between DCM and water. The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated.
  • 2,2,2-Trifluoroethanamine (101 mg, 1.02 mmol) was added to a suspension of 6-(l- methylbenzimidazol-4-yl)-5-methylsulfmyl-3-[4-(4-oxidomorpholin-4-ium-4- yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL).
  • the resulting mixture was stirred at 140 °C for 20 minutes in a Biotage microwave reactor. The reaction was then concentrated and the resulting residue was partitioned between DCM and H20. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated.
  • the resulting mixture was stirred at 140 °C for 20 minutes in a Biotage microwave reactor was heated at 140oc for 20 m. The reaction was then concentrated and the resulting residue was partitioned between DCM and H2O. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated.
  • N',N' -Dim ethyl ethane- 1,2-diamine (90 mg, 1.0 mmol) was added to a suspension of 4-(4-((3- carbamoyl-5-(l-methyl-lH-benzo[d]imidazol-4-yl)-6-(methylsulfmyl)pyrazin-2- yl)amino)phenyl)morpholine 4-oxide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140 °C for 20 minutes in a Biotage microwave reactor. The reaction was then concentrated and the resulting residue was partitioned between DCM and H2O.
  • Prop-2-yn-l -amine (0.071 mL, 1.1 mmol) was added to a suspension of 6-(l- methylbenzimidazol-4-yl)-5-methylsulfmyl-3-[4-(4-oxidomorpholin-4-ium-4- yl)anilino]pyrazine-2-carboxamide (28 mg, 0.060 mmol) in 1,4-dioxane (1 mL). The resulting mixture was stirred at 110 °C for 30 minutes. The reaction was then concentrated.
  • Potassium carbonate (0.120 g, 0.88 mmol) was added to a suspension of (26')-2-fluoropropan- 1-amine hydrochloride (0.047 g, 0.41 mmol) and 6-(l-methylbenzimidazol-4-yl)-5- methylsulfmyl-3-[4-(4-oxidomorpholin-4-ium-4-yl)anilino]pyrazine-2-carboxamide (0.042 g, 0.080 mmol) in dioxane (1.5 mL). The resulting mixture was stirred at 110 °C for 30 minutes. The reaction was then quenched with water and extracted with DCM. The organic layer was concentrated.
  • Oxetan-3-ylmethanamine (36 mg, 0.41 mmol) was added to a solution of 6-(l- methylbenzimidazol-4-yl)-5-methylsulfmyl-3-[4-(4-oxidomorpholin-4-ium-4- yl)anilino]pyrazine-2-carboxamide (35 mg, 0.070 mmol) in DMF (690 ⁇ L). The resulting mixture was stirred at 25 C for 16 hours. The reaction was then quenched with sodium hydrogen sulfite (36 mg, 0.34 mmol) and stirred at 25 C for 1 hour.
  • Tricyclohexylphosphonium tetrafluorob orate (136 mg, 0.370 mmol) was added to a mixture of methyl 3-amino-6-chloro-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate (680 mg, 1.85 mmol), (l-methylbenzimidazol-4-yl)boronic acid (650 mg, 3.70 mmol), potassium phosphate (785 mg, 3.70 mmol), and PCy3 Pd G3 (240 mg, 0.370 mmol) in l,4-dioxane/H 2 0 (20 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours. The reaction was then concentrated.
  • Methyl 3-amino-5,6-dichloro-pyrazine-2-carboxylate 500 mg, 2.25 mmol was added to a mixture of bis(dibenzylideneacetone)palladium (129 mg, 0.230 mmol), DPEPhos (243 mg, 0.450 mmol) and [l,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene]- (difluoromethyl)silver (1.24 g, 2.25 mmol) in toluene (30 mL) under nitrogen. The resulting solution was stirred at 80 °C for 18 hours. The reaction was then concentrated.
  • PdCh(dppf) (0.45 g, 0.62 mmol) was added to a suspension of methyl 3-amino-6-chloro-5- [(4-methoxyphenyl)methoxy]pyrazine-2-carboxylate (2.00 g, 6.18 mmol), (1- methylbenzimidazol-4-yl)boronic acid (1.09 g, 6.18 mmol), and cesium fluoride (1.88 g, 12.4 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 4 hours. The reaction was then concentrated.
  • Methyl 5-[(4-methoxyphenyl)methoxy]-6-(l-methylbenzimidazol-4-yl)-3-(4- morpholinoanilino)pyrazine-2-carboxylate (1.8 g, 3.10 mmol) was added to a mixture of TFA (5 mL) and DCM (20 mL). The resulting mixture was stirred at 25 °C for 1 hour. The reaction was then concentrated.
  • Phosphoryl trichloride (5.00 mL, 53.7 mmol) was added to methyl 5-hydroxy-6-(l- methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.30 g, 0.65 mmol). The resulting mixture was stirred at 100 °C for 16 hours. The reaction was then concentrated. The resulting residue was redissolved in EtOAc and washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated.
  • PdCb(dppf) 28 mg, 0.040 mmol
  • l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzimidazole 185 mg, 65 wt%, 0.46 mmol
  • cesium fluoride 177 mg, 1.16 mmol
  • 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide 165 mg, 0.39 mmol
  • Dioxane (1.55 mL) and water (0.39 mL) were added.
  • Methyl 3-amino-5,6-dichloro-pyrazine-2-carboxylate 500 mg, 2.25 mmol
  • 4,4'-di-tert-butyl- 2,2'-bipyridine 60 mg, 0.23 mmol
  • Ir(dFCF3ppy)2(dtbbpy) hexafluorophosphate 25 mg, 0.020 mmol
  • NiCh diglyme 50 mg, 0.23 mmol
  • Triethylamine (0.727 mL, 5.22 mmol) was added to a mixture of 6-chloro-5-ethoxy-3-(4- morpholinoanilino)pyrazine-2-carboxylic acid (0.494 g, 1.30 mmol), ammonium chloride (0.349 g, 6.52 mmol), and HATU (0.744 g, 1.96 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 3.5 hours. The reaction was then diluted with saturated aqueous sodium bicarbonate and water.
  • Ethyl 3 -ethoxy-3 -imino-propanoate hydrochloride (5.00 g, 25.6 mmol) was added to 2 M ethanolic ammonia (40 mL, 80 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes at 25 °C for 3.5 hours. A solution of sodium nitrite (1.94 g, 28.1 mmol) in water (8 mL) was added. 6 N aqueous HC1 (15 mL, 90 mmol) was added. The resulting mixture was stirred at 25 °C overnight. The reaction was then concentrated to one-third volume, diluted with water, and neutralized with saturated aqueous sodium bicarbonate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/EP2022/070137 2021-07-20 2022-07-19 Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer Ceased WO2023001794A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US18/580,664 US20240374606A1 (en) 2021-07-20 2022-07-19 Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer
JP2024502652A JP7851393B2 (ja) 2021-07-20 2022-07-19 癌の治療のためのｈｐｋ１阻害剤としての置換ピラジン－２－カルボキサミド阻害剤
EP22754791.6A EP4373817B1 (en) 2021-07-20 2022-07-19 Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer
CN202280049292.0A CN117693503A (zh) 2021-07-20 2022-07-19 作为hpk1抑制剂用于治疗癌症的经取代的吡嗪-2-甲酰胺
ES22754791T ES3036245T3 (en) 2021-07-20 2022-07-19 Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163223633P 2021-07-20 2021-07-20
US63/223,633 2021-07-20

Publications (1)

Publication Number Publication Date
WO2023001794A1 true WO2023001794A1 (en) 2023-01-26

Family

ID=82932501

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/070137 Ceased WO2023001794A1 (en) 2021-07-20 2022-07-19 Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer

Country Status (9)

Country Link
US (1) US20240374606A1 (https=)
EP (1) EP4373817B1 (https=)
JP (1) JP7851393B2 (https=)
CN (1) CN117693503A (https=)
AR (1) AR126500A1 (https=)
ES (1) ES3036245T3 (https=)
TW (1) TW202321239A (https=)
UY (1) UY39865A (https=)
WO (1) WO2023001794A1 (https=)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024008128A1 (zh) 2022-07-06 2024-01-11 上海科恩泰生物医药科技有限公司 一种具有fgfr抑制作用的亚砜亚胺类化合物、包含其的药物组合物及其用途
WO2024240242A1 (zh) * 2023-05-25 2024-11-28 正大天晴药业集团股份有限公司 含有酰胺取代的芳香环的化合物、其药物组合物及用途
EP4574830A4 (en) * 2022-09-23 2025-11-26 Guangzhou Vinnocent Pharmaceutical Ltd PYRIDINE INHIBITOR, RINGED STEROID SYNTHETASE, ITS PREPARATION PROCESS AND ITS USE

Citations (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016205942A1 (en) 2015-06-25 2016-12-29 University Health Network Hpk1 inhibitors and methods of using same
WO2018049191A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridone derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049200A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049152A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyrimidine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049214A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018081531A2 (en) 2016-10-28 2018-05-03 Ariad Pharmaceuticals, Inc. Methods for human t-cell activation
WO2018102366A1 (en) 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
US20180228786A1 (en) * 2017-02-15 2018-08-16 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
WO2018183964A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Isoquinolines as inhibitors of hpk1
WO2018228923A1 (en) 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyridine-derivatives as map4k1 modulators for the treatment of cancer diseases
WO2018228920A1 (en) 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyridine-derivatives
WO2018228925A1 (en) 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyridine-derivatives
WO2019016071A1 (en) 2017-07-18 2019-01-24 Bayer Pharma Aktiengesellschaft SUBSTITUTED PYRROLOPYRIDINE DERIVATIVES
WO2019051196A1 (en) 2017-09-08 2019-03-14 Commscope Technologies Llc ENCLOSURE OF HEAT DISSIPATION
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
US20190256500A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
US20190256520A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
WO2019164846A1 (en) 2018-02-20 2019-08-29 Incyte Corporation N-(phenyl)-2-(phenyl)pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer
US20190315717A1 (en) 2018-04-13 2019-10-17 Incyte Corporation Benzimidazole and indole compounds and uses thereof
WO2019206049A1 (en) 2018-04-25 2019-10-31 Zhuhai Yufan Biotechnologies Co., Ltd Hpk1 inhibitors, preparation method and application thereof
WO2019238067A1 (en) 2018-06-13 2019-12-19 Beigene, Ltd. Pyrrolo [2, 3-b] pyridines or pyrrolo [2, 3-b] pyrazines as hpk1 inhibitor and the use thereof
WO2020023551A1 (en) 2018-07-24 2020-01-30 Genentech, Inc. Naphthyridine compounds and uses thereof
WO2020023560A1 (en) 2018-07-24 2020-01-30 F. Hoffmann-La Roche Ag Isoquinoline compounds and uses thereof
US20200048141A1 (en) 2016-10-07 2020-02-13 Nihon Yamamura Glass Co., Ltd. Crystallized glass sealing material
WO2020061377A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
WO2020069402A1 (en) 2018-09-30 2020-04-02 Genentech, Inc. Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
WO2020072627A1 (en) 2018-10-02 2020-04-09 Genentech, Inc. Isoquinoline compounds for the treatment of cancer
WO2020072695A1 (en) 2018-10-03 2020-04-09 Genentech, Inc. 8-aminoisoquinoline compounds and uses thereof
WO2020070332A1 (en) 2018-10-05 2020-04-09 Ichnos Sciences S.A. Oxindole compounds for use as map4k1 inhibitors
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
WO2020100027A1 (en) 2018-11-15 2020-05-22 Pfizer Inc. 2,3-dihydro-1h-pyrrolo[3,4-c]pyridin-1-one derivatives as hpk1 inhibitors for the treatment of cancer
WO2020103896A1 (en) 2018-11-22 2020-05-28 Beigene, Ltd. Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof
WO2020120257A1 (en) 2018-12-11 2020-06-18 Bayer Aktiengesellschaft Substituted pyrrolopyridine-derivatives
WO2020193511A1 (en) 2019-03-26 2020-10-01 Janssen Pharmaceutica Nv Hpk1 inhibitors
WO2020193512A1 (en) 2019-03-26 2020-10-01 Janssen Pharmaceutica Nv Bicyclic hpk1 inhibitors
WO2020227325A1 (en) 2019-05-06 2020-11-12 Icahn School Of Medicine At Mount Sinai Heterobifunctional compounds as degraders of hpk1
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
WO2021000935A1 (en) 2019-07-04 2021-01-07 Qilu Regor Therapeutics Inc. Hpk1 inhibitors and uses thereof
WO2021000925A1 (en) 2019-07-04 2021-01-07 Beigene, Ltd. PYRROLO [2, 3-b] PYRAZINES AS HPK1 INHIBITOR AND THE USE THEREOF
WO2021013083A1 (en) 2019-07-17 2021-01-28 Beigene, Ltd. Tricyclic compounds as hpk1 inhibitor and the use thereof
WO2021026180A1 (en) 2019-08-06 2021-02-11 Incyte Corporation Solid forms of an hpk1 inhibitor
WO2021032148A1 (en) 2019-08-21 2021-02-25 Beigene, Ltd. Aminopyrazine compounds as hpk1 inhibitor and the use thereof
WO2021050964A1 (en) 2019-09-13 2021-03-18 Nimbus Saturn, Inc. Hpk1 antagonists and uses thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076980A1 (en) 1999-06-10 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Novel nitrogen-contaiing heterocyclic derivatives or salts thereof
PL377215A1 (pl) * 2002-10-17 2006-01-23 Amgen Inc. Pochodne benzimidazolu oraz ich zastosowanie w charakterze ligandów receptora waniloidowego
CN111163780A (zh) 2017-07-18 2020-05-15 诺维逊生物股份有限公司 作为腺苷拮抗剂的杂环化合物
AU2021284676A1 (en) 2020-06-01 2023-02-02 Wigen Biomedicine Technology (shanghai) Co., Ltd. New pyrazine compound

Patent Citations (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016205942A1 (en) 2015-06-25 2016-12-29 University Health Network Hpk1 inhibitors and methods of using same
WO2018049191A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridone derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049200A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049152A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyrimidine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049214A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
US20200048141A1 (en) 2016-10-07 2020-02-13 Nihon Yamamura Glass Co., Ltd. Crystallized glass sealing material
WO2018081531A2 (en) 2016-10-28 2018-05-03 Ariad Pharmaceuticals, Inc. Methods for human t-cell activation
WO2018102366A1 (en) 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
US20180228786A1 (en) * 2017-02-15 2018-08-16 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2018152220A1 (en) 2017-02-15 2018-08-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
WO2018183964A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Isoquinolines as inhibitors of hpk1
WO2018228920A1 (en) 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyridine-derivatives
WO2018228925A1 (en) 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyridine-derivatives
WO2018228923A1 (en) 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyridine-derivatives as map4k1 modulators for the treatment of cancer diseases
WO2019016071A1 (en) 2017-07-18 2019-01-24 Bayer Pharma Aktiengesellschaft SUBSTITUTED PYRROLOPYRIDINE DERIVATIVES
WO2019051196A1 (en) 2017-09-08 2019-03-14 Commscope Technologies Llc ENCLOSURE OF HEAT DISSIPATION
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
US20190256500A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
US20190256520A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
WO2019164846A1 (en) 2018-02-20 2019-08-29 Incyte Corporation N-(phenyl)-2-(phenyl)pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer
US20190315717A1 (en) 2018-04-13 2019-10-17 Incyte Corporation Benzimidazole and indole compounds and uses thereof
WO2019206049A1 (en) 2018-04-25 2019-10-31 Zhuhai Yufan Biotechnologies Co., Ltd Hpk1 inhibitors, preparation method and application thereof
WO2019238067A1 (en) 2018-06-13 2019-12-19 Beigene, Ltd. Pyrrolo [2, 3-b] pyridines or pyrrolo [2, 3-b] pyrazines as hpk1 inhibitor and the use thereof
WO2020023560A1 (en) 2018-07-24 2020-01-30 F. Hoffmann-La Roche Ag Isoquinoline compounds and uses thereof
WO2020023551A1 (en) 2018-07-24 2020-01-30 Genentech, Inc. Naphthyridine compounds and uses thereof
WO2020061377A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
WO2020069402A1 (en) 2018-09-30 2020-04-02 Genentech, Inc. Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
WO2020072627A1 (en) 2018-10-02 2020-04-09 Genentech, Inc. Isoquinoline compounds for the treatment of cancer
WO2020072695A1 (en) 2018-10-03 2020-04-09 Genentech, Inc. 8-aminoisoquinoline compounds and uses thereof
WO2020070332A1 (en) 2018-10-05 2020-04-09 Ichnos Sciences S.A. Oxindole compounds for use as map4k1 inhibitors
WO2020070331A1 (en) 2018-10-05 2020-04-09 Ichnos Sciences S.A. Indolinone compounds for use as map4k1 inhibitors
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
WO2020100027A1 (en) 2018-11-15 2020-05-22 Pfizer Inc. 2,3-dihydro-1h-pyrrolo[3,4-c]pyridin-1-one derivatives as hpk1 inhibitors for the treatment of cancer
WO2020103896A1 (en) 2018-11-22 2020-05-28 Beigene, Ltd. Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof
WO2020120257A1 (en) 2018-12-11 2020-06-18 Bayer Aktiengesellschaft Substituted pyrrolopyridine-derivatives
WO2020193511A1 (en) 2019-03-26 2020-10-01 Janssen Pharmaceutica Nv Hpk1 inhibitors
WO2020193512A1 (en) 2019-03-26 2020-10-01 Janssen Pharmaceutica Nv Bicyclic hpk1 inhibitors
WO2020227325A1 (en) 2019-05-06 2020-11-12 Icahn School Of Medicine At Mount Sinai Heterobifunctional compounds as degraders of hpk1
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
WO2021000935A1 (en) 2019-07-04 2021-01-07 Qilu Regor Therapeutics Inc. Hpk1 inhibitors and uses thereof
WO2021000925A1 (en) 2019-07-04 2021-01-07 Beigene, Ltd. PYRROLO [2, 3-b] PYRAZINES AS HPK1 INHIBITOR AND THE USE THEREOF
WO2021013083A1 (en) 2019-07-17 2021-01-28 Beigene, Ltd. Tricyclic compounds as hpk1 inhibitor and the use thereof
WO2021026180A1 (en) 2019-08-06 2021-02-11 Incyte Corporation Solid forms of an hpk1 inhibitor
WO2021032148A1 (en) 2019-08-21 2021-02-25 Beigene, Ltd. Aminopyrazine compounds as hpk1 inhibitor and the use thereof
WO2021050964A1 (en) 2019-09-13 2021-03-18 Nimbus Saturn, Inc. Hpk1 antagonists and uses thereof

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BLOOD, vol. 101, 2003, pages 3687 - 89
BUNN, C.W.: "Chemical Crystallography", 1948, CLARENDON PRESS
CANCER IMMUNOL. IMMUNOTHER., vol. 59, 2010, pages 419 - 29
CELL REPORTS, vol. 25, 2018, pages 80 - 94
DEGNAN ANDREW P. ET AL: "Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 3, 19 February 2021 (2021-02-19), US, pages 443 - 450, XP055964950, ISSN: 1948-5875, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.0c00660> DOI: 10.1021/acsmedchemlett.0c00660 *
EMBO J., vol. 15, 1996, pages 7013 - 25
IMMUNITY, vol. 12, 2000, pages 399 - 408
J. BIOL. CHEM., vol. 276, 2001, pages 18908 - 14
J. BIOL. CHEM., vol. 282, 2007, pages 34693 - 99
J. CELL BIOL., vol. 195, 2011, pages 839 - 853
J. EXP. MED., vol. 204, 2007, pages 681 - 91
JENKINS, RSNYDER, R.L.: "Introduction to X-Ray Powder Diffractometry", 1996, JOHN WILEY & SONS
KITAIGORODSKY, A.I.: "Molecular Crystals and Molecules", 1973, ACADEMIC PRESS
KLUG, H.P.ALEXANDER, L.E.: "X-ray Diffraction Procedures", 1974, JOHN WILEY & SONS
NAT IMMUNOL., vol. 8, 2007, pages 84 - 91
NAT. IMMUNOL., vol. 8, 2007, pages 84 - 91
NATURE REVIEWS DRUG DISCOVERY, vol. 7, 2008, pages 255
NATURE REVIEWS IMMUNOLOGY, vol. 20, 2020, pages 651 - 668
NATURE, vol. 541, 2017, pages 321 - 330
ONCOGENE, vol. 20, 2001, pages 1703 - 14
P.H. STAHLP.G. VERMUTH: "Handbook of Pharmaceutical Salts: Properties, selection and use", 2002, CHURCHILL LIVINGSTONE
P.J. KOCIENSKI: "Protecting Groups", 2005, GEORG THIEME VERLAG
T.W. GREENEP.G.M. WUTS: "Protective Groups in Organic Synthesis", 2006, WILEY-INTERSCIENCE
VARA BRANDON A. ET AL: "Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 4, 19 March 2021 (2021-03-19), US, pages 653 - 661, XP055938211, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.1c00096 *
YU ELSIE C. ET AL: "Identification of Potent Reverse Indazole Inhibitors for HPK1", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 3, 1 March 2021 (2021-03-01), US, pages 459 - 466, XP055978410, ISSN: 1948-5875, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.0c00672> DOI: 10.1021/acsmedchemlett.0c00672 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024008128A1 (zh) 2022-07-06 2024-01-11 上海科恩泰生物医药科技有限公司 一种具有fgfr抑制作用的亚砜亚胺类化合物、包含其的药物组合物及其用途
EP4574830A4 (en) * 2022-09-23 2025-11-26 Guangzhou Vinnocent Pharmaceutical Ltd PYRIDINE INHIBITOR, RINGED STEROID SYNTHETASE, ITS PREPARATION PROCESS AND ITS USE
WO2024240242A1 (zh) * 2023-05-25 2024-11-28 正大天晴药业集团股份有限公司 含有酰胺取代的芳香环的化合物、其药物组合物及用途

Also Published As

Publication number Publication date
EP4373817A1 (en) 2024-05-29
EP4373817B1 (en) 2025-05-21
CN117693503A (zh) 2024-03-12
US20240374606A1 (en) 2024-11-14
UY39865A (es) 2023-01-31
JP2024527623A (ja) 2024-07-25
JP7851393B2 (ja) 2026-04-24
TW202321239A (zh) 2023-06-01
AR126500A1 (es) 2023-10-18
ES3036245T3 (en) 2025-09-18

Similar Documents

Publication Publication Date Title
KR102632018B1 (ko) Fgfr 저해제로서의 이환식 복소환
KR102483020B1 (ko) Tam 저해제로서의 피롤로트리아진 화합물
DK3083625T3 (en) Pyrimidopyrimidinones useful as wee-1 kinase inhibitors
KR101862493B1 (ko) Fgfr4 억제제로서의 고리-융합된 비시클릭 피리딜 유도체
ES2551592T3 (es) Pirazolo[1,5-a]piridinas como inhibidores de TRK
TWI866258B (zh) 用於治療發炎性病症之新穎化合物及其醫藥組合物
MX2013005603A (es) Derivados de pirrolopiridina sustituidos con ciclobutilo como inhibidores de janus cinasas (jak).
CA3040805A1 (en) Piperidine derivatives as inhibitors of ubiquitin specific protease 7
KR20230007369A (ko) 암의 치료를 위한 ent 저해제로서의 거대환식 다이아민 유도체 및 이와 아데노신 수용체 길항제와의 조합물
EA030253B1 (ru) Азахиназолиновые ингибиторы атипичной протеинкиназы c
SG187747A1 (en) Inhibitors of bruton&#39;s tyrosine kinase
WO2023001794A1 (en) Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer
EP2721016A1 (en) Trpv4 antagonists
CA3043561C (en) PYRIDO[3,4-D]PYRIMIDINE DERIVATIVE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
AU2014368725A1 (en) Isochromene derivatives as phosphoinositide 3-kinases inhibitors
US12435063B2 (en) Nitrogen containing heterocycles as CDK12 inhibitors
WO2021003314A1 (en) Heterocyclic compounds as kinase inhibitors
EP3746432B1 (en) 4-hydroxypiperidine derivatives and their use as inhibitors of ubiquitin specific protease 19 (usp19)
TW202317106A (zh) 作為egfr抑制劑之取代胺基吡啶化合物
WO2020116662A1 (ja) シクロアルカン−１，３−ジアミン誘導体
CN116969923A (zh) 杂芳基氨基化合物及其制备方法和应用
CN119546604A (zh) 作为hpk1抑制剂的吡啶并[3,2-d]嘧啶
US12258327B2 (en) 5-membered heteroaryl-containing aminopyridine compounds as EGFR inhibitors
HK1171742A (en) Tricyclic pyrazol amine derivatives

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: 22754791

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280049292.0

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 2024502652

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2022754791

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022754791

Country of ref document: EP

Effective date: 20240220

WWG Wipo information: grant in national office

Ref document number: 2022754791

Country of ref document: EP