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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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

Definitions

• the present disclosure relates to novel compounds which exhibit Rearranged during Transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, it relates to substituted pyrazolo[l,5-a]pyridine compounds useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.
• RET Rearranged during Transfection
• RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation and maintenance of several tissues and cell types (Mulligan, L. M., Nature Reviews Cancer, 2014, 14, 173-186).
• the extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a juxtamembrane cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains.
• RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev., 2005, 16, 441-67).
• GDNF glial cell line-derived neurotrophic factor
• NTRN neurturin
• ARTN artemin
• PSPN persephin
• RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF family receptor- ex (GFRa) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage.
• GFLs and GFRa family members form binary complexes that in turn bind to RET and recruit it into cholesterol -rich membrane subdomains
• RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways.
• Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PI3K-Akt/mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET- mediated functions.
• substituted pyrazolo[l,5-a]pyridine compounds are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases such as cancers.
• composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
• Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
• Also provided herein is a method of treating a RET-associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
• Also provided herein is a method of treating cancer and/or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
• IBS irritable bowel syndrome
• the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
• Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.
• Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer and/or inhibiting metastasis associated with a particular cancer.
• IBS irritable bowel syndrome
• a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.
• a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of RET kinase activity is also provided.
• Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a RET-associated disease or disorder.
• Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer and/or inhibiting metastasis associated with a particular cancer.
• a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein in the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.
• IBS irritable bowel syndrome
• a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.
• Also provided herein is a use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RET kinase activity.
• Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a RET-associated disease or disorder.
• a pharmaceutical combination for treating cancer e.g., a RET-associated cancer, such as a RET-associated cancer having one or more RET inhibitor resistance mutations
• cancer e.g., a RET-associated cancer, such as a RET-associated cancer having one or more RET inhibitor resistance mutations
• a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of Formula I or the pharmaceutically acceptable salt or solvate thereof and the additional therapeutic are formulated as separate compositions or dosages for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the cancer.
• a pharmaceutical combination for treating cancer e.g., a RET-associated cancer, such as a RET-associated cancer having one or more RET inhibitor resistance mutations
• a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of cancer. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.
• Also provided herein is a method for reversing or preventing acquired resistance to an anticancer drug, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, to a patient at risk for developing or having acquired resistance to an anticancer drug.
• the patient is administered a dose of the anticancer drug (e.g., at substantially the same time as a dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the patient).
• Also provided herein is a method of delaying and/or preventing development of cancer resistant to an anticancer drug in an individual, comprising administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of an effective amount of the anticancer drug.
• Also provided herein is a method of treating an individual with cancer who has an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of Formula I before, during, or after administration of (b) an effective amount of the anticancer drug.
• a first RET inhibitor e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, and/or one or more RET inhibitor resistance mutations listed in Tables 3 and 4
• Also provided are methods of treating an individual with a RET- associated cancer that include administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (e.g., a first RET kinase inhibitor).
• a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof before, during, or after administration of another anticancer drug (e.g., a first RET kinase inhibitor).
• a method for treating irritable bowel syndrome (IBS) in a patient in need thereof comprising (a) determining if the IBS is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and (b) if the IBS is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
• IBS irritable bowel syndrome
• a pharmaceutical combination for treating irritable bowel syndrome (IBS) in a patient in need thereof which comprises administering (a) a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of IBS, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the IBS.
• a pharmaceutical composition comprising such a combination.
• the use of such a combination for the preparation of a medicament for the treatment of the IBS is also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of the IBS a patient in need thereof.
• Also provided herein is a process for preparing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. [0037] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof obtained by a process of preparing the compound as defined herein.
• X 1 , X 2 , X 3 and X 4 are independently CH, CCH 3 , CF or N, wherein zero, one or two of X 1 , X 2 , X 3 and X 4 is N;
• A is H, CN, CI, methyl, ethyl or cyclopropyl
• hetA ⁇ Cl-CS alkyl- where hetAr 1 is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents;
• Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, (ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen;
• each R a is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-;
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S wherein hetAr 3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros),
• R c is hydrogen or C1-C6 alkyl
• n 0, 1, 2, 3, 4, 5 or 6; [0066] misOorl;
• R and R h are independently H or CI -C6 alkyl
• R h O w here R and R h are independently H or C1-C6 alkyl and Q is H, C1-C6 a -,
• Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S0 2 -, R ⁇ - and (R ⁇ Cl-Ce alkyl- where each R e and R f is independently H or C1-C6 alkyl;
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;
• hetCyc 5 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;
• R 3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH 2 -, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH 2 0-, hetCyc 7 0-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;
• R 4 is H or Cl-C6 alkyl
• R 5 is Ar 2 , hetAr 3 , Ar 2 CH 2 -, hetCyc 6 -CH 2 -, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH 2 -, or C1-C6 alkyl optionally substituted with 1-3 fluoros;
• Ar 2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R3 ⁇ 4 h N- where R g and R h are independently H or C1-C6 alkyl, or Ar 2 is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl
• hetAr 4 is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
• hetCyc 6 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S;
• hetCyc 7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.
• a substituent group is typically named before the group to which it attaches.
• methoxyethyl comprises an ethyl backbone with a methoxy substituent.
• halogen means -F (sometimes referred to herein as “fluoro” or “fluoros”), -CI, -Br and -I.
• C1-C3 alkyl saturated linear or branched-chain monovalent hydrocarbon radicals of one to three, three to six, one to six, or two to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-butyl, 2- methyl-2-propyl, pentyl, neopentyl, and hexyl.
• C1-C6 alkyl optionally substituted with 1-3 fluoros refers to a C1-C6 alkyl radical as defined herein, wherein one to three hydrogen atoms is replaced with one to three fluoro atoms, respectively. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-and trifluoroethyl.
• C1-C6 alkoxy refers to saturated linear or branched-chain monovalent alkoxy radicals of one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
• (C1-C6 alkoxy)Cl-C6 alkyl refers to saturated linear or branched-chain monovalent radicals of one to six carbon atoms, wherein one of the carbon atoms is substituted with a C1-C6 alkoxy group as defined herein. Examples include methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2-).
• (C1-C6 alkoxy)Cl-C6 alkoxy refers to a C1-C6 alkoxy radical as defined herein, wherein one of the carbon atoms is substituted with a C1 -C6 alkoxy group as defined herein. Examples include methoxymethoxy (CH3OCH2O-) and ethoxymethoxy (CH3CH2O-CH2O-).
• hydroxyC l-C6 alkyl and "hydroxyC2-C6 alkyl”, as used herein refers to saturated linear or branched-chain monovalent alkyl radicals of one to six or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy group.
• dihydroxyC3-C6 alkyl refers to a C3-C6 alkyl radical as defined herein, wherein two hydrogen atoms are replaced with a hydroxy group, provided the hydroxy groups are not on the same carbon.
• (R ⁇ Cl-Ce alkyl) refers to a C1 -C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a R3 ⁇ 4 2 N- group, wherein R 1 and R 2 are as defined herein.
• hetA ⁇ C l-Ce alkyl refers to a C1 -C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetAr 1 group, wherein hetAr 1 is as defined herein.
• C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• C3-C6 cycloalkylidene ring refers to a divalent C3-C6 cycloalkane ring derived from a saturated 3-6 membered hydrocarbon ring by removal of two hydrogen atoms from the same carbon atom, such as for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
• (C3-C6 cycloalkyl)Cl-C3 alkyl refers to a C1-C3 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a C3-C6 cycloalkyl ring.
• An example is cyclobutylmethyl.
• (hetCyc a )Cl-C3 alkyl refers to a C1-C3 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetCyc 3 group, wherein hetCyc 3 is as defined herein.
• a ⁇ Cl-Ce alkyl refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with an Ar 1 group, wherein Ar 1 is as defined herein.
• hetAr 2 Cl-C6 alkyl refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetAr 2 group, wherein hetAr 2 is as defined herein.
• a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and substituted with an oxo may be, for example, a pyrrolidinyl ring substituted with oxo (e.g., a pyrrolidinonyl ring), which may be represented by the structure:
• spirocyclic ring refers to a group having two rings joined by a spirocyclic linkage through a common single carbon atom, wherein each ring is a 4-7- membered ring (including the common carbon atom).
• heterospirocyclic refers to a group having two rings joined by a spirocyclic linkage through a carbon atom, wherein each ring has 4 to 6 ring atoms (with one ring carbon atom being common to both rings), and wherein one of the ring atoms is a nitrogen atom.
• tautomer refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer.
• X 1 , X 2 , X 3 and X 4 are independently CH or CF. In certain embodiments, each of X 1 , X 2 , X 3 and X 4 is CH.
• X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein one of X 1 , X 2 , X 3 and X 4 is N and the remainder are independently CH or CF.
• X 1 is N
• X 2 , X 3 and X 4 are independently CH or CF.
• X 1 is N
• X 2 , X 3 and X 4 are CH.
• X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein two of X 1 , X 2 , X 3 and X 4 are N.
• X 1 and X 3 are N and X 2 and X 4 are independently CH or CF.
• X 1 and X 3 are N and X 2 and X 4 are CH.
• A is H.
• A is CI.
• A is CN
• A is methyl
• A is ethyl
• A is cyclopropyl
• B is hydrogen
• B is C1-C6 alkyl optionally substituted with 1-3 fluoros.
• Non-limiting examples include methyl, ethyl, propyl, isopropyl, isobutyl, sec- butyl, 2-ethylbutyl, neopentyl, difluorom ethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.
• B is methyl or ethyl.
• B is hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments, the alkyl portion is unsubstituted.
• Non-limiting examples include the structures:
• B is dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• a non-limiting example includes 2,3-dihydroxypropyl.
• B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros.
• B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluoros.
• Non-limiting examples include the structures:
• R ⁇ N ⁇ l-Ce alkyl- include the structures:
• B is hetA ⁇ Cl-CS alkyl-, where hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.
• hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O and is optionally substituted with Cl- C6 alkyl.
• Non-limiting examples of hetA ⁇ Cl-CS alkyl- include the structures:
• B is (C3-C6 cycloalkyl)Cl-C3 alkyl- wherein said cycloalkyl is optionally substituted with OH.
• a non-limiting example is cyclobutylmethyl .
• B is (hetCyc a )Cl-C3 alkyl-, where hetCyc 3 is as defined for Formula I.
• Non-limiting examples include the structures:
• B is hetCyc 3 , where hetCyc 2 is as defined for Formula I.
• hetCyc 3 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl-.
• Non-limiting examples include the structures:
• R 1 and R 2 are independently selected from H and C1-C6 alkyl.
• R 1 and R 2 are independently selected from H and C1-C6 alkyl.
• Non-limiting examples include the structure:
• a non-limiting example includes the structure:
• B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl-.
• Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, (ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen, wherein the E group may be bonded to any ring carbon atom of Ring D, each R a may be bonded to any ring carbon atom of Ring D, and R b may be bonded to any ring carbon of Ring D, provided that the ring carbon atom bonded to the E group is optionally substituted with only one of R a or R b .
• Ring D is a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• the phrase "having one ring heteroatom which is nitrogen" when Ring D is a saturated monocyclic 4-7 membered heterocyclic ring means that said ring nitrogen atom is the nitrogen atom shown in Ring D of Formula I.
• Nonlimiting examples include the structures:
• n is 0, 1, 2, 3 or 4.
• n is 0, 1 or 2.
• n is 0.
• n is 1.
• n is 2.
• m is 0 or 1.
• m is 0.
• m is 1.
• n is 0 and m is 0 or 1.
• n is 0 or 1 and m is 0.
• Ring D is a saturated monocyclic 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen selected from the structures
• n is 0, 1, 2, 3 or 4. In one embodiment, n is 0, 1 or 2. In one embodiment, n is zero. In one embodiment, n is one. In one embodiment, n is two. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1.
• Ring D is a saturated monocyclic 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen having the structure:
• each R a is independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-.
• n is 0, 1, 2, 3 or 4.
• n is 0.
• n is 1.
• n is 2.
• m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Ring D is a saturated monocyclic 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Ring D is a saturated monocyclic 5 membered heterocyclic ring having one ring heteroatom which is nitrogen
• Ring D is a saturated monocyclic 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen selected from the structures:
• each R a is independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros) or (C1-C6 alkoxy)Cl-C6 alkyl-.
• n is 0, 1, 2, 3 or 4.
• n is 0, 1 or 2.
• n is 0.
• n is one.
• m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 or 1 and m is 0 or 1.
• Ring D is an optionally substituted saturated 4-7 membered heterocyclic ring include the structures:
• Ring D is a saturated monocyclic 6 membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structure: ere n and m are zero, that is, Ring D may be represented by the structure:
• Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen;
• R g and R h are independently H or CI -C6 alkyl and Q is H, CI -C6
• R g is H or C1-C6 alkyl and Q is
• each R a is independently selected from a C1-C6 substituent (optionally substituted with 1-3 fluoros).
• R b is (a) OH, (c) hetCyc b CH 2 - wherein hetCyc b is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) R c R d N- or (f) R c R d NCH 2 -; R c is hydrogen or C1-C6 alkyl; and R d is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Ring D is a saturated monocyclic 6-membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structure:
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (Cl- C6 alkoxy)Cl-C6 alkyl-. In one embodiment, R a is C1-C6 alkyl.
• Ring D is a saturated monocyclic 6-membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structures:
• R b is (a) OH, (c) hetCyc b CH 2 - , (e) R ⁇ N- or (f) R c R d NCH 2 -; R c is hydrogen or C1-C6 alkyl; R d is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCyc b is as defined for Formula I.
• R b is (c) hetCyc b CH 2 - , (e) R c R d N- or (f) R c R d NCH 2 -; R c is hydrogen or C1-C6 alkyl; R d is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCyc b is as defined for Formula I.
• Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen;
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom. In one embodiment, Ring D is a saturated 5 membered heterocyclic ring having one ring heteroatom.
• n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1.
• Non-limiting examples include the structures:
• n 0, 1 or 2 and m is 0 or 1.
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0 or 1.
• a non-limiting example includes the structure:
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1.
• Non-limiting examples include the structures:
• Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, R a , R b , n, and m are as defined for Formula I, and E is alkyl wherein said alkyl portion is optionally substituted with 1-3 fluoros and where Ar 1 is as defined for Formula I.
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• R b is OH.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0 or 1.
• Non-limiting examples include the structures:
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros).
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0 or 1 and m is 0 or 1.
• n is 0 and m is 0.
• n is 0 and m is 1.
• Non-limiting examples include the structures:
• n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, R b is R c R d N-. Non-limiting examples include the structures:
• Ar 1 is unsubstituted or substituted with one or more substituents independently selected from halogen, CN and C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Ring D is a saturated 4 or 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0.
• Non-limiting examples include the structures:
• hetAr 2 is a 5-6-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), C1-C6 alkyl (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy.
• Ring D is a saturated 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• Ring D is a saturated 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, R a is C1-C6 alkyl. In one embodiment, R b is R c R d N-. Non-limiting examples include the structures:
• Ar 1 is optionally substituted with one or more halogens.
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0.
• a non-limiting example includes the structure:
• hetAr 2 is a pyridyl ring optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen.
• n is 0, 1 or 2 and m is 0 or 1.
• R a is C1-C6 alkyl.
• n is 0 and m is 0.
• Non-limiting examples include the structures:
• R g is hydrogen.
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 or 1 and m is 0.
• m is 1 and n is 0.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R b is hydroxy, hetCyc b CH 2 -, R c R d N-, R c R d NCH 2 -, C1-C6 alkoxy, (R'R"N)C1-C6 alkoxy(CH 2 )n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or hetCyc b (Cl-C3 alkyl)OCH 2 -, where hetCyc b , R c and R d are as defined for Formula I.
• R b is hetCyc b CH 2 - where hetCyc b is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and RR'N- where R and R" are independently hydrogen or C1-C6 alkyl.
• R b is R c R d N- or R c R d NCH 2 - where R c is hydrogen or C1-C6 alkyl and R d is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R c is hydrogen or C1-C6 alkyl
• R d is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Non-limiting examples include the structures:
• Ar 1 is unsubstituted or substituted with one or more substituents independently selected from halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S0 2 -, and (R ⁇ Cl-Ce alkyl- where each R e and R f is independently H or C1-C6 alkyl.
• Ring D is a saturated 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, n is i and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl. In one embodiment, R b is C1-C6 alkoxy, hetCyc b CH 2 - or R c R d NCH 2 -, where hetCyc b , R c and R d are as defined for Formula I.
• R b is hetCyc b CH 2 - where hetCyc b is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros) and (C1-C6 alkoxy)Cl-C6 alkyl-.
• R b is R c R d NCH 2 - where R c is H or C1-C6 alkyl and R d is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, R b is hydroxyl.
• Non-limiting examples include the structures:
• hetAr 2 is a 5-6-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros) and C1-C6 alkoxy (optionally substituted with 1-3 fluoros).
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 or 1 and m is 0.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl.
• R b is hydroxy, hetCyc b CH 2 -, R c R d NCH 2 -, C1-C6 alkoxy, or hetCyc b (Cl-C3 alkyl)OCH 2 -, where hetCyc b , R c and R d are as defined for Formula I.
• R b is hetCyc b CH 2 - where hetCyc b is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with one or more substituents independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R b is R c R d NCH 2 - where R c is H or C1-C6 alkyl and R d is C1-C6 alkyl (optionally substituted with -3 fluoros).
• Non-limiting examples include the structures:
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 or 1 and m is 0.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl.
• R b is hetCyc b CH 2 - , R c R d NCH 2 -, or hetCyc b (Cl-C3 alkyl)OCH 2 -, where hetCyc b , R c and R d are as defined for Formula I.
• R b is R c R d NCH 2 - where R c is H or C1-C6 alkyl and R d is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R c is H or C1-C6 alkyl and R d is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Non-limiting examples includes the structures:
• Ar 1 is unsubstituted or substituted with one or more halogens.
• m is 0.
• n is 0 or 1.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:
• hetAr 1 is a 5-6 membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros) and C1-C6 alkoxy (optionally substituted with 1-3 fluoros).
• m is 0.
• n is 0 or 1.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R 4 and R 5 are independently hydrogen or C1-C6 alkyl.
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 or 1 and m is 0.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• n is 0 and m is 1.
• R b is hetCyc b CH 2 - where hetCyc b is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R b is R c R d NCH 2 - where R c is H or C1-C6 alkyl and R d is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Non-limiting examples include the structures:
• Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 or 1 and m is 0.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Ar 1 is unsubstituted or substituted with one or more halogens.
• n is 0 or 1 and m is 0.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• Non-limiting examples include the structures:
• hetAr 2 is a 5-6-membered heteroaryl ring. In one embodiment, hetAr 2 is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0.
• a non-limiting example includes the structure:
• hetAr 2 is a 5-6-membered heteroaryl ring. In one embodiment, hetAr 2 is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0.
• a non-limiting example includes the structure:
• hetAr 2 is unsubstituted or substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• n is 0.
• m is 0 or 1.
• R b is OH.
• hetAr 2 is a 5-6-membered heteroaryl ring. In one embodiment, hetAr 2 is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0.
• Non-limiting examples include the structures:
• hetAr 2 is a 5-6-membered heteroaryl ring. In one embodiment, hetAr 2 is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0.
• Non-limiting examples include the structures:
• Ar 1 is unsubstituted or substituted with one or more halogens.
• m is 0.
• n is 0 or 1.
• R 1 is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• hetAr 2 is a 5-6-membered heteroaryl ring. In one embodiment, hetAr 2 is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. A non-limiting example is the structure:
• Ar 2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R g R h N- where R g and R h are independently H or C1-C6 alkyl.
• Ar 2 is phenyl optionally substituted with one or more independently selected C1-C6 alkyl (optionally substituted with 1-3 fluoros) substituents.
• m is 0 or 1.
• n is 0.
• Non-limiting examples include the structures:
• hetCyc 5 is a 5-6 membered heterocyclic ring having a ring nitrogen atom.
• m is 0 or 1.
• n is 0.
• R b is R c R d NCH 2 - where R c and R d are as defined for Formula I.
• R c and R d are hydrogen or C1-C6 alkyl.
• Non-liming examples include the structures:
• m is 0.
• n is 0 or 1.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• R g is H or C1-C6 alkyl and Q is H, Cl-
• C6 alkyl or (C1-C6 alkyl)OC( 0)-.
• m is 0.
• n is 0 or 1.
• R a is C1-C6 alkyl (optionally substituted with 1-3 fluoros).
• n is 0 or 1.
• m is 0 or 1.
• R b is hydroxy, C1-C6 alkoxy- or hetCyc b (Cl-C3 alkyl)OCH 2 -, where hetCyc b is as defined for Formula I.
• hetCyc b is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O.
• Non-limiting examples include the structures:
• Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.
• the phrase "having one ring heteroatom which is nitrogen" when Ring D is a saturated 7-8 membered bridged heterocyclic ring means that the one ring nitrogen atom is the nitrogen atom shown in Ring D of Formula I.
• Non-limiting exam les include rings such as
• n is 0 or 1. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0 or 1.
• Ring D is a saturated 7 membered bridged heterocyclic ring havin one ring heteroatom which is nitrogen.
• Non-limiting examples include structures:
• R a , n, R b and m are as defined for Formula I.
• n is 0 or 1 and m is 0 or 1.
• n is 0 and m is 0 or 1.
• R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or C1-C6 alkyl.
• R b is R°R d N- where R c and R d are H.
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen having the structure
• R b and m are as defined for Formula I.
• m is 0.
• m is 1.
• R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or CI -C6 alkyl.
• R b is R c R d N- where R c and R d are H.
• Non-limiting examples include the structures:
• Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0 or 1.
• a non-limiting example includes the structure:
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0.
• a non-limiting example includes the structure:
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and is 0.
• a non-limiting example includes the structure:
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen. In one embodiment, hetAr 2 is unsubstituted. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, n is 0 and m is 0. Non-limiting examples include the structures:
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from C1-C6 alkoxy, halogen and C1-C6 alkoxy (optionally substituted with 1-3 fluoros).
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0.
• Non-limiting examples include the structures:
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0.
• Non-limiting examples includes the structures:
• Ar 1 is substituted with one or more substituents independently selected from halogen, CN and C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Ar 1 is unsubstituted. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkoxy.
• Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.
• n is 0, 1 or 2 and m is 0 or 1.
• n is 0 and m is 0.
• a non-limiting example includes the structure:
• Ring D is a saturated 7-11 membered heterospirocyclic ring system
• said one ring nitrogen is the ring nitrogen atom shown in Ring D of Formula I.
• Ring D is a saturated 9 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen.
• Ring D is a 7-azaspiro[3.5]nonanyl ring, e.g., a 7- azaspiro[3.5]nonan-2-yl ring.
• Nonlimiting examples include the structures:
• n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0.
• Ring D is a 7- azaspiro[3.5]nonanyl ring, e.g., a 7-azaspiro[3.5]nonan-2-yl ring.
• n is 0 and m is 0 or 1.
• Non-limiting examples include the structures:
• Formula I includes compounds of Formula I- A, wherein: [00262] X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein zero, one or two of X 1 ,
• X 2 , X 3 and X 4 is N;
• A is H, CN, CI, methyl, ethyl or cyclopropyl
• hetA ⁇ Cl-CS alkyl- where hetAr 1 is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl groups;
• each R a is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-;
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAr 3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros);
• R c is hydrogen or C1-C6 alkyl
• n 0, 1, 2, 3, 4, 5 or 6;
• m is O or l
• R and R h are independently H or CI -C6 alkyl
• (qq) and R h are independently H or C1-C6 alkyl and Q is H, C1-C6 a -,
• Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S0 2 -, ⁇ R ⁇ - and (R ⁇ Cl-Ce alkyl- where each R e and R f is independently H or C1-C6 alkyl;
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;
• hetCyc 5 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;
• R 3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH 2 -, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH 2 0-, hetCyc 7 0-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;
• R 4 is H or Cl-C6 alkyl
• R 5 is Ar 2 , hetAr 3 , Ar 2 CH 2 -, hetCyc 6 -CH 2 -, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH 2 -, or C1-C6 alkyl optionally substituted with 1-3 fluoros;
• Ar 2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R S R ⁇ N- where R g and
• R h are independently H or C1-C6 alkyl, or Ar 2 is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl
• hetAr 4 is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
• hetCyc 6 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S;
• hetCyc 7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.
• X 1 is N; X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I- A, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.
• Ring D is:
• R a , n, R b and m are as defined for Formula I-A.
• n is 0, 1, 2, 3 or 4.
• n is 0.
• n is 0 or 1 and m is 0 or 1.
• n is 0 and m is 1.
• R b is hydroxy, or R°R d N- where R c is hydrogen or C1-C6 alkyl and R d is hydrogen or C1-C6 alkyl.
• Ring D is:
• R a , n, R b and m are as defined for Formula I-A.
• n is 0, 1, 2, 3 or 4.
• n is 0.
• n is 0 or 1 and m is 0 or 1.
• n is 0 and m is 1.
• R b is hydroxy, or R°R d N- where R c is hydrogen or C1-C6 alkyl and R d is hydrogen or C1-C6 alkyl.
• Ring D is:
• n is 0, 1, 2, 3 or 4.
• n is 0.
• n is 0 or 1 and m is 0 or 1.
• n is 0 and m is 1.
• R b is hydroxy, or R c R d N- where R c is hydrogen or C1-C6 alkyl and R d is hydrogen or C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted cloalkylidene ring; and Ring D is:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is a piperidin-4-yl ring having the structure:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is a piperidin-4-yl ring having the structure:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is a piped din- -yl ring having the structure:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is a piperidin-4-yl ring having the structure:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is a piperidin-4-yl ring having the structure:
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is a piperidin-4-yl ring having the structure:
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr 2 Cl-C6 alkyl-, (g) A ⁇ O-, (h) hetAr 2 0-, (1)
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is
• Formula I includes compounds of Formula I-B, wherein:
• X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein zero, one or two of X 1 ,
• X 2 , X 3 and X 4 is N;
• A is H, CN, CI, methyl, ethyl or cyclopropyl
• hetA ⁇ Cl-CS alkyl- where hetAr 1 is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl groups;
• hetCyc 3 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl;
• Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen;
• each R a is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl;
• n 0, 1, 2, 3, 4, 5 or 6;
• m is O or l
• Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R ⁇ R ⁇ f- where R e and R f are independently H or C1-C6 alkyl;
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (Cl- C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);
• R 4 is H or Cl-C6 alkyl
• R 5 is Ar 2 , hetAr 3 or C1-C6 alkyl optionally substituted with 1-3 fluoros;
• Ar 2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R3 ⁇ 4 h N- where R g and R h are independently H or C1-C6 alkyl; and
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros).
• X 1 is N; X 2 , X 3 and X 4 are CH.
• A is CN.
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-B, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is hydroxyC2-C6 alkyl-.
• Ring D is
• n is 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 1. In one embodiment, R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or C1-C6 alkyl. In one embodiment, R b is R c R d N- where R c and R d are H.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is
• R b and m are as defined for Formula I-B.
• m is 0.
• m is 1.
• R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or C1-C6 alkyl.
• R b is R c R d N- where R c and R d are H.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is
• m is 0. In one embodiment, m is 1. In one embodiment, R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or C1-C6 alkyl. In one embodiment, R b is R c R d N- where R c and R d are H.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B -C6 alkyl optionally substituted with 1-3 fluoros; Ring D is
• m is 1.
• R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or C1-C6 alkyl.
• R b is R c R d N- where R c and R d are H.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B hydroxyCl-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is
• m is 0. In one embodiment, m is 1. In one embodiment, R b is R c R d N- where R c is H or C1-C6 alkyl and R d is H or C1-C6 alkyl. In one embodiment, R b is R°R d N- where R c and R d are H.
• Formula I includes compounds of Formula I-C,
• X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein zero, one or two of X 1 ,
• X 2 , X 3 and X 4 is N;
• A is H, CN, CI, methyl, ethyl or cyclopropyl
• hetA ⁇ Cl-CS alkyl- where hetAr 1 is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl groups;
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAr 3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros);
• R c is hydrogen or C1-C6 alkyl
• R is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or
• Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S0 2 -, R3 ⁇ 43 ⁇ 4- and (R ⁇ Cl-Ce alkyl- where each R e and R f is independently H or C1-C6 alkyl;
• hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;
• hetCyc 5 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;
• R 3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH 2 -, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH 2 0-, hetCyc 7 0-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;
• R 4 is H or Cl-C6 alkyl
• R 5 is Ar 2 , hetAr 3 , Ar 2 CH 2 -, hetCyc 6 -CH 2 -, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH 2 -, or C1-C6 alkyl optionally substituted with 1-3 fluoros;
• Ar 2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R3 ⁇ 4 h N- where R g and R h are independently H or C1-C6 alkyl, or Ar 2 is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
• hetAr 3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros); [00528] hetAr 4 is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
• hetCyc 6 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S;
• hetCyc 7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-C, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.
• R b is hetCyc b CH 2 - where hetCyc b is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl- C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-.
• R b is R c R d N-;
• R c is hydrogen or C1-C6 alkyl; and
• R b is R c R d NCH 2 -;
• R c is hydrogen or C1-C6 alkyl; and
• A is CN
• B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring
• A is CN
• B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring
• A is CN
• B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring
• Formula I includes compounds of Formula I-D, wherein:
• X 1 and X 3 are N, and X 2 and X 4 are CH or CF; and A, B, E, R a , R b , m and n are as defined for Formula I.
• A is CN
• A is CN;
• B is (c) hydroxyC2-C6 alkyl - wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,
• hetA ⁇ Cl-CS alkyl- where hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCy
• m is 1; and n is 0 or 1.
• n 0 or 1.
• A is CN;
• Ring D is
• A is CN;
• wavy line indicates the point of attachment of Ring D to the ring comprising X 1 , X 2 , X 3 and X 4
• the asterisk indicates the point of attachment of Ring D to the E group.
• m is 1, n is 0, and R b is hydroxy.
• m is 0, n is 1, and R b is C1-C6 alkyl optionally substituted with 1-3 fluoros.
• compounds of Formula I include compounds of Formula I-E:
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• B is C1-C6 alkyl optionally substituted with 1-3 fluoros.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros.
• compounds of Formula I include compounds of Formula I-F
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros or (e) hetAr 2 Cl-C6 alkyl-;
• X 1 , X 1 , X 3 , X 4 , A, B, Ar 1 , hetAr 2 , R c and R d are as defined for Formula I.
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• A is CN.
• E is (d) Ar l Cl- C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• B is C1-C6 alkyl optionally substituted with 1- 3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.
• E is (d) ⁇ 1 6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and R b is (a) hydroxy.
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and R b is (e) R c R d N- where R c and R d are as defined for Formula I.
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and R b is (e) R c R d N- where R c and R d are as defined for Formula I.
• E is (d) A ⁇ Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros.
• E is (e) hetAr 2 Cl-C6 alkyl-.
• compounds of Formula I include compounds of Formula I-G
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is hetA ⁇ Cl-CS alkyl-, where hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and
• B is (hetCyc a )Cl-C3 alkyl-, where hetCyc 3 is as defined for Formula I.
• compounds of Formula I include compounds of Formula I-H
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1 -C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and
• B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (a) hydroxy.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (c) hetCyc b CH 2 -.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (f) R c R d NCH 2 -.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (g) C 1-C6 alkoxy-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (j) hetCyc b (Cl-C3 alkyl)OCH 2 -
• compounds of Formula I include compounds of Formula I-I
• R b is (c) hetCyc b CH 2 -, (f) R c R d NCH 2 - or (j) hetCyc b (Cl-C3 alkyl)OCH 2 -;
• X 1 , X 1 , X 3 , X 4 , A, B, hetCyc b , R c , R d , R 4 and R 5 are as defined for Formula I.
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• B is (b) C 1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C 1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R b is (c) hetCyc b CH 2 -.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (f) R c R d NCH 2 -.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is
• R b is (j) hetCyc b (Cl-C3 alkyl)OCH 2 -
• compounds of Formula I include compounds of Formula I-I
• R b is (c) hetCyc b CH 2 -, (f) R c R d NCH 2 -, or (j) hetCyc b (Cl-C3 alkyl)OCH 2 -;
• X 1 , X 1 , X 3 , X 4 , A, B, R 4 , R 5 , hetCyc b , R c and R d are as defined for Formula I.
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• B is (b) CI -C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyc a )Cl-C3 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (i) (hetCyc a )Cl-C3 alkyl-.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyc a )Cl-C3 alkyl-; and R b is (c) hetCyc b CH 2 -.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyc a )Cl-C3 alkyl-; and R b is (f) R c R d NCH 2 -.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyc a )Cl-C3 alkyl-; and R b is Q) hetCyc b (Cl-C3 alkyl)OCH 2 -.
• compounds of Formula I include compounds of Formula I-J
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.
• B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl-
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl-.
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (a) hydrogen.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3- C6 cycloalkylidene ring.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (g) hetA ⁇ Cl-CS alkyl-, where hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (i) (hetCyc a )Cl-C3 alkyl-, where hetCyc 3 is as defined for Formula I.
• compounds of Formula I include compounds of Formula I-L where E is A ⁇ O- or (h) hetAr 2 -0-; Ring D is
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• X 1 is N; X 2 , X 3 X 4 are CH; and A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.
• X 1 is N; X 2 , X 3 X 4 are CH; and A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.
• compounds of Formula I include compounds of Formula I-M
• X 1 is N; and X 2 , X 3 and X 4 are CH.
• A is CN
• X 1 is N; X 2 , X 3 and X 4 are CH; and A is CN.
• B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.
• X 1 is N; X 2 , X 3 and X 4 are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.
• R 3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R'R"N- where R and R" are independently hydrogen or C1-C6 alkyl.
• the compounds of Formula I include pharmaceutically acceptable salts thereof.
• the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I.
• Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include monohydrochloride, dihydrochloride, trifluoroacetic acid, and di-trifluoroacetic acid salts.
• compounds of Formula I include trifluoroacetic acid and dihydrochloride salts.
• the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
• compounds of Formula I and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• the compounds of Formula I include the compounds of Examples 1-819 and stereoisomers and pharmaceutically acceptable salts and solvates thereof.
• the compounds of Examples 1-819 are in the free base form.
• the compounds of Examples 1-819 are dihydrochloride or trifluoroacetic acid salts.
• pharmaceutically acceptable indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the patient being treated therewith.
• Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
• the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes.
• Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
• Schemes 1-6 show general methods for preparing the compounds provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
• Scheme 1 shows a general scheme for the synthesis of compound X where A is CN, and B, X 1 , X 2 , X 3 , X 4 , Ring D, R a , R b , n, m and E are as defined for Formula I.
• Compound 2 is obtained by treating 3-bromo-5-methoxypyridine (compound 1), which is commercially available, with 0-(mesitylsulfonyl)hydroxylamine.
• the O- mesitylsulfonylhydroxylamine may be prepared as described in Mendiola, J., et al., Org. Process Res. Dev. 2009, 13(2), 263-267.
• Compound 2 may be reacted with ethyl propiolate to provide a mixture of compounds 3A and 3B, which typically are obtained in a ratio of approximately 2: 1 to 9: 1, respectively.
• the mixture of compounds 3A and 3B may be treated with 48% HBr at elevated temperatures, followed by recrystallization or chromatography purifications, to isolate compound 4A as the minor isomer and compound 4B as the major isomer.
• compound 4A may be treated with POCb to provide compound 5.
• the formyl group may be converted to an oxime group using H2OH to provide compound 6.
• the oxime group may be converted to a nitrile group using acetic anhydride to provide compound 7.
• the methoxy group of compound 7 may be converted to a hydroxy group by treating compound 7 with aluminum trichloride to provide compound 8.
• compound 12 may be prepared by coupling compound 8 with the corresponding boronic ester compound 10 (where Ring D, E, X 1 , X 2 , X 3 and X 4 are as defined for Formula I; Z is -B(OR x )(OR y ) and R z and R y are H or (l-6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) to provide compound 11a using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with
• the amino protecting group if present on a substituent of Ring D of compound 11a may be removed under standard conditions (for example, a Boc group may be removed by treating compound 11a to acidic conditions, e.g., HC1) to provide compound 12 where B is hydrogen.
• the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 12 where B is hydrogen and E is as defined for Formula I except that E is not hydrogen.
• Compound 12 may then be prepared from compound 11 as described above.
• compound 9 may be prepared by reacting compound 8 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R ⁇ R ⁇ Cl-Ce alkyl-X, hetA ⁇ Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc a )Cl-C3 alkyl-X, het
• compound when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 8 with a C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate.
• X is a halogen such as Br or CI, or a leaving group such as triflate.
• Compound 11 may then be prepared by coupling compound 9 with the corresponding boronic ester compound 10 using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an R b substituent that is R c R d N- wherein one or both of R c and R d is hydrogen, the nitrogen atom of R b may be protected with an appropriate amino protecting group prior to coupling.
• Compound 12 may then be prepared from compound 11 as described above.
• Scheme 2 shows another general scheme for the synthesis of compound 17 where A is CN, and B, X 1 , X 2 , X 3 , X 4 , Ring D, R a , R b , n, m and E are as defined for Formula I.
• Compound 9 (prepared, e.g., as described in Scheme 1) in which B is as defined for Formula I, may be coupled with compound 13 (where X 1 , X 2 , X 3 and X 4 are as defined for Formula I; L 2 is a leaving group such as a triflate or halide); Z is -B(OR x )(OR y ) and R z and R y are H or (l-6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)), using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3 in dioxane at elevated
• R 15 is substituted with an R b substituent that is R c R d N- wherein one or both of R c and R d is hydrogen, the nitrogen atom of R b may be protected with an appropriate amino protecting group prior to coupling.
• the amino protecting group if present may then be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HC1) to provide compound 17 where E is H.
• the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 17 where E is as defined for Formula I except that E is not H.
• Scheme 3 shows a general scheme for the synthesis of Compound 21 where A is H, and B, X 1 , X 2 , X 3 , X 4 , Ring D, R a , R b , n, m and E are as defined for Formula I.
• Compound 18 may be prepared by coupling compound 4A (prepared e.g., as described in Scheme 1) with the corresponding boronic ester compound 10 (where Ring D, X 1 , X 2 , X 3 and X 4 are as defined for Formula I; Z is -B(OR x )(OR y ) and R z and R y are H or (1- 6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substitute
• compound 20 may be prepared by reacting compound 19 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R ⁇ Cl-Ce alkyl-X, hetA ⁇ Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc a )Cl-C3 alkyl-X, hetCyc a )Cl-C3 alkyl-X, hetC
• compound when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 19 with C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate. Compound 21 may then be prepared from compound 20. If Ring D comprises a substituent having an amino protecting group, the amino protecting group may be removed under standard conditions (for example, a Boc group may be removed by treating compound 20 to acidic conditions, e.g., HC1) to provide compound 21 where E is H.
• a Boc group may be removed by treating compound 20 to acidic conditions, e.g., HC1 to provide compound 21 where E is H.
• the E group of compound 20 may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 21 where E is as defined for Formula I except that E is not H.
• Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.
• compound 19 may be prepared by coupling compound 22 with the corresponding boronic ester compound 10 (where Ring D, X 1 , X 2 , X 3 and X 4 are as defined for Formula I; Z is -B(OR x )(OR y ) and R z and R y are H or (l-6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium- catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an R b substituent that
• compound 23 may be prepared by reacting compound 22 with a reagent such as C1-C6 alkyl- X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (RAR ⁇ Cl-Ce alkyl-X, hetA ⁇ Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc a )Cl-C3 alkyl-X, het
• compound when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with Cl- C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate.
• Compound 20 may be prepared by coupling compound 23 with compound 10 as described in Scheme 3.
• Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.
• compound 20 may be prepared by reacting compound 19 with a group such as (C1-C6 alkyl)OH, an appropriately substituted (C1-C3 alkyl)OH, an appropriately substituted (C1-C6 alkyl)OH, or hetCyc a OH (i.e., where hetCyc 3 a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl) under Mitsunobu reaction conditions (PPh 3 and diisopropyl azodicarboxylate).
• Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.
• Scheme 5 shows an alternative general scheme for the synthesis of Compound 21 where A is H, and B, X 1 , X 2 , X 3 , X 4 , Ring D, R a , R b , n, m and E are as defined for Formula I.
• Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.
• compound 23 may be prepared by reacting compound 22 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R ⁇ R ⁇ Cl-Ce alkyl-X, hetA ⁇ Cl-CS alkyl -
• a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene
• a protecting group e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups.
• compound when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate.
• X is a halogen such as Br or CI, or a leaving group such as triflate.
• Compound 24 may be prepared by reacting compound 23 with compound 13 (where
• X I , X 2 , X 3 and X 4 are as defined for Formula I;
• L 2 is a leaving group such as a triflate or halide);
• Z is -B(OR x )(OR y ) and R z and R y are H or (l-6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross- coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3 in dioxane at elevated temperatures).
• Suzuki coupling reaction conditions for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base
• compound 24 may be prepared by reacting compound 22 directly with compound 13 as described above.
• Compound 20 may be prepared by coupling compound 24 with compound 15 where Ring D and E are as defined for Formula I under appropriate SNAr conditions (for example, optionally in the presence of a base such as K 2 C0 3 and at elevated temperature). If Ring D of compound 15 comprises a substituent having a primary or secondary ring nitrogen atom, the nitrogen atom is protected with an appropriate amino protecting group prior to coupling, and then the amino protecting group may be removed subsequent to coupling as described above.
• Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.
• Scheme 6 shows a general scheme for the synthesis of Compound 31 where A is CI, and B, X 1 , X 2 , X 3 , X 4 , Ring D, R a , R b , n, m and E are as defined for Formula I.
• Compound 25 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.
• Compound 26 may be prepared by treating compound 25 with aluminum trichloride.
• compound 27 may be prepared by reacting compound 26 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R ⁇ R ⁇ Cl-Ce alkyl-X, hetA ⁇ Cl-CS alkyl - X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (he
• compound when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 26 with C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate.
• X is a halogen such as Br or CI, or a leaving group such as triflate.
• Compounds 28 (when group B is methyl), 29 (when group B is hydrogen) and 30 (when group B is other than hydrogen) may be prepared by coupling compounds 25, 26 and 27, respectively, with the corresponding boronic ester compound 10 (where Ring D, E, X 1 , X 2 , X 3 and X 4 are as defined for Formula I; Z is -B(OR x )(OR y ) and R z and R y are H or (1- 6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 )4 and Na 2 C0 3
• the amino protecting group if present on a substituent of Ring D of compound 29 or 30 may be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HC1) to provide compound 31 where E is H.
• a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HC1) to provide compound 31 where E is H.
• the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 31 where E is as defined for Formula I except that E is not H.
• the E group of compounds 11, 11a, 16, 19, 20, 29 and 30 described in Schemes 1- 6 may be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce an E group, where E is any of the E groups defined for Formula I with the exception of hydrogen, using standard chemistry well known to persons skilled in the art.
• the term "functionalized” refers to a process step in the E group of a compound of general Formula I is reacted or treated with an appropriate reagent to provide a compound of Formula I where E is as defined for Formula I except that E is other than hydrogen.
• a base e.g., an amine base such as DIEA
• an appropriate solvent such as DCM
• compound 11 wherein E is - H 2 may be reacted with an carboxylic acid using conventional amide bond formation conditions, for example by treating the carboxylic acid with an activating agent (e.g., HATU) followed by addition of compound 11 in the presence of a base (e.g., an amine base such as DIEA) in an appropriate solvent (such as DMA) to provide a functionalized compound 12.
• an activating agent e.g., HATU
• a base e.g., an amine base such as DIEA
• an appropriate solvent such as DMA
• an appropriate base e.g., DIEA
• an alkoxy, aryloxy or heteroaryloxy derivative may be prepared by reacting a compound 11 where E is hydroxy with a compound having the formula (C 1-C6 alkoxy)Cl-C6 alkyl-X, Ar x -X or hetAr 2 -X, where X is a halogen, in the presence of an inorganic base (e.g., an alkali metal hydride, such as sodium hydride or potassium hydride) in an appropriate solvent (e.g., an aprotic solvent such as DMA).
• an inorganic base e.g., an alkali metal hydride, such as sodium hydride or potassium hydride
• an appropriate solvent e.g., an aprotic solvent such as DMA
• amino protecting group refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound.
• suitable protecting groups for use in any of the processes described herein include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group.
• Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc”), benzyloxycarbonyl (“CBz”) and 9- fluorenylmethyleneoxycarbonyl ("Fmoc”). Further examples of these groups, and other protecting groups, are found in T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.
• Z is -B(OR x )(OR y ) and R x and R y are H or (l-6C)alkyl, or R x and R y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl), and Ring D, E, X 1 , X 2 , X 3 , X 4 , R a , R b , m and n are as defined for Formula I, wherein if Ring D is substituted with an R b substituent that is R c R d N- wherein one or both of R c and R d is hydrogen, the nitrogen atom of R b may be protected with an amino protecting group prior to coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, optionally followed by removal of the amino protecting group if present; or
• R a , R b , m, n, and E are as defined for Formula I with the exception that E is not hydrogen, functionalizing a correspondin compound of the formula
• Ring D, B, X 1 , X 2 , X 3 ,X 4 , R a , R b , m and n are as defined for Formula I
• Ring D, B, X 1 , X 2 , X 3 , and X 4 are as defined for Formula I and L 2 is a leaving group such as a halogen or triflate with a compound of the formula 15
• Ring D, R a , R b , m, n, and E are as defined for Formula I and wherein if Ring D is substituted with an R b substituent that is R c R d N- wherein one or both of R c and R d is hydrogen, the nitrogen atom of R b may be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or
• Ring D, R a , R b , m and n are as defined for Formula I and E is hydrogen, wherein if Ring D is substituted with an R b substituent that is R c R d N- wherein one or both of R c and R d is hydrogen, the nitrogen atom of R b may be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or

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