US20210387966A1 - 2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors - Google Patents

2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors Download PDF

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US20210387966A1
US20210387966A1 US17/289,123 US201917289123A US2021387966A1 US 20210387966 A1 US20210387966 A1 US 20210387966A1 US 201917289123 A US201917289123 A US 201917289123A US 2021387966 A1 US2021387966 A1 US 2021387966A1
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trifluoromethyl
nicotinamide
sulfamoylpyridin
pyridine
alkyl
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Ashok Arasappan
Ian M. Bell
Michael J. Breslin
Christopher James Bungard
Christopher S. Burgey
Harry R. Chobanian
Jason M. Cox
Anthony T. Ginnetti
Deodial Guy Guiadeen
Kristen L. G. Jones
Mark E. Layton
Hong Liu
Jian Liu
James J. Perkins
Shawn J. Stachel
Linda M. Suen-Lai
Zhe Wu
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Merck Sharp and Dohme LLC
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • 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
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

  • Voltage-gated sodium channels mediate the selective influx of sodium ions in excitable cells and play a central role in initiating and propagating action potentials (Yu et al., Genome Biology 4:207 (2003)). Voltage-gated sodium channels are ubiquitous in the central and peripheral nervous system where they play a central role in the initiation and propagation of action potentials, and also in skeletal and cardiac muscle where the action potential triggers cellular contraction (Goldin et al., Ann N Y Acad Sci. 1999 Apr. 30; 868:38-50). Alterations in VGSC function or their expression can profoundly affect normal cell excitability (Huang et al., J Neurosci. 2013 Aug.
  • Voltage-gated sodium channels are multimeric complexes characterized by one ⁇ -subunit, which forms an ion-conducting aqueous pore, and at least one ⁇ -subunit that modifies the kinetics and voltage-dependence of the channel gating.
  • ⁇ -subunits include Na v 1.8, also known as SNS, PN3 or Na v 1.8 (Goldin et al., Neuron. 2000 November; 28 (2):365-8).
  • Na v 1.8 voltage-gated sodium ion channels are expressed primarily in sensory neurons, which are responsible for conveying information from the periphery (e.g. skin, muscle and joints) to the central nervous system via the spinal cord.
  • Sodium channels are integral to this process as sodium channel activity is required for initiation and propagation of action potentials triggered by noxious stimuli (thermal, mechanical and chemical) activating peripheral nociceptors (Catterall et al., Nat Chem Biol. 2017 Apr. 13; 13(5):455-463).
  • VGSC protein level at the cell surface or an alteration in activity of the VGSC channels can result in disease states such as migraine, neurodegeneration following ischemia, epilepsies, and chronic neuropathic and inflammatory pain states.
  • Gain of function mutations in Nav1.7, Nav1.8, and Nav1.9 manifest in a variety of pain syndromes where patients experience spontaneous pain without an external stimulus (Bennett et al., Lancet Neurol. 2014 June; 13(6):587-99; Huang et al., J Neurosci. 2013 Aug. 28; 33(35): 14087-97; Kist et al., PLoS One. 2016 Sep. 6; 11(9):e0161789; Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81; and Schreiber et al., World J Diabetes. 2015 Apr. 15; 6(3):432-44).
  • Na v 1.8 voltage-gated sodium ion channels are believed to play a role in various maladies, including neuropathic pain, chronic itch, and inflammatory pain perception (Belkouch et al., J Neuroinflammation. 2014 Mar. 7; 11:45; Coward et al., Pain. 2000 March; 85(1-2):41-50; Yiangou et al., FEBS Lett. 2000 Feb. 11; 467(2-3):249-52; Black et al., Ann Neurol. 2008 December; 64(6):644-53; Bird et al., Br J Pharmacol. 2015 May; 172(10):2654-70; Liu et al., Neuron. 2010 Nov. 4; 68(3):543-56; and Zhao et al., J Clin Invest. 2013).
  • therapeutic agents suitable for use in addressing nociception, cough, or itch disorders require specificity in their action, for example, discriminating between action upon Na v 1.5 sodium ion channels, thought to be important in regulation of cardiac function, and action upon Na v 1.8 sodium ion channels, thought to be central in inflammatory nociception, or itch and disorders arising from dysfunctional and/or upregulated Na v 1.8 sodium ion channels.
  • inhibitors of Na v 1.8 voltage-gated sodium ion channel activity may useful to treat or prevent diseases, disorders and conditions involving Na v 1.8 receptors and/or stemming specifically from dysfunction of Na v 1.8 voltage-gated sodium ion channels (Han et al., J Neurol Neurosurg Psychiatry 2014 May; 85(5):499-505), including but not limited to, migraine, neurodegeneration following ischemia, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, post-operative pain, neuropathic pain, chronic itch, and itch disorders.
  • the compounds of the present invention are useful for the treatment and prevention of diseases, disorders and conditions involving Na v 1.8 receptors and Na v 1.8 voltage-gated sodium ion channels.
  • Na v 1.8 compounds are also disclosed in: WO 2009/049180, WO 2009/049181, WO 2009/049183, WO 2014/120808; WO 2014/120815; WO 2014/120820; WO 2015/010065; and WO 2015/089361; WO 2017/209322; U.S. Pat. Nos. 8,519,137; 9,051,270; 9,108,903; 9,163,042; and 9,783,501.
  • the present invention relates to novel compounds of structural formula I:
  • the compounds of structural formula I, and embodiments thereof, are inhibitors of Na v 1.8 sodium ion channel activity (or Na v 1.8 inhibitors) and may be useful in the treatment and prevention of diseases, disorders and conditions mediated by Na v 1.8 sodium ion channel activity, such as nociception, osteoarthritis, peripheral neuropathy, inherited erythromelalgia, multiple sclerosis, asthma, itch, atopy, allergic or contact dermatitis, renal failure, cholestasis, pruritus, acute itch, chronic itch, migraine, neurodegeneration following ischemia, epilepsy, pain, inflammatory pain, spontaneous pain, acute pain, acute pain due to fractures, musculoskeletal damage, pancreatitis and renal colic, peri-operative pain, post-operative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, sciatica,
  • the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also relates to methods for the treatment, management, prevention, alleviation, amelioration, suppression or control of disorders, diseases, and conditions that may be responsive to inhibition of Na v 1.8 sodium ion channel activity in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
  • the present invention also relates to the use of compounds of the present invention for manufacture of a medicament useful in treating diseases, disorders and conditions that may be responsive to the inhibition of Na v 1.8 sodium ion channel activity.
  • the present invention is also concerned with treatment or prevention of these diseases, disorders and conditions by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent that may be useful to treat the disease, disorder and condition.
  • the invention is further concerned with processes for preparing the compounds of this invention.
  • the present invention is concerned with novel compounds of structural Formula I:
  • A is heteroaryl or heteroaryl fused to a saturated or unsaturated 5- or 6-membered ring containing 0-3 heteroatoms independently selected from O, S and N(R h ) q , wherein each heteroaryl, 5-membered ring and 6-membered ring is unsubstituted or substituted with one to five substituents selected from R a :
  • B is heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from R b ;
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c ; each R a is selected from the group consisting of:
  • each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ; each R b is independently selected from the group consisting of:
  • each R b is unsubstituted or substituted with one to five substituents selected from R f ; each R c is independently selected from the group consisting of:
  • R c is unsubstituted or substituted with one to five substituents selected from R g ;
  • R d is independently selected from the group consisting of:
  • each R e is independently selected from the group consisting of:
  • each R f is selected from the group consisting of:
  • each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ; each R g is selected from the group consisting of:
  • each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ; each R h is independently selected from the group consisting of:
  • each R i is independently selected from the group consisting of:
  • each R j is selected from the group consisting of:
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ; each R k is selected from the group consisting of:
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ; each R L is selected from the group consisting of:
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ; each R m is independently selected from the group consisting of:
  • the invention has numerous embodiments, which are summarized below.
  • the invention includes the compounds as shown, and also includes individual diastereoisomers, enantiomers, and epimers of the compounds, and mixtures of diastereoisomers and/or enantiomers thereof including racemic mixtures.
  • A is heteroaryl or heteroaryl fused to a saturated or unsaturated 5- or 6-membered ring containing 0-3 heteroatoms independently selected from O, S and N(R h ) q , wherein each heteroaryl, 5-membered ring and 6-membered ring is unsubstituted or substituted with one to five substituents selected from R a .
  • A is unsubstituted or substituted with one to four substituents selected from R a .
  • A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a . In another class of this embodiment, A is unsubstituted or substituted with one substituent selected from R a . In another class of this embodiment, A is substituted with one substituent selected from R a . In another class of this embodiment A is not substituted with a substituent selected from R a . In another class of this embodiment A is unsubstituted.
  • A is heteroaryl or heteroaryl fused to a saturated or unsaturated 5- or 6-membered ring containing 0-3 heteroatoms independently selected from O, S and N(R h ) q , wherein each heteroaryl, 5-membered ring and 6-membered ring is unsubstituted or substituted with one to four substituents selected from R a .
  • A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a . In another class of this embodiment, A is substituted with one substituent selected from R a . In another class of this embodiment A is not substituted with a substituent selected from R a . In another class of this embodiment A is unsubstituted.
  • A is heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to four substituents selected from R a .
  • A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a .
  • A is substituted with one substituent selected from R a .
  • A is not substituted with a substituent selected from R a .
  • A is unsubstituted.
  • A is selected from the group consisting of: pyridine, pyrimidine, pyrazine, pyridazine, indazole, imidazo[1,2-a]pyridine, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, benzimidazole, imidazole, pyrazole, thiophene, furan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, oxazole, isoxazole, isothiazole, thiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 4H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxide
  • A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a .
  • A is substituted with one substituent selected from R a .
  • A is not substituted with a substituent selected from R a .
  • A is unsubstituted.
  • A is selected from the group consisting of: pyridine, pyrimidine, pyrazine, pyridazine, indazole, imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, benzimidazole, imidazole, pyrazole, thiophene, furan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, oxazole, isoxazole, isothiazole, thiazole, 1,2,4-thiadiazole, and 1,3,4-thiadiazole, wherein A is unsubstituted or substituted with one to four substituents selected from R a , In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a . In another class of this embodiment, A is unsubstituted or substituted with one substituent selected from R a . In another class of this embodiment, A is substituted with one substituent selected from R a . In another class of this embodiment A is not substituted with a substituent selected from R a . In another class of this embodiment A is unsubstituted.
  • A is selected from the group consisting of: pyridine, pyrimidine, pyrazine, pyridazine, indazole, imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, benzimidazole, imidazole, pyrazole, thiophene, 1,2,4-oxadiazole, 1,3,4-oxadiazole, oxazole, isothiazole, thiazole, 1,2,4-thiadiazole, and 1,3,4-thiadiazole, wherein A is unsubstituted or substituted with one to four substituents selected from R a .
  • A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a .
  • A is substituted with one substituent selected from R a .
  • A is not substituted with a substituent selected from R a .
  • A is unsubstituted.
  • A is selected from the group consisting of: pyridine, pyrimidine, pyrazine, indazole, imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, pyrazole, thiophene, and 1,2,4-oxadiazole, wherein A is unsubstituted or substituted with one to four substituents selected from R a . In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R a . In another class of this embodiment, A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a . In another class of this embodiment, A is substituted with one substituent selected from R a . In another class of this embodiment A is not substituted with a substituent selected from R a . In another class of this embodiment A is unsubstituted.
  • A is selected from the group consisting of: pyridine, pyrimidine, pyrazine, pyridazine, indazole, imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, pyrazole, thiophene, and 1,2,4-oxadiazole, wherein A is unsubstituted or substituted with one to four substituents selected from R a . In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R a . In another class of this embodiment, A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a . In another class of this embodiment, A is substituted with one substituent selected from R a . In another class of this embodiment A is not substituted with a substituent selected from R a . In another class of this embodiment A is unsubstituted.
  • A is selected from the group consisting of: pyridine, pyrimidine, and pyrazine, wherein A is unsubstituted or substituted with one to four substituents selected from R a .
  • A is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a .
  • A is substituted with one substituent selected from R a .
  • A is not substituted with a substituent selected from R a .
  • A is unsubstituted.
  • A is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R a .
  • A is unsubstituted or substituted with one to two substituents selected from R a .
  • A is unsubstituted or substituted with one substituent selected from R a .
  • A is substituted with one substituent selected from R a .
  • A is not substituted with a substituent selected from R a .
  • A is unsubstituted.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is a first amine
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • B is heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from R b .
  • B is unsubstituted or substituted with one to two substituents selected from R b .
  • B is unsubstituted or substituted with one substituent selected from R b .
  • B is not substituted with a substituent selected from R b .
  • B is unsubstituted.
  • B is selected from the group consisting of: pyrazine, pyridine, pyrimidine, and pyridazine, wherein each B is unsubstituted or substituted with one to three substituents selected from R b .
  • B is unsubstituted or substituted with one or two substituents selected from R b .
  • B is unsubstituted or substituted with one substituent selected from R b .
  • B is substituted with one substituent selected from R b .
  • B is not substituted with a substituent selected from R b .
  • B is unsubstituted.
  • B is pyrazine, wherein pyrazine is unsubstituted or substituted with one to three substituents selected from R b .
  • B is pyrazine, wherein pyrazine is unsubstituted or substituted with one or two substituents selected from R b .
  • B is pyrazine, wherein pyrazine is unsubstituted or substituted with one substituent selected from R b .
  • B is pyrazine, wherein pyrazine is substituted with one substituent selected from R b .
  • pyrazine is not substituted with a substituent selected from R b .
  • pyrazine is unsubstituted.
  • B is selected from the group consisting of: pyridine, pyrimidine, and pyridazine, wherein each B is unsubstituted or substituted with one to three substituents selected from R b .
  • B is unsubstituted or substituted with one to two substituents selected from R b .
  • B is unsubstituted or substituted with one substituent selected from R b .
  • B is substituted with one substituent selected from R b .
  • B is not substituted with a substituent selected from R b .
  • B is unsubstituted.
  • B is pyridazine, wherein pyridazine is unsubstituted or substituted with one to three substituents selected from R b .
  • B is pyridazine, wherein pyridazine is unsubstituted or substituted with one or two substituents selected from R b .
  • B is pyridazine, wherein pyridazine is unsubstituted or substituted with one substituent selected from R b .
  • B is pyridazine, wherein pyridazine is substituted with one substituent selected from R b .
  • pyridazine is not substituted with a substituent selected from R b .
  • pyridazine is unsubstituted.
  • B is pyrimidine, wherein pyrimidine is unsubstituted or substituted with one to three substituents selected from R b . In another embodiment, B is pyrimidine, wherein pyrimidine is unsubstituted or substituted with one or two substituents selected from R b . In another embodiment, B is pyrimidine, wherein pyrimidine is unsubstituted or substituted with one substituent selected from R b . In another embodiment, B is pyrimidine, wherein pyrimidine is substituted with one substituent selected from R b . In another class of this embodiment, pyrimidine is not substituted with a substituent selected from R b . In another class of this embodiment, pyrimidine is unsubstituted.
  • B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b . In another embodiment, B is pyridine, wherein pyridine is unsubstituted or substituted with one or two substituents selected from R b . In another embodiment, B is pyridine, wherein pyridine is unsubstituted or substituted with one substituent selected from R b . In another embodiment, B is pyridine, wherein pyridine is substituted with one substituent selected from R b . In another class of this embodiment, pyridine is not substituted with a substituent selected from R b . In another class of this embodiment, pyridine is unsubstituted.
  • R 1 is selected from the group consisting of: hydrogen, —SO 3 H, —SO 2 NH 2 , —SO 2 NR e C 1-6 alkyl, —SO 2 NR e C(O)C 1-6 alkyl, —SO 2 NR e C 2-6 alkenyl, —SO 2 NR e C 3-6 cycloalkyl, —SO 2 NR e C(O)C 3-6 cycloalkyl, —SO 2 NR e C 2-6 cycloheteroalkyl, —SO 2 NR e C(O)C 2-6 cycloheteroalkyl, —SO 2 NR e -aryl, —SO 2 NR e -heteroaryl, —SO 2 C 1-6 alkyl, —SO 2 C 1-6 alkenyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 2-6 cycloheteroalkyl,
  • R 1 is selected from the group consisting of: hydrogen, —SO 3 H, —SO 2 NH 2 , —SO 2 NR e C 1-6 alkyl, —SO 2 NR e C 2-6 alkenyl, —SO 2 N(C 2-6 alkenyl) 2 , —SO 2 NR e C 3-6 cycloalkyl, —SO 2 NR e C 2-6 cycloheteroalkyl, —SO 2 NR e -aryl, —SO 2 NR e -heteroaryl, —SO 2 C 1-6 alkyl, —SO 2 C 1-6 alkenyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 2-6 cycloheteroalkyl, —SO 2 aryl, —SO 2 heteroaryl, —S(O)R j , —SR j , —C(O)NH 2 , —C(O)
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R d .
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to two substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 NR e C 1-6 alkyl, —SO 2 NR e C 2-6 alkenyl, —SO 2 N(C 2-6 alkenyl) 2 , —SO 2 NR e C 3-6 cycloalkyl, —SO 2 NR e C 2-6 cycloheteroalkyl, —SO 2 NR e -aryl, —SO 2 NR e -heteroaryl, —SO 2 C 1-6 alkyl, —SO 2 C 1-6 alkenyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 2-6 cycloheteroalkyl, —SO 2 aryl, —SO 2 heteroaryl, —S(O)R j , —SR j , —C(O)NH 2 , —C(O)NR
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R d .
  • each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to two substituents selected from R d .
  • R 1 is selected from the group consisting of: hydrogen, —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 3-6 cycloheteroalkyl, —C(O)NH 2 , —CO 2 H, —CO 2 C 1-6 alkyl, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 cycloalkyl, CF 3 , —SO 2 NR e C(O)C 1-6 alkyl, —SO 2 NR e C(O)C 3-6 cycloalkyl, and —SO 2 NR
  • R 1 is selected from the group consisting of: hydrogen, —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 3-6 cycloheteroalkyl, —C(O)NH 2 , —CO 2 H, —CO 2 C 1-6 alkyl, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 cycloalkyl, and CF 3 , wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to four substituents selected from
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 NH—C 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —SO 2 C 3-6 cycloalkyl, —SO 2 C 3-6 cycloheteroalkyl, —C(O)NH 2 , —CO 2 H, —CO 2 C 1-6 alkyl, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 cycloalkyl, and CF 3 , wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to four substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 3-6 cycloheteroalkyl, —C(O)NH 2 , —CO 2 H, —CO 2 C 1-6 alkyl, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 cycloalkyl, and CF 3 , wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to four substituents selected from R
  • R 1 is hydrogen
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —SO 2 C 3-6 cycloheteroalkyl, —C(O)NH 2 , —CO 2 H, —CO 2 C 1-6 alkyl, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-NH 2 , —C 2-6 alkenyl, —C 1-6 cycloalkyl, and CF 3 , wherein each alkyl, alkenyl, cycloalkyl and cyclohetero
  • R 1 is selected from the group consisting of: hydrogen, —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 NH—C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —C(O)NH 2 , —CO 2 H, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 1-6 cycloalkyl, and CF 3 , wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: hydrogen, —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —C(O)NH 2 , —CO 2 H, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-NH 2 , —C 1-6 cycloalkyl-OH, —C 1-6 cycloalkyl-NH 2 , and CF 3 , wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —C(O)NH 2 , —CO 2 H, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-NH 2 , —C 1-6 cycloalkyl-OH, —C 1-6 cycloalkyl-NH 2 , and CF 3 , wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 C 1-6 alkyl-NH 2 , —SO 2 NH—C 1-6 alkyl, —SO 2 C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —C(O)NH 2 , —CO 2 H, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, and CF 3 , wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 (CH 2 ) 2 —NH 2 , —SO 2 NH—C(CH 3 ) 3 , —SO 2 CH 3 , —SO 2 CH 2 CH 3 , —SO 2 -cyclopropyl, —C(O)NH 2 , —CO 2 H, —CN, F, Br, Cl, —OH, —OCH 3 , —CH 3 , —CH 2 OH and —CF 3 , wherein each alkyl and cyclopropyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 3 H, —SO 2 NH 2 , —SO 2 (CH 2 ) 2 —NH 2 , —SO 2 NH—C(CH 3 ) 3 , —SO 2 CH 3 , —SO 2 CH 2 CH 3 , —SO 2 -cyclopropyl, —C(O)NH 2 , —CO 2 H, —CN, F, Br, —OH, —OCH 3 , —CH 3 , —CH 2 OH, and —CF 3 , wherein each alkyl and cyclopropyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 2 NR e C(O)C 1-6 alkyl, —SO 2 NR e C(O)C 3-6 cycloalkyl, and —SO 2 NR e C(O)C 2-6 cycloheteroalkyl, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to four substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 NH—C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —C(O)NH 2 , —CO 2 H, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, CF 3 , —SO 2 NR e C(O)C 1-6 alkyl, —SO 2 NR e C(O)C 3-6 cycloalkyl, and —SO 2 NR e C(O)C 2-6 cycloheteroalkyl, wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 NH—C 1-6 alkyl, —SO 2 C 3-6 cycloalkyl, —C(O)NH 2 , —CO 2 H, —CN, halogen, —OH, —OC 1-6 alkyl, —C 1-6 alkyl, and CF 3 , wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d .
  • R 1 is selected from the group consisting of: —SO 2 NH 2 , —C(O)NH 2 , and —OH. In another embodiment of the present invention, R 1 is selected from the group consisting of: —SO 2 NH 2 and —C(O)NH 2 . In another embodiment of the present invention, R 1 is —SO 2 NH 2 . In another embodiment of the present invention, R 1 is —C(O)NH 2 . In another embodiment of the present invention, R 1 is —OH.
  • R 2 is selected from the group consisting of: hydrogen, and —C 1-6 alkyl. In another embodiment, R 2 is —C 1-6 alkyl. In another embodiment, R 2 is hydrogen.
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-5 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from NH, O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • each cycloalkyl and cycloheteroalkyl may be fused to phenyl or thiene. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl may be fused to phenyl. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl ring may be fused to thiene. In another class of this embodiment and subclass of these classes, the cycloheteroalkyl contains nitrogen and is attached to the B ring via a bond to the nitrogen. In another class of this embodiment, R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 Cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-5 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from NH, O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • each cycloalkyl and cycloheteroalkyl may be fused to phenyl or thiene. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl may be fused to phenyl. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl ring may be fused to thiene. In another class of this embodiment and subclass of these classes, the cycloheteroalkyl contains nitrogen and is attached to the B ring via a bond to the nitrogen. In another class of this embodiment, R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substitutents selected from R c .
  • R 3 is selected from the group consisting of: 1) a monocyclic, bicyclic or spirocyclic C 3-5 cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from NH, O, and S, wherein each cycloalkyl and cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substitutents selected from R c .
  • each cycloalkyl and cycloheteroalkyl may be fused to phenyl or thiene. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl may be fused to phenyl.
  • each cycloalkyl and cycloheteroalkyl ring may be fused to thiene.
  • the cycloheteroalkyl contains nitrogen and is attached to the B ring via a bond to the nitrogen.
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, wherein each cycloalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, wherein each cycloalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • each cycloalkyl may be fused to phenyl or thiene.
  • each cycloalkyl may be fused to phenyl.
  • each cycloalkyl may be fused to thiene.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 Cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from NH, O, and S, wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • each cycloheteroalkyl may be fused to phenyl or thiene.
  • each cycloheteroalkyl may be fused to phenyl. In another class of this embodiment, each cycloheteroalkyl ring may be fused to thiene. In another class of this embodiment and subclass of these classes, the cycloheteroalkyl contains nitrogen and is attached to the B ring via a bond to the nitrogen. In another class of this embodiment, R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl and cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-5 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl and cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from NH, O, and S, wherein each cycloalkyl and cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • each cycloalkyl and cycloheteroalkyl may be fused to phenyl or thiene. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl may be fused to phenyl. In another class of this embodiment, each cycloalkyl and cycloheteroalkyl ring may be fused to thiene. In another class of this embodiment and subclass of these classes, the cycloheteroalkyl is attached to the B ring via a bond to the R 3 nitrogen. In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, wherein each cycloalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-5 cycloalkyl ring, wherein each cycloalkyl may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • each cycloalkyl may be fused to phenyl or thiene.
  • each cycloalkyl may be fused to phenyl.
  • each cycloalkyl may be fused to thiene.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from NH, O, and S, wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to six substitutents selected from R c .
  • the cycloheteroalkyl contains a nitrogen and 0-2 heteroatoms independently selected from N, O, and S.
  • each cycloheteroalkyl may be fused to phenyl or thiene. In another class of this embodiment, each cycloheteroalkyl may be fused to phenyl. In another class of this embodiment, each cycloheteroalkyl ring may be fused to thiene. In another class of this embodiment and subclass of these classes, the cycloheteroalkyl is attached to the B ring via a bond to the R 3 nitrogen. In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from NH, O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • the cycloheteroalkyl contains nitrogen and is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, wherein each cycloalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, wherein each cycloalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-10 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from NH, O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c .
  • the cycloheteroalkyl contains nitrogen and is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-5 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substitutents selected from R c .
  • R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from NH, O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substitutents selected from R c .
  • the cycloheteroalkyl contains a nitrogen and 0-2 heteroatoms independently selected from N(R m ) r , O, and S. In another class of this embodiment, the cycloheteroalkyl contains a nitrogen and 0-2 heteroatoms independently selected from NH, O, and S. In another class of this embodiment and a subclass of this class, the cycloheteroalkyl is attached to the B ring via a bond to the R 3 nitrogen. In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and wherein each cycloalkyl is unsubstituted or substituted with one to four substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and wherein each cycloalkyl is unsubstituted or substituted with one to four substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to four substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from NH, O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to four substitutents selected from R c .
  • R 3 is a monocyclic, bicyclic or spirocyclic C 2-10 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to four substitutents selected from R c .
  • the cycloheteroalkyl contains a nitrogen and 0-2 heteroatoms independently selected from N(R m ) r , O, and S.
  • the cycloheteroalkyl contains a nitrogen and 0-2 heteroatoms independently selected from NH, O, and S.
  • the cycloheteroalkyl is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: cyclohexane, cycloheptane, pyrrolidine, azetidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane, dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, and hexahydrofuro[3,2-b]pyrrole, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c
  • R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c .
  • R 3 is unsubstituted or substituted with one substituent selected from R c .
  • R 3 is selected from the group consisting of: cyclohexane, and cycloheptane, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c .
  • R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c .
  • R 3 is unsubstituted or substituted with one substituent selected from R c .
  • R 3 is selected from the group consisting of: pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, thiomorpholine dione, oxazepane, 1,4-thiazepane, isoindoline, dihydroisoquinoline, tetrahydroisoquinoline, octahydro-isoindole, azabicyclo[2.2.1]heptane, oxa-azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo[3.2.1]octane, oxa-azabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa-azabic
  • R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c .
  • R 3 is unsubstituted or substituted with one substituent selected from R c .
  • R 3 is selected from the group consisting of: pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, 1,4-thiazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.1]heptane, oxa-azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]-octane, diazabicyclo[3.2.1]octane, oxa-azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspir
  • R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c .
  • R 3 is unsubstituted or substituted with one substituent selected from R c .
  • R 3 is selected from the group consisting of: pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.1]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxa-azaspiro[3.5
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to three substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: pyrrolidine, azetidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]-heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane, dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, and hexahydrofuro[3,2-b]pyrrole, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to four substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to three substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: pyrrolidine, azetidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, 1,4-oxazepane, isoindoline, 3,4-dihydroisoqinoline, 2-azabicyclo[2.2.1]heptane, 3-azabicyclo-[3.1.1]heptane, 3-azabicyclo[4.1.0]heptane, 3-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.0]-heptane, 6-azaspiro[2.5]octane, 5-azaspiro[2.5]octane, 6,7-dihydrothieno[3,2-c]pyridine, 6,8-dihydroimidazo[1,2-a]pyrazine, and 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole, wherein
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to three substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: piperidine, azepane, morpholine, and azaspiro[2.5]octane, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: piperidine, azepane, morpholine, and 6-azaspiro[2.5]octane, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: piperidine, azepane, and morpholine, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, R 3 is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • R 3 is selected from the group consisting of: piperidine, and azepane, wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to six substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to two substituents selected from R c .
  • R 3 is unsubstituted or substituted with one substituent selected from R c .
  • R 3 is attached to the B ring via a bond to the R 3 nitrogen.
  • piperidine and azepane are each individually attached to the B ring via a bond to the piperidine or azepane nitrogen.
  • R 3 is piperidine, wherein piperidine is unsubstituted or substituted with one to eight substituents selected from R c .
  • piperidine is unsubstituted or substituted with one to six substituents selected from R c .
  • piperidine is unsubstituted or substituted with one to four substituents selected from R c .
  • piperidine is unsubstituted or substituted with one to three substituents selected from R c .
  • piperidine is unsubstituted or substituted with one to two substituents selected from R c .
  • piperidine is unsubstituted or substituted with one substituent selected from R c .
  • piperidine is attached to the B ring via a bond to the R 3 nitrogen.
  • piperidine is attached to the B ring via a bond to the piperidine nitrogen.
  • R 3 is azepane, wherein azepane is unsubstituted or substituted with one to eight substituents selected from R c .
  • azepane is unsubstituted or substituted with one to six substituents selected from R c .
  • azepane is unsubstituted or substituted with one to four substituents selected from R c .
  • azepane is unsubstituted or substituted with one to three substituents selected from R c .
  • azepane is unsubstituted or substituted with one to two substituents selected from R c . In another class of this embodiment, azepane is unsubstituted or substituted with one substituent selected from R c . In another class of this embodiment and a subclass of these classes, azepane is attached to the B ring via a bond to the R 3 nitrogen. In another class of this embodiment and a subclass of these classes, azepane is attached to the B ring via a bond to the azepane nitrogen.
  • R 3 is morpholine, wherein morpholine is unsubstituted or substituted with one to eight substituents selected from R c .
  • morpholine is unsubstituted or substituted with one to six substituents selected from R c .
  • morpholine is unsubstituted or substituted with one to four substituents selected from R c .
  • morpholine is unsubstituted or substituted with one to three substituents selected from R c .
  • morpholine is unsubstituted or substituted with one to two substituents selected from R c .
  • morpholine is unsubstituted or substituted with one substituent selected from R c .
  • morpholine is attached to the B ring via a bond to the R 3 nitrogen.
  • morpholine is attached to the B ring via a bond to the morpholine nitrogen.
  • each R a is selected from the group consisting of: —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —OH, oxo, —CN, —C 3-6 cycloalkyl, and —C 2-5 cycloheteroalkyl, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ;
  • R a is substituted with a halogen selected from: F, Br, and Cl.
  • the halogen is F or Cl.
  • the halogen is Cl.
  • the halogen is F.
  • each R a is selected from the group consisting of: —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —OH, oxo, —CN, and —C 3-6 cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 .
  • R a is substituted with a halogen selected from: F, Br, and Cl.
  • the halogen is F or Cl.
  • the halogen is Cl.
  • the halogen is F.
  • each R a is selected from the group consisting of: —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —OH, oxo, and CN, wherein each alkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 .
  • R a is substituted with a halogen selected from: F, Br, and Cl.
  • the halogen is F or Cl.
  • the halogen is Cl.
  • the halogen is F.
  • each R a is selected from the group consisting of: —C 1-6 alkyl, halogen, —OH, oxo, and CN, wherein each alkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 .
  • R a is substituted with a halogen selected from: F, Br, and Cl.
  • the halogen is F or Cl.
  • the halogen is Cl.
  • the halogen is F.
  • each R a is selected from the group consisting of: —C 1-6 alkyl, halogen, —OH, and oxo, wherein each alkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 .
  • R a is substituted with a halogen selected from: F, Br, and Cl.
  • the halogen is F or Cl.
  • the halogen is Cl.
  • the halogen is F.
  • each R a is selected from the group consisting of: —C 1-6 alkyl, halogen, —OH, and oxo. In a class of this embodiment, each R a is selected from the group consisting of: CH 3 , halogen, —OH, and oxo.
  • each R a is selected from the group consisting of: —C 1-6 alkyl and halogen. In another embodiment, each R a is selected from the group consisting of: CH 3 and halogen.
  • each R a is halogen
  • R a is —C 1-6 alkyl, wherein alkyl is substituted with a halogen selected from: F, Br, and Cl.
  • a halogen selected from: F, Br, and Cl.
  • the halogen is F or Cl.
  • the halogen is Cl.
  • the halogen is F.
  • R a is —C 1-6 alkyl. In a class of this embodiment, R a is CH 3 .
  • each R b is independently selected from the group consisting of: —CF 3 , —CF 2 CF 3 , —CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —OCF 3 , CN, halogen, —Si(C 1-6 alkyl) 3 , —C 1-6 alkyl-O—R k , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, aryl, heteroaryl, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 1-6 alkyl-C 2-6 cycloheteroalkyl, —C 1-6 alkyl-aryl, —C 1-6 alkyl-heteroaryl, —C 2-6 alkenyl-C 3-6 cyclo
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , —OCHF 2 , —OCH 2 CF 3 . —OCF 3 , CN, halogen, —Si(C 1-6 alkyl) 3 , —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, —C 2-6 alkyl-C 3-6 cycloalkyl, —C 2-6 alkynyl-C 3-6 cycloalkyl, and heteroaryl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —OCF 3 , CN, F, Cl, Br, —Si(CH 3 ) 3 , —CH 3 , —C(CH 3 ) 3 , —OCH 3 , cyclopropyl, cyclobutyl, piperidine, —CH 2 -cyclopropyl, —C 2 alkynyl-cyclopropyl, and pyrazole, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —OCF 3 , CN, halogen, —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, —C 2-6 alkyl-C 3-6 cycloalkyl, —C 2-6 alkynyl-C 3-6 cycloalkyl, and heteroaryl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —OCF 3 , CN, F, Cl, Br, —CH 3 , —C(CH 3 ) 3 , —OCH 3 , cyclopropyl, cyclobutyl, piperidine, —CH 2 -cyclopropyl, —C 2 alkynyl-cyclopropyl, and pyrazole, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , —OCHF 2 , CN, halogen, —C 1-6 alkyl, —C 3-6 cycloalkyl, and —C 2-6 alkyl-C 3-6 cycloalkyl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , —OCHF 2 , CN, F, Cl, Br, —CH 3 , —C(CH 3 ) 3 , cyclopropyl, cyclobutyl, and —CH 2 -cyclopropyl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , halogen, —C 1-6 alkyl, and —C 3-6 cycloalkyl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , F, Cl, Br, —CH 3 , —C(CH 3 ) 3 , cyclopropyl, and cyclobutyl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , —CHF 2 , F, Cl, —CH 3 , cyclopropyl and cyclobutyl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , and —C 1-6 alkyl, wherein each R b is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , and —C 1-6 alkyl.
  • each R b is independently selected from the group consisting of: —CF 3 , and —CH 3 , wherein —CH 3 is unsubstituted or substituted with one to five substituents selected from R f .
  • each R b is independently selected from the group consisting of: —CF 3 , and —CH 3 . In another class of this embodiment, each R b is —CH 3 . In another class of this embodiment, each R b is CF 3 .
  • each R c is independently selected from the group consisting of: —CF 3 , —CH 2 CF 3 , —CHF 2 , —OCHF 2 , —OCF 3 , CN, oxo, —OH, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 1-6 alkyl-C 2-6 cycloheteroalkyl, —C 1-6 alkyl-aryl, —C 1-6 alkyl-heteroaryl, —C 1-6 alkenyl-C 3-6 cycloalkyl, —C 1-6 alkenyl-aryl, —C 1-6 alkenyl heteroaryl, —C 1-6 alkenyl-
  • each R c is independently selected from the group consisting of: —CF 3 , —CH 2 CF 3 , —CHF 2 , —OCF 3 , CN, halogen, —C 1-6 alkyl, oxo, —OH, —C 1-6 alkyl-OH, —O-aryl, —O-heteroaryl, aryl, heteroaryl, —C 1-6 alkyl-aryl, and —C 1-6 alkyl-heteroaryl, wherein each R c is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is independently selected from the group consisting of: —CF 3 , —CH 2 CF 3 , —CHF 2 , —OCF 3 , CN, F, Cl, —CH 3 , —CH 2 CH 3 , oxo, —OH, —CH 2 OH, —O-phenyl, phenyl, pyrazole, and —CH 2 -phenyl, wherein each R c is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is independently selected from the group consisting of: —CF 3 , —CH 2 CF 3 , —CHF 2 , —OCF 3 , CN, halogen, —C 1-6 alkyl, oxo, —OH, —C 1-6 alkyl-OH, —O-aryl, aryl, heteroaryl, and —C 1-6 alkyl-aryl, wherein each R c is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is independently selected from the group consisting of: —CF 3 , —CH 2 CF 3 , —CHF 2 , —OCF 3 , CN, F, Cl, —CH 3 , —CH 2 CH 3 , oxo, —OH, —CH 2 OH, —O-phenyl, phenyl, pyrazole, and —CH 2 -phenyl, wherein each R c is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is independently selected from the group consisting of: —CF 3 , halogen, and —C 1-6 alkyl, wherein each R c is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is independently selected from the group consisting of: —CF 3 , F, Cl, —CH 3 and —CH 2 CH 3 .
  • each R c is independently selected from the group consisting of: —CF 3 , F, and —CH 3 .
  • each R c is independently selected from the group consisting of: halogen and —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is independently selected from the group consisting of: halogen and —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R g .
  • each R c is independently selected from the group consisting of: halogen and —C 1-6 alkyl.
  • each R c is independently selected from the group consisting of: F and —CH 3 .
  • each R c is —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R g .
  • each R c is —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R g .
  • each R c is —C 1-6 alkyl.
  • each R c is —CH 3 .
  • each R c is halogen. In a class of this embodiment, each R c is F.
  • R d is independently selected from the group consisting of: hydrogen, halogen, OH, oxo, —C 1-6 alkyl, —OC 1-6 alkyl, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 alkyl) 2 .
  • R d is independently selected from the group consisting of: halogen, OH, oxo, —C 1-6 alkyl, —OC 1-6 alkyl, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 alkyl) 2 .
  • R d is independently selected from the group consisting of: hydrogen, halogen, OH, oxo, —C 1-6 alkyl, —OC 1-6 alkyl, and NH 2 .
  • R d is independently selected from the group consisting of: halogen, OH, oxo, —C 1-6 alkyl, —OC 1-6 alkyl, and NH 2 .
  • R d is independently selected from the group consisting of: hydrogen, halogen, —OH, N(R g ) 2 , and C 1-6 alkyl. In a class of this embodiment, R d is independently selected from the group consisting of: hydrogen, F, —OH, NH 2 , and CH 3 .
  • R d is independently selected from the group consisting of: hydrogen, halogen, —OH, oxo, N(R g ) 2 , and C 1-6 alkyl. In a class of this embodiment, R d is independently selected from the group consisting of: hydrogen, F, —OH, NH 2 , and CH 3 . In another embodiment, R d is independently selected from the group consisting of: halogen, —OH, oxo, N(R g ) 2 , and C 1-6 alkyl. In a class of this embodiment, R d is independently selected from the group consisting of: F, —OH, NH 2 , and CH 3 .
  • R d is independently selected from the group consisting of: halogen, —OH, N(R g ) 2 , and C 1-6 alkyl.
  • R d is independently selected from the group consisting of: F, —OH, NH 2 , and CH 3 .
  • R d is independently selected from the group consisting of: hydrogen, halogen, and C 1-6 alkyl. In a class of this embodiment, is independently selected from the group consisting of: hydrogen, F and CH 3 . In another embodiment, is independently selected from the group consisting of: halogen, and C 1-6 alkyl. In a class of this embodiment, is independently selected from the group consisting of: F and CH 3 .
  • each R e is independently selected from the group consisting of: hydrogen, —C 1-6 alkyl, and —C 2-6 alkenyl. In another embodiment, is independently selected from the group consisting of: —OH, and N(R g ) 2 .
  • R d is independently selected from the group consisting of: —OH, and NH 2 . In another class of this embodiment, R d is —OH. In another class of this embodiment, R d is NH 2 .
  • each R e is independently selected from the group consisting of: hydrogen, and —C 1-6 alkyl.
  • R e is hydrogen.
  • R e is —C 1-6 alkyl.
  • each R f is selected from the group consisting of: halogen, —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —OC 2-6 cycloheteroalkyl, CN, —NH 2 , —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —NH(C 2-6 cycloheteroalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , and —N(C 2-6 cycloheteroalkyl) 2 , wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R f is selected from the group consisting of: halogen, —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —OC 2-6 cycloheteroalkyl, CN, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 , wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R f is selected from the group consisting of: halogen, —C 1-6 alkyl, —OH, —OC 1-6 alkyl, CN, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 , wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R f is selected from the group consisting of: halogen, —C 1-6 alkyl, —OH, —OC 1-6 alkyl, and CN, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R f is selected from the group consisting of: halogen, —C 1-6 alkyl, and —OH, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R f is selected from the group consisting of: F, —CH 3 , and —OH.
  • each R f is halogen. In a class of this embodiment, R f is F.
  • each R f is —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R f is —C 1-6 alkyl.
  • R f is —CH 3 .
  • each R f is —OH.
  • each R g is selected from the group consisting of: halogen, C 1-6 alkyl, —OH, —OC 1-6 alkyl, —S(O) m —C 1-6 alkyl, —CN, —CF 3 , —OCHF 2 , and —OCF 3 , wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R g is selected from the group consisting of: halogen, C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —CF 3 , —OCHF 2 , and —OCF 3 , wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R g is selected from the group consisting of: halogen, C 1-6 alkyl, —OH, —CN, —CF 3 , wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 .
  • each R g is selected from the group consisting of: halogen, —OH, —CN, and —CF 3 .
  • each R g is selected from the group consisting of: F, —OH, —CN, and —CF 3 .
  • each R h is independently selected from the group consisting of: hydrogen, and —C 1-6 alkyl.
  • R h is hydrogen.
  • R h is —C 1-6 alkyl.
  • each R 1 is independently selected from the group consisting of: hydrogen, and —C 1-6 alkyl. In a class of this embodiment, R 1 is hydrogen. In another class of this embodiment, R 1 is —C 1-6 alkyl.
  • each R g halogen.
  • each R g is F.
  • each R j is selected from the group consisting of: —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R j is selected from the group consisting of: —C 1-6 alkyl, —C 2-6 alkenyl. —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R j is selected from the group consisting of: —C 1-6 alkyl, —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R j is selected from the group consisting of: —C 1-6 alkyl, —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, cycloalkyl, and cycloheteroalkyl.
  • each R j is —C 1-6 alkyl, wherein each alkyl, is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R j is —C 1-6 alkyl.
  • each R k is selected from the group consisting of: —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R k is selected from the group consisting of: —C 1-6 alkyl, —C 2-6 alkenyl. —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R k is selected from the group consisting of: —C 1-6 alkyl, —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R k is —C 1-6 alkyl, wherein each alkyl, is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R k is —C 1-6 alkyl.
  • each R L is selected from the group consisting of: —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, —C 2-6 cycloheteroalkyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R L is selected from the group consisting of: —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R L is selected from the group consisting of: —C 1-6 alkyl, —C 3-6 cycloalkyl, and —C 2-6 cycloheteroalkyl, wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R L is —C 1-6 alkyl, wherein each alkyl, is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 .
  • each R L is —C 1-6 alkyl.
  • each R m is independently selected from the group consisting of: hydrogen, and —C 1-6 alkyl.
  • R m is hydrogen.
  • R m is —C 1-6 alkyl.
  • n is 0, 1, 2, 3 or 4. In a class of this embodiment, n is 0, 1, 2 or 3. In another class of this embodiment, n is 0, 1 or 2. In a class of this embodiment, n is 0 or 1. In a class of this embodiment, n is 1, 2, 3 or 4. In another class of this embodiment, n is 1, 2 or 3. In another class of this embodiment, n is 1 or 2. In another class of this embodiment, n is 0. In another class of this embodiment, n is 1. In another class of this embodiment, n is 2. In another class of this embodiment, n is 3. In another class of this embodiment, n is 4.
  • m is 0, 1 or 2. In a class of this embodiment, m is 0 or 1. In another class of this embodiment, m is 1 or 2. In another class of this embodiment, m is 0. In another class of this embodiment, m is 1. In another class of this embodiment, m is 2.
  • p is 0, 1, 2, 3 or 4. In a class of this embodiment, p is 0, 1, 2 or 3. In another class of this embodiment, p is 0, 1 or 2. In a class of this embodiment, p is 0 or 1. In a class of this embodiment, p is 1, 2, 3 or 4. In another class of this embodiment, p is 1, 2 or 3. In another class of this embodiment, p is 1 or 2. In another class of this embodiment, p is 0. In another class of this embodiment, p is 1. In another class of this embodiment, p is 2. In another class of this embodiment, p is 3. In another class of this embodiment, p is 4.
  • q is 0 or 1. In another class of this embodiment, q is 0. In another class of this embodiment, q is 1.
  • r is 0 or 1. In another class of this embodiment, r is 0. In another class of this embodiment, r is 1.
  • the invention relates to compounds of structural formula Ia:
  • A is pyridine.
  • A is a compound having the same in another class of this embodiment.
  • A is a compound having the same in another class of this embodiment.
  • A is,
  • A is a compound having the same in another class of this embodiment.
  • A is a compound having the same in another class of this embodiment.
  • A is:
  • the invention relates to compounds of structural formula Ib:
  • A is pyridine. In another class of this embodiment, A is
  • A is a compound having the same in another class of this embodiment.
  • A is a compound having the same in another class of this embodiment.
  • A is:
  • A is:
  • the invention relates to compounds of structural formula Ic:
  • A is pyridine. In another class of this embodiment. A is
  • A is a compound having the same in another class of this embodiment.
  • A is a compound having the same in another class of this embodiment.
  • A is a compound having the same in another class of this embodiment.
  • A is:
  • A is:
  • the compound of structural formula I includes the compounds of structural formulas Ia, Ib, and Ic, and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • A is selected from the group consisting of:
  • A is unsubstituted or substituted with one to five substituents selected from R a ;
  • B is selected from the group consisting of:
  • each B is unsubstituted or substituted with one to three substituents selected from R b ;
  • R 1 is selected from the group consisting of:
  • each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d ;
  • R 2 is hydrogen;
  • R 3 is selected from the group consisting of:
  • R 3 is unsubstituted or substituted with one to eight substituents selected from R c ; or a pharmaceutically acceptable salt thereof.
  • A is selected from the group consisting of:
  • A is unsubstituted or substituted with one to five substituents selected from R a ;
  • B is selected from the group consisting of:
  • each B is unsubstituted or substituted with one to three substituents selected from R b ;
  • R 1 is selected from the group consisting of:
  • each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d ;
  • R 2 is hydrogen;
  • R 3 is selected from the group consisting of:
  • R 3 is unsubstituted or substituted with one to eight substituents selected from R c ; or a pharmaceutically acceptable salt thereof.
  • A is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R a ;
  • B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b ;
  • R 1 is selected from the group consisting of:
  • R 3 is unsubstituted or substituted with one to eight substituents selected from R c ; or a pharmaceutically acceptable salt thereof.
  • Illustrative, but non-limiting, examples of the compounds of the present invention that are useful as inhibitors of Na v 1.8 channel activity are the following compounds:
  • stereoisomers including diastereoisomers, enantiomers, epimers, and mixtures of these may also have utility in treating Na v 1.8 mediated diseases.
  • Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • Alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means a saturated monocyclic, bicyclic, spirocyclic or bridged carbocyclic ring, having a specified number of carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • cycloalkyl is selected from: cyclopropane, cyclobutane and cyclohexane.
  • cycloalkyl is cyclopropane, cyclobutane or cyclopentane.
  • cycloalkyl is cyclopropane or cyclobutane. In another embodiment, cycloalkyl is cyclopropane. In another embodiment, cycloalkyl is cyclobutane. In another embodiment, cycloalkyl is cyclopentane. In another embodiment, cycloalkyl is cyclohexane. In another embodiment, cycloalkyl is cycloheptane.
  • Cycloheteroalkyl means a saturated or partly unsaturated non-aromatic monocyclic, bicyclic, spirocyclic or bridged ring or ring system having a specified number of carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO 2 ) and O.
  • the cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogen or sulfur.
  • Examples of cycloheteroalkyl include tetrahydrofuran, pyrrolidine, tetrahydrothiophene, azetidine, piperazine, piperidine, morpholine, oxetane and tetrahydropyran.
  • cycloheteroalkyl is selected from: pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, thiomorpholine dione, oxazepane, 1,4-thiazepane, isoindoline, dihydroisoquinoline, tetra-hydroisoquinoline, octahydro-isoindole, azabicyclo[2.2.1]heptane, oxa-azabicyclo[2.2.1]-heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo[3.2.1]octane, oxa-azabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane
  • cycloheteroalkyl is selected from: pyrrolidine, azetidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]-heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane, dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, and hexahydrofuro[3,2-b]pyrrole.
  • cycloheteroalkyl is selected from: azepane, morpholine and piperidine. In another embodiment, cycloheteroalkyl is azepane. In another embodiment, cycloheteroalkyl is morpholine. In another embodiment, cycloheteroalkyl is piperidine.
  • Aryl means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one of the rings is aromatic.
  • aryl include phenyl and naphthyl. In one embodiment of the present invention, aryl is phenyl.
  • Heteroaryl means a monocyclic, bicyclic or tricyclic ring or ring system containing 5-14 ring atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO 2 ) and O, wherein at least one of the heteroatom containing rings is aromatic.
  • heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.
  • heteroaryl is a 5 or 6 membered heteroaryl ring.
  • heteroaryl is selected from: pyrazole, pyridyl, isoxazole and thiazole.
  • heteroaryl is selected from: pyridine, pyrimidine, pyrazine, pyridazine, indazole, imidazo[1,2-a]pyridine, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, benzimidazole, imidazole, pyrazole, thiophene, furan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, oxazole, isox
  • Halogen includes fluorine, chlorine, bromine and iodine. In one embodiment, halogen is fluorine, chorine or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is fluorine or bromine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine.
  • Unsaturated means containing at least one double or triple bond. In one embodiment, unsaturated means containing at least one double bond. In another embodiment, unsaturated means containing at least one triple bond.
  • any variable e.g., R 1 , R a , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a squiggly line across a bond in a substituent variable represents the point of attachment.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurals. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, salts and/or dosage forms which are, using sound medical judgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to encompass all such isomeric forms of the compounds of Formula I.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • the compounds of formula I include the following tautomers:
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of structural formula I.
  • different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H).
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies.
  • Isotopically-enriched compounds within structural formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
  • references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine, cho
  • esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl
  • acyl derivatives of alcohols such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl
  • esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.
  • prodrug means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of Formula A to a compound of Formula A, or to a salt thereof; a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • the scope of this invention includes prodrugs of the novel compounds of this invention.
  • Solvates, and in particular, the hydrates of the compounds of the present invention are included in the present invention as well.
  • the compound of the present invention are selective inhibitors of Na v 1.8 sodium ion channel activity or have selective activity as Na v 1.8 sodium ion channel blockers.
  • the compounds of the present invention exhibit at least 10-fold selectivity for Na v 1.8 sodium channels over Na v 1.5 sodium channels, and in some embodiments exhibit at least 100-fold selectivity for Na v 1.8 sodium channels over Na v 1.5 sodium channels based on functional potency (IC 50 values) for each channel in Qube® assay system.
  • the compounds of the present invention are potent inhibitors of Na v 1.8 channel activity.
  • the compounds, and pharmaceutically acceptable salts thereof may be efficacious in the treatment of diseases, disorders and conditions that are mediated by the inhibition of Na v 1.8 sodium ion channel activity and/or Na v 1.8 receptors.
  • Diseases, disorders or conditions mediated by Na v 1.8 sodium ion channel activity and/or Na v 1.8 receptors include but are not limited to nociception, osteoarthritis, peripheral neuropathy, inherited erythromelalgia, multiple sclerosis, asthma, pruritus, acute itch, chronic itch, migraine, neurodegeneration following ischemia, epilepsy, inflammatory pain, spontaneous pain, acute pain, peri-operative pain, post-operative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, pain syndromes, and complex regional pain syndromes.
  • One or more of these conditions or diseases may be treated, managed, prevented, reduced, alleviated, ameliorated or controlled by the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment.
  • the compounds of the present invention may be used for the manufacture of a medicament which may be useful for treating, preventing, managing, alleviating, ameliorating or controlling one or more of these conditions, diseases or disorders: nociception, osteoarthritis, peripheral neuropathy, inherited erythromelalgia, multiple sclerosis, asthma, pruritus, acute itch, chronic itch, migraine, neurodegeneration following ischemia, epilepsy, inflammatory pain, spontaneous pain, acute pain, peri-operative pain, post-operative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, pain syndromes, and complex regional pain
  • Preferred uses of the compounds may be for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment.
  • the compounds may be used for manufacturing a medicament for the treatment of one or more of these diseases:
  • the pain condition is an acute pain or chronic pain disorder. In another embodiment of the present invention, the pain condition is an acute pain disorder.
  • the compounds of the present invention may be effective in treating nociception.
  • Nociception or pain is essential for survival and often serves a protective function.
  • the pain associated with surgical procedures and current therapies to relieve that pain can delay recovery after surgery and increase the length of hospital stays.
  • the compounds of the present invention may be effective in treating osteoarthritis.
  • Osteoarthritis is type of arthritis caused by inflammation, breakdown, and eventual loss of cartilage in the joints.
  • the standards of care for pain associated with osteoarthritis are non-steroidal anti-inflammatory drugs (NSAIDs), for example celecoxib and diclofenac (reviewed in Zeng et al., 2018).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Patients that do not respond to NSAID therapies are typically treated with low dose opiates, such as hydrocodone. Patients that are refractory to the above therapies will usually opt for total joint replacement.
  • the compounds of the present invention may be effective in treating peripheral neuropathy.
  • Peripheral neuropathy is nerve damage caused by chronically high blood sugar and diabetes. It leads to numbness, loss of sensation, and sometimes pain in distal limbs such as feet, legs, or hands. It is the most common complication of diabetes.
  • the standards of care for the treatment of painful diabetic neuropathy are gabapentinoids, for example gabapentin and pregabalin.
  • Some patients will respond well to tricyclic antidepressants such as amitriptyline, while other patients get significant relief using SRI/NRI drugs such as duloxetine (Schreiber et al., World J Diabetes. 2015 Apr. 15; 6(3):432-44).
  • SRI/NRI drugs such as duloxetine (Schreiber et al., World J Diabetes. 2015 Apr. 15; 6(3):432-44).
  • Many options are available, however side-effects are common (e.g. dizziness, nausea) which limit their full potential
  • the compounds of the present invention may be effective in treating inherited erythromelalgia.
  • Inherited erythromelalgia is a chronic pain syndrome which has been linked to mutations in several voltage-gated sodium channels, including Nav1.8 (Kist et al., PLoS One. 2016 Sep. 6; 11(9):e0161789).
  • medications that affect voltage-gated sodium channels eg, lidocaine and mexiletine
  • show promise there is no current standard of care to treat IEM.
  • the compounds of the present invention may be effective in treating neuropathic pain.
  • Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system. It has been demonstrated in human patients, as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. (Colloca et al., Nat Rev Dis Primers. 2017 Feb. 16; 3:17002; Coward et al., Pain. 2000 March; 85(1-2):41-50; Yiangou et al., FEBS Lett. 2000 Feb.
  • neuropathic pain examples include, but are not limited to, post herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, lumbar radiculopathy, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias, and painful conditions that arise due to gain-of-function mutations in Nav1.8 (Huang et al., J Neurosci. 2013 Aug. 28; 33(35): 14087-97; Kist et al, PLoS One. 2016 Sep. 6; 11(9):e0161789; Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81; and Schreiber et al., World J Diabetes. 2015 Apr. 15; 6(3):432-44.
  • neuropathic pain The ectopic activity of normally silent sensory neurons is thought to contribute to the generation and maintenance of neuropathic pain, which is generally assumed to be associated with an increase in sodium channel activity in the injured nerve.
  • first line therapies are typically pregabalin, gabapentin, tricyclic antidepressants (e.g. amitriptyline), and SRI/NRI drugs (e.g. duloxetine).
  • Patients refractory to these therapies are usually prescribed low dose opiates (e.g. hydrocodone).
  • the compounds of the present invention may be effective in treating multiple sclerosis.
  • Nav1.8 expression in cerebellum has been identified in tissues taken from animal models of multiple sclerosis (EAE model) and in postmortem brains from patients suffering from multiple sclerosis (MS) (Shields et al., Ann Neurol. 2012 February; 71(2):186-94; Black et al., Proc Natl Acad Sci USA. 2000 Oct. 10; 97(21): 11598-602).
  • EAE model animal models of multiple sclerosis
  • MS multiple sclerosis
  • two SCN10A polymorphisms showed significant association with MS (Roostaei et al., Neurology. 2016 Feb. 2; 86 (5):410-7).
  • mice When Nav1.8 is overexpressed in cerebellum, mice develop ataxic-related motor deficits which are ameliorated with oral delivery of a selective small molecule Nav1.8 antagonist (Shields et al., PLoS One. 2015 Mar. 6; 10(3)). These studies suggest that a Nav1.8 antagonist may be a useful therapy to treat symptoms related to multiple sclerosis.
  • the compounds of the present invention may be effective in treating asthma. Asthma is caused by airway inflammation in which a person's airways become hyper-responsive, narrow and swollen, which makes it difficult to breathe. These symptoms are typically triggered through an allergic reaction (Nair P et al., J Allergy Clin Immunol Pract. 2017 May-June; 5(3):649-659). In a preclinical model of asthma, deletion of Nav1.8-containing neurons, or inhibition of nerve fibers via small molecules reduces airway inflammation and immune cell infiltration (Talbot et al., Neuron. 2015 Jul. 15; 87(2):341-54). Selective Nav1.8 antagonists may be a useful therapy to prevent airway hypersensitivity caused by immune cell infiltration.
  • the compounds of the present invention may be effective in treating pruritus.
  • Pruritus also commonly known as itch
  • itch affects approximately 4% of the global population is an unpleasant sensation that elicits the desire or reflex to scratch, and is regarded as closely related to pain (Luo et al., Cell Mol Life Sci. 2015 September; 72 (17): 3201-23).
  • Lets on the origin of itch implicate the subtle, low-frequency activation of nociceptors (pain-sensing neurons); however, it has been described that some afferents preferentially respond to histamine, which induces itch (Schmelz et al., JNeurosci. 1997 Oct. 15; 17(20):8003-8).
  • itch can arise from many different insults, diseases and disorders, and may be classified as dermal or pruriceptive, neurogenic, neuropathic, or psychogenic: itch can arise from both systemic disorders, skin disorders, as well as physical or chemical insult to the dermis.
  • the invention also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable carrier.
  • the compounds, or pharmaceutically acceptable salts thereof, may be useful in treating pain conditions, pruritic conditions, and cough conditions.
  • a compound of the present invention may be used in the manufacture of a medicament for the treatment of pain conditions, pruritic conditions, and cough conditions in a human or other mammalian patient.
  • a method of treating a pain conditions comprises the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, to a patient in need of treatment.
  • a method of treating a pruritic condition comprises the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, to a patient in need of treatment.
  • a method of treating a cough condition comprises the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, to a patient in need of treatment.
  • Other medical uses of the compounds of the present invention are described herein.
  • pain condition includes, but are not limited to, acute pain, peri-operative pain, pre-operative pain, post-operative pain, neuropathic pain, post herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, chronic pelvic pain, vulvodynia, complex regional pain syndrome and related neuralgias, pain associated with cancer and chemotherapy, pain associated with HIV, and HIV treatment-induced neuropathy, nerve injury, root avulsions, painful traumatic mononeuropathy, painful polyneuropathy, erythromyelalgia, paroxysmal extreme pain disorder, small fiber neuropathy, burning mouth syndrome, central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system), postsurgical pain syndromes (e.g., post mastectomy syndrome, post thoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, myofascial pain (mus
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno-synovitis and gout), shoulder tendonitis or bursitis, gouty arthritis, and aolymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic arthritic pain and related neuralgias acute pain, migraine, migraine headache, headache pain, cluster headache, non-vascular headache, traumatic nerve injury, nerve compression or entrapment, and neuroma pain,
  • pruritic condition or “pruritic disorder” as used herein includes, but is not limited to, conditions with an unpleasant sensation that provokes the desire to scratch, such as chronic itch.
  • cough condition or “cough disorder” as used herein includes, but is not limited to, chronic cough, neuropathic cough or cough due to neurological conditions.
  • Treatment of a disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors refers to the administration of the compounds of the present invention to a subject with the disease, disorder or condition.
  • One outcome of treatment may be reducing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors.
  • Another outcome of treatment may be alleviating the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors.
  • Another outcome of treatment may be ameliorating the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors.
  • Another outcome of treatment may be suppressing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors.
  • Another outcome of treatment may be managing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors.
  • Another outcome of treatment may be preventing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors.
  • Prevention of the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors refers to the administration of the compounds of the present invention to a subject at risk of the disease, disorder or condition.
  • One outcome of prevention may be reducing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors in a subject at risk of the disease, disorder or condition.
  • Another outcome of prevention may be suppressing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors in a subject at risk of the disease, disorder or condition.
  • Another outcome of prevention may be ameliorating the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors in a subject at risk of the disease, disorder or condition. Another outcome of prevention may be alleviating the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors in a subject at risk of the disease, disorder or condition. Another outcome of prevention may be managing the disease, disorder or condition mediated by Na v 1.8 sodium ion channel activity or Na v 1.8 receptors in a subject at risk of the disease, disorder or condition.
  • One outcome of treatment may be reducing the amount of pain experienced by a subject relative to that subject's pain immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be alleviating the amount of pain experienced by a subject relative to that subject's pain immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be ameliorating the amount of pain experienced by a subject relative to that subject's pain immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be suppressing the amount of pain experienced by a subject relative to that subject's pain immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be managing the amount of pain experienced by a subject relative to that subject's pain immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be ameliorating the amount of pain experienced by a subject relative to that subject's pain immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be preventing further pain experienced by a subject after the administration of the compounds of the present invention.
  • Prevention of pain refers to the administration of the compounds of the present invention to reduce the pain of a subject at risk of pain.
  • Prevention includes, but is not limited to, the administration to a subject prior to surgery or other expected painful event.
  • One outcome of prevention may be reducing pain in a subject at risk of pain.
  • Another outcome of prevention may be suppressing pain in a subject at risk of pain.
  • Another outcome of prevention may be ameliorating pain in a subject at risk of pain.
  • Another outcome of prevention may be alleviating pain in a subject at risk of pain.
  • Another outcome of prevention may be managing pain in a subject at risk of pain.
  • administering should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual or mammal in need of treatment.
  • the administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the mammal in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, intravenous, infusion, subcutaneous, transcutaneous, intramuscular, intradermal, transmucosal, intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • a suitable dosage level will generally be about 0.0001 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • a suitable dosage level may be about 0.001 to 500 mg per kg patient body weight per day.
  • a suitable dosage level may be about 0.001 to about 250 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day.
  • a suitable dosage level may be about 0.1 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.05 to 100 mg/kg per day.
  • a suitable dosage level may be about 0.1 to 50 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.05 to 0.5 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.5 to 5 mg/kg per day. In another embodiment, a suitable dosage level may be about 5 to 50 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 mg of the active ingredient, particularly 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 8 times per day; preferably, 1 to 4 times a day; more preferably once or twice per day. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of this invention may be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier.
  • the compounds of this invention may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients.
  • the compounds of this invention may also be used in pharmaceutical compositions in which the compound of the present invention or a pharmaceutically acceptable salt thereof is the only active ingredient.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • Compounds of the present invention may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • more than one drug is commonly administered.
  • the compounds of this invention may generally be administered to a patient who is already taking one or more other drugs for these conditions. Often the compounds will be administered to a patient who is already being treated with one or more anti-pain compounds when the patient's pain is not adequately responding to treatment.
  • the combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • Examples of other active ingredients that may be administered in combination with a compound of the present invention, and either administered separately or in the same pharmaceutical composition, include but are not limited to:
  • NSAID non-steroidal anti-inflammatory drug
  • the pharmaceutical composition comprises:
  • NSAID non-steroidal anti-inflammatory drug
  • a Nav 1.7 biological means a protein, including, but not limited to, antibodies, nanobodies and peptides, that inhibits the function of the Nav 1.7 channel.
  • a Nav 1.8 biological means a protein, including, but not limited to, antibodies, nanobodies and peptides, that inhibits the function of the Nav1.8 channel.
  • Specific compounds of use in combination with a compound of the present invention include: sodium channel inhibitors, including but not limited to, lidocaine including the lidocaine patch; tricyclic antidepressants including, but not limited to, amitriptyline; and SRI/NRI drugs, including but not limited to, duloxetine.
  • Suitable opioid agonists include, but are not limited to, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, buprenorphine, butorphanol, dezocine, nalbuphine, pentazocine, and tramadol.
  • Suitable opioid antagonists include, but are not limited to, naltrexone and naloxone.
  • Suitable calcium channel antagonists include, but are not limited to, Amlodipine, Diltiazem, Felodipine, gabapentin, Isradipine, Nicardipine, Nifedipine, Nisoldipine, pregabalin, Verapamil, and zicomtide.
  • Suitable NMDA receptor antagonists include, but are not limited to, ketamine, methadone, memantine, amantadine, and dextromethorphan.
  • Suitable COX-2 inhibitors include, but are not limited to, celecoxib, atoricoxih and parecoxib.
  • Suitable NSAIDs or non-steroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, and tolmetin.
  • Suitable analgesics include, but are not limited to, acetaminophen and duloxetine.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • Non-limiting examples include combinations of compounds with two or more active compounds selected from: opioid agonists; opioid antagonists; calcium channel antagonists; NMDA receptor agonists; NMDA receptor antagonists; COX-2 selective inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs); and an analgesic.
  • the compounds of the present invention may also be used in combination with spinal cord stimulation therapy and cutaneous stimulation therapy.
  • the present invention also provides a method for the treatment or prevention of a Na v 1.8 sodium ion channel activity mediated disease, disorder or condition, which method comprises administration to a patient in need of such treatment or at risk of developing a Na v 1.8 sodium ion channel activity mediated disease with a therapeutically effective amount of a Na v 1.8 sodium ion channel activity inhibitor and an amount of one or more active ingredients, such that together they give effective relief.
  • a pharmaceutical composition comprising a Na v 1.8 sodium ion channel activity inhibitor and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.
  • a Na v 1.8 sodium ion channel activity inhibitor and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a Na v 1.8 sodium ion channel activity mediated disease, disorder or condition.
  • a product comprising a Na v 1.8 sodium ion channel activity inhibitor and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a Na v 1.8 sodium ion channel activity mediated disease, disorder or condition.
  • Such a combined preparation may be, for example, in the form of a twin pack.
  • a compound of the present invention may be used in conjunction with another pharmaceutical agent effective to treat that disease, disorder or condition.
  • the present invention also provides a method for the treatment or prevention of pain conditions, pruritic conditions and cough conditions, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent effective to threat that disorder, disease or condition, such that together they give effective relief.
  • the present invention also provides a method for the treatment or prevention of pain conditions, pruritic conditions and cough conditions, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent useful in treating that particular condition, disorder or disease, such that together they give effective relief.
  • terapéuticaally effective amount means the amount the compound of structural formula I that will elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
  • the novel methods of treatment of this invention are for disorders known to those skilled in the art.
  • the term “mammal” includes humans, and companion animals such as dogs and cats.
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a COX-2 inhibitor the weight ratio of the compound of the Formula I to the COX-2 inhibitor will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds of the present invention can be prepared according to the procedures of the following Examples, using appropriate materials.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the Examples further illustrate details for the preparation of the compounds of the present invention.
  • Those skilled in the art will readily understand that known variations of protecting groups, as well as of the conditions and processes of the following preparative procedures, can be used to prepare these compounds.
  • a chemical reagent such as a boronic acid or a boronate is not commercially available, such a chemical reagent can be readily prepared following one of numerous methods described in the literature. All temperatures are degrees Celsius unless otherwise noted.
  • Mass spectra (MS) were measured either by electrospray ion-mass spectroscopy (ESMS) or by atmospheric pressure chemical ionization mass spectroscopy (APCI).
  • Reverse phase chromatography was carried out on a Gilson GX-281 equipped with a column selected from the following: Phenomenexd Synergi C 1-8 (150 mm ⁇ 30 mm ⁇ 4 micron), YMC-Actus Pro C18 (150 mm ⁇ 30 mm ⁇ 5 micron), Xtimate C18 (150 mm ⁇ 25 mm ⁇ 5 micron), Boston Green ODS (150 mm ⁇ 30 mm ⁇ 5 micron), XSELECT C18 (150 mm ⁇ 30 mm ⁇ 5 micron), and Waters XSELECT C 1-8 (150 mm ⁇ 30 mm ⁇ 5 micron).
  • LC/MS determinations were carried out on a Waters Classing Aquity system equipped with TUV and MS detectors and a Waters SQD mass spectrometer, a Shimadzu 20 UV 254 and 220 nM with Shimadzu 2010 or 2020 mass spectrometer, or an Agilent 1200 HPLC quipped with DAD/ELSD and G6110 MSD using one of the following conditions: 1) Ascentis Express C18 (3 ⁇ 50 mm) 2.7 ⁇ m column using mobile phase containing A: 0.05% Trifluoroacetic acid in water and B: 0.05% Trifluoroacetic acid in acetonitrile with a gradient from 90:10 (A:B) to 5:95 (A:B) over 6 min at a flow rate of 1.8 mL/min, UV detection at 210 nm; 2) Aquity BEH C18, (1.0 ⁇ 50 mm) 1.7 ⁇ m column using mobile phase containing A: 0.05% Trifluoroacetic acid in water and B: 0.05% Tri
  • Proton or 1 H NMR was acquired using a Varian Unity-Inova 400 MHz NMR spectrometer equipped with a Varian 400 ATB PFG 5 mm, Nalorac DBG 400-5 or a Nalorac IDG 400-5 probe, a Varian-400 MHz MR spectrometer equipped with an Auto X ID PFG Probe 5 mm, a Varian 400 MHz VNMRS spectrometer equipped with a PFG 4Nuc Probe 5 mm, or a Bruker Avancelll 500 MHz spectrometer equipped with a PABBO Probe 5 mm in accordance with standard analytical techniques, unless specified otherwise, and results of spectral analysis are reported.
  • TMSC1 trimethylsilyl chloride
  • UV ultraviolet
  • XantPhos Pd G2 or XantPhos-Pd-G2 is chloro[(4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene)-2-(2′-amino-1,1′-biphenyl)]-palladium(II);
  • Xantphos G3 or XantPhos-Pd-G3 is [(4,5-Bis-(diphenyl-phosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]-palladium(II) methane-sulf
  • compounds of the invention can be prepared by nucleophilic aromatic substitution between an appropriately functionalized carboxylic acid A-1 and an amine A-2, under basic conditions using a base such as DIPEA, to afford intermediate A-3.
  • Intermediate A-3 can then be transformed into a primary carboxamide A-4 which can be coupled to an appropriately functionalized heteroaryl halide A-5 to provide compounds of Formula A-5.
  • a protecting group such as 2,4-dimethoxybenzyl (DMB), tert-butyl or Boc may need to be removed after the C—N coupling to afford the compound of Formula A-6.
  • DMB 2,4-dimethoxybenzyl
  • tert-butyl or Boc may need to be removed after the C—N coupling to afford the compound of Formula A-6.
  • Amines of type A-2 and heteroaryl halides of type A-5 are commercially available or may be synthesized from appropriate intermediates.
  • the nucleophilic aromatic substitution may also occur in the presence of the carboxamide A-4, or alternative functional groups that can be converted to the carboxamide A-4 such as a halide, ester or cyano functional group, before being coupled to a heteroaryl halide A-5 to provide compounds of Formula A-6.
  • Hydrolysis of ester B-1 to give the carboxylic acid A-3 allows direct amide coupling with an appropriately functionalized heteroarylamine B-2, by using amide coupling agents such as EDC or by forming the acid chloride from POCl 3 , to afford compounds of Formula A-6.
  • amide coupling can occur first on an appropriately functionalized carboxylic acid (A-1) with a heteroaryl amine B-2, preferably using amide coupling agents such as EDC or by forming the acid chloride from POCh, or a C—N coupling between primary carboxamide C-2 and heteroaryl halide A-5 to afford intermediates of type C-1.
  • Intermediates of type C-1 can undergo nucleophilic aromatic substitution reactions with secondary amines A-2 by displacing a heteroaryl chloride in the presence of a base, such as K 2 CO 3 or DIPEA, or cross electrophile coupling reactions with alkyl halides to yield a compound of Formula A-6 as shown in Scheme C.
  • the compound of Formula A-6 may also be prepared via reaction of heteroaryl chloride with an amine A-2, followed by halogenation of the adjacent position of the heteroaryl ring D-2.
  • the heteroaryl halide D-2 such as a heteroaryl bromide, can be converted to a nitrile, which can be hydrolyzed to give a primary carboxamide A-4 and then coupled to a heteroaryl halide A-5 to afford compounds of Formula A-6.
  • halide D-2 can be converted directly into amide A-6 via carbonylation in the presence of carbon monoxide and a catalyst, such as palladium. The resulting adduct may need to be deprotected using standard conditions to afford compounds of Formula A-6.
  • Step 1 2-(benzylthiol-6-chloropyrazine To a solution of 2,6-dichloropyrazine (2.0 g, 13 mmol) in DMF (30 mL) was added K 2 CO 3 (1.7 g, 12 mmol) and phenylmethanethiol (1.7 g, 13 mmol). The mixture was stirred at 30° C. for 13 hours, then diluted with water, extracted with EtOAc. The organic phase was separated, washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound.
  • Step 2 6-chloropyrazine-2-sulfonyl chloride
  • CCl 2 40 mL
  • water 10 mL
  • dichlorine 0.30 g, 4.2 mmol
  • the resulting mixture was diluted with water and extracted with DCM.
  • the organic phase was separated, washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound.
  • Step 3 6-chloro-N,N-bis(2,4-dimethoxybenzyl)pyrazine-2-sulfonamide
  • DCM dimethylethylamine
  • 6-chloropyrazine-2-sulfonyl chloride 0.30 g crude. The mixture was stirred at 29° C. for 1 hour, then concentrated and purified by silica gel chromatography (0-18% petroleum ether/EtOAc) to give the title compound.
  • Step 1 2-(benzylthio)-4-bromopyridine
  • sodium hydride 32 g, 0.8 mol
  • phenylmethanethiol 99 g, 0.8 mol
  • the mixture was stirred at 0° C. for 2 h, then a solution of 4-bromo-2-fluoropyridine (140 g, 0.8 mol) in tetrahydrofuran (1.4 L) was added to the mixture dropwise with stirring at 0° C.
  • Step 2 4-bromopyridine-2-sulfonyl chloride To a solution of 2-(benzylthio)-4-bromopyridine (200 g, 0.72 mol) in DCM (2.8 L), AcOH (0.4 L) and water (0.8 L) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (424 g, 2.2 mol) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 16 hours. Then the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was slurried with 3 volumes of PE and filtered to give the title compound.
  • Step 3 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide
  • DCM dimethylethyl sulfonyl chloride
  • DIPEA dimethylethyl sulfonyl sulfonyl chloride
  • bis(2,4-dimethoxybenzyl)amine 56 g, 0.18 mol
  • the mixture was stirred at 20° C. for 1.5 h, then diluted with water and extracted with DCM.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (10% ethyl acetate/petroleum ether) to give the title compound.
  • Step 1 2-(benzylthio)-4-iodopyridine
  • sodium hydride 54 g, 1.3 mol
  • phenylmethanethiol 54 g, 1.3 mol
  • the mixture was stirred at 0° C. for 2 hours.
  • 2-fluoro-4-iodopyridine 300 g, 1.3 mol
  • 2-fluoro-4-iodopyridine 300 g, 1.3 mol
  • Step 2 4-iodopyridine-2-sulfonyl chloride
  • a 2-(benzylthio)-4-iodopyridine 430 g, 1.3 mol
  • DCM DCM
  • AcOH 0.8 L
  • water 1.7 L
  • 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione 780 g, 3.9 mol
  • the mixture was stirred at room temperature for 16 h, then quenched with water and extracted with DCM.
  • the combined organic layers were washed with sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was was slurried with 3 volumes of PE and filtered to give the title compound.
  • Step 3 N. N-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide
  • DCM dimethylethyl
  • DIPEA 1,3-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide
  • DIPEA 1,3-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide
  • DIPEA 0.43 L, 2.5 mol
  • bis(2,4-dimethoxybenzyl)amine 130 g, 0.41 mol
  • the mixture was stirred at 20° C. for 1.5 h, then diluted with water and extracted with DCM.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (10% ethyl acetate/petroleum ether) to give the title compound.
  • Step 4 4-amino-N,N-bis(2,4dimethoxybenzyl)pyridine-2-sulfonamide
  • N,N-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide 70 g, 0.12 mol
  • NMP 1.14 L
  • ammonium acetate 92 g, 1.2 mol
  • copper(II) acetylacetonate 9.4 g, 0.036 mol
  • 2-acetylcyclohexanone 10 g, 0.072 mol
  • Cs 2 CO 3 120 g, 0.36 mol
  • Step 1 2-(benzylthio)-4-chloropyridine
  • XantPhos 4.5 g, 7.8 mmol
  • DIPEA 4.5 g, 7.8 mmol
  • Pd 2 (dba) 3 2.4 g, 2.6 mmol
  • phenylmethanethiol 6.1 mL, 52 mmol.
  • the mixture was stirred at 100° C. for 13 h, then diluted in water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-2% EtOAc/petroleum ether) to give the title compound.
  • Step 2 4-chloropyridine-2-sulfonamide To a solution of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (22 g, 110 mmol) in acetonitrile (40 mL) at 0° C. was added acetic acid (4.0 mL) and water (3.2 mL). The mixture was stirred at 0° C. for 5 min, then 2-(benzylthio)-4-chloropyridine (10 g, 45 mmol) was added. The mixture was stirred at 0° C. for 0.5 h, then NL 4 OH (56 g, 450 mmol) was added. The mixture was stirred at 0° C.
  • Step 3 tert-butyl tert-butyl((4-chloropyridin-2-yl)sulfonyl) carbamate
  • Boc 2 O 3.2 mL, 14 mmol
  • DMAP 0.76 g, 6.2 mmol
  • Step 1 4-bromopyridine-2-sulfonamide
  • NH 4 OH 1.5 kg, 13 mol
  • the mixture was stirred at room temperature for 3 h, then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was slurried with DCM to give the title compound.
  • Step 2 tert-butyl ((4-bromopyridin-2-yl)-sulfonyl)(tert-butyl)carbamate
  • Boc 2 O 230 g, 1.1 mol
  • DMAP 26 g, 0.21 mol
  • the mixture was stirred at 25° C. for 0.5 hour, then the mixture was stirred at 70° C. for 16 hours.
  • the mixture was then cooled to 15° C., quenched with water and extracted with ethyl acetate.
  • Step 1 4-iodopyridine-2-sulfonamide
  • a solution of 4-iodopyridine-2-sulfonyl chloride (550 g, 1.8 mol) in acetonitrile (11.0 L) at 0° C. was added NH 4 OH (2.1 kg, 18 mol) dropwise with stirring.
  • the mixture was stirred at room temperature for 3 h, then quenched with water and extracted with EtOAc.
  • the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was slurried with DCM to give the title compound.
  • Step 2 tert-butyl tert-butyl((4-iodopyridin-yl) sulfonyl)carbamate
  • Boc 2 O 480 g, 2.2 mol
  • DMAP 11 g, 0.088 mol
  • Step 3 tert-butyl ((4-aminopyridin-2-yl)sulfonyl)(tertbutyl)carbamate
  • a solution of tert-butyl tert-butyl((4-iodopyridin-2-yl)sulfonyl)carbamate (50 g, 0.11 mol) in DMF (1.0 L) under an atmosphere of nitrogen was added NH 4 OH (64 g, 0.57 mol), copper(II) acetylacetonate (8.9 g, 0.033 mol), 2-acetylcyclohexanone (9.6 g, 0.066 mol) and Cs 2 CO 3 (37 g, 0.11 mol) at room temperature.
  • Step 1 tert-butyl (3-carbamoyl-1,2,4-oxadiazol-5-yl)carbamate
  • Ammonia gas was bubbled through a solution of ethyl 5-((tert-butoxycarbonyl)amino)-1,2,4-oxadiazole-3-carboxylate (0.10 g, 0.39 mmol) in EtOH (3 mL) at 20° C. for 15 minutes. The mixture was stirred at 20° C. for 1 hour, then concentrated under reduced pressure to give the title compound.
  • Step 2 5-amino-1,2,4-oxadiazole-3-carbonitrile
  • a solution of tert-butyl (3-carbamoyl-1,2,4-oxadiazol-5-yl)carbamate (20 mg, 0.088 mmol) in DCM (2 mL) at 20° C. was added phosphoryl trichloride (27 mg, 0.17 mmol) and a drop of DMF.
  • Step 1 1-(tert-butyl) 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate
  • DMF dimethyl methyl
  • NaH 0.8 g, 3.50 mmol
  • Mel 0.79 mL, 13 mmol
  • the mixture was stirred at 20° C. for 2 h, then quenched with water and extracted with EtOAc.
  • Step 2 tert-butyl 4-methyl-5-oxoazepane-1-carboxylate A mixture of KOH (4.2 mL, 8.3 mmol) and 1-(tert-butyl) 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate (0.50 g, 1.7 mmol) in dioxane (5 mL) was stirred at 100° C. for 12 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound.
  • Step 3 tert-butyl 4,4-difluoro-5-methylazepane-1-carboxylate
  • a mixture of tert-butyl 4-methyl-5-oxoazepane-1-carboxylate (0.37 g, 1.6 mmol) and BAST (0.90 mL, 4.9 mmol) in CHCl 3 (5 mL) was degassed and backfilled with nitrogen three times.
  • the mixture was heated to 55° C. for 12 h, then quenched with water and extracted with EtOAc.
  • the organic layer was separated, washed with brine, concentrated and filtered under reduced pressure to give a residue that was purified by silica gel chromatography (0-4% petroleum ether/ethyl acetate) to give the title compound.
  • Step 4 (R and S)-4,4-difluoro-5-methylazepane hydrochloride A mixture of tert-butyl 4,4-difluoro-5-methylazepane-1-carboxylate (0.30 g, 1.2 mmol) in MeOH (2 mL) and HCl/dioxane (2 mL) was stirred at 20° C. for 12 h. Then the mixture was concentrated under reduced pressure to give the title compound.
  • Step 1 Benzyl 4,4-dichloro-3-methylpiperidine-1-carboxylate Tungsten(VI) chloride (1.6 g, 4.1 mmol) was added to a solution of benzyl 3-methyl-4-oxopiperidine-1-carboxylate (0.34 g, 1.4 mmol) in DCM (16 mL). The mixture was heated at 40° C. for 10 minutes, then quenched with aqueous sodium hydrogen carbonate (saturated) and extracted with dichloromethane. The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound.
  • Step 2 4,4-Dichloro-3-methylpiperidine hydrochloride A solution of benzyl 4,4-dichloro-3-methylpiperidine-1-carboxylate (0.39 g, 1.3 mmol) in EtOH was added to a suspension of Pd—C (0.14 g, 0.13 mmol) in nitrogen degassed EtOH (13 mL total). The mixture was evacuated and backfilled with hydrogen, and then stirred under a balloon of hydrogen for 1 hour. The reaction mixture was purged with nitrogen, and then filtered through a pad of CeliteTM. The filtrate was treated with 4M HCl (1.6 mL, 6.4 mmol) in dioxane, stirred for 10 minutes, and then concentrated under reduced pressure to give the title compound.
  • 4M HCl 1.6 mL, 6.4 mmol
  • Step 1 Benzyl 4,4-dichloroazepane-1-carboxylate Tungsten(VI) chloride (1.2 g, 3.1 mmol) was added to a solution of benzyl 4-oxoazepane-1-carboxy late (0.26 g, 1.0 mmol) in DCM (10 mL). The mixture was heated at 40° C. for 10 minutes, then quenched with aqueous sodium hydrogen carbonate (saturated) and extracted with dichloromethane. The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound.
  • Step 2 4,4-Dichloroazepane hydrochloride A solution of benzyl 4,4-dichloroazepane-1-carboxylate (0.12 g, 0.40 mmol) in EtOH was added to a suspension of Pd—C (43 mg, 0.040 mmol) in nitrogen degassed EtOH (4 mL total). The mixture was evacuated and backfilled with hydrogen, then stirred under a balloon of hydrogen for 1 hour. The mixture was purged with nitrogen, and then filtered through a pad of CeliteTM. The filtrate was treated with 4M HCl (0.50 mL, 2.0 mmol) in dioxane, stirred for 10 minutes, and then concentrated under reduced pressure to give the title compound.
  • 4M HCl (0.50 mL, 2.0 mmol
  • Step 1 (R)-3-((3,3,3-trifluoro-2-hydroxypropyl)amino)propan-1-ol (R)-2-(trifluoro-methyl)oxirane (3.7 g, 33 mmol) was added to a stirred solution of 3-amino-1-propanol (2.5 g, 33 mmol) in THF (33 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour, then warmed to ambient temperature for 16 hours. Then the mixture was concentrated and azeotroped with THF to give the title compound.
  • Step 2 (R)—N-(3-hydroxypropyl)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide
  • Tosyl-Cl (6.7 g, 35 mmol) was added to a solution of (R)-3-((3,3,3-trifluoro-2-hydroxypropyl)amino)propan-1-ol (6.0 g, 32 mmol) and TEA (8.9 mL, 64 mmol) in dichloromethane (80 mL) at 0° C.
  • the mixture was stirred at 0° C. for 1 hour, then warmed to ambient temperature for 16 hours.
  • the mixture was then diluted with EtOAc.
  • the organic layer was separated, washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound.
  • Step 3 (R)-4-tosyl-2-(trifluoromethyl)-1,4-oxazepane
  • (R)—N-(3-hydroxypropyl)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide 4.0 g, 12 mmol
  • sodium hydride 1.2 g, 29 mmol
  • the mixture was stirred 5 minutes, then treated with 1-(p-toluenesulfonyl)imidazole (2.6 g, 12 mmol) at 0° C.
  • Step 4 (R)-2-(trifluoromethyl)-1,4-oxazepane hydrobromide To a mixture of (R)-4-tosyl-2-(trifluoromethyl)-1,4-oxazepane (3.0 g, 9.3 mmol) and phenol (1.6 mL, 19 mmol) at room temperature was added HBr in AcOH (1.7 mL, 9.3 mmol). The mixture was heated to 80° C. for 6 hours. Then the mixture was cooled to ambient temperature, concentrated under reduced pressure and azeotroped with toluene. The resulting residue was tritiated with Et 2 O, collected by filtration, washed with Et 2 O and dried under reduced pressure to give the title compound.
  • Step 1 (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol
  • (R)-(+)-3,3,3-trifluoro-1,2-epoxy propane 5.5 g, 49 mmol
  • benzylamine 5.1 mL, 47 mmol
  • the reaction mixture was stirred at ambient temperature for 18 hours. Then the mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound.
  • Step 2 N-benzyl-2-bromo-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide
  • TEA 2.5 mL, 18 mmol
  • 2-bromopropionyl chloride 1.5 mL, 15 mmol
  • Step 3 (6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one
  • N-benzyl-2-bromo-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide 4.0 g, 11 mmol
  • THF 45 mL
  • NaH 0.68 g, 17 mmol
  • the mixture was warmed to ambient temperature and stirred for 3 hours.
  • the mixture was diluted with 1 ⁇ 2 saturated brine and extracted with DCM.
  • the combined organic layers were filtered through a pad of CeliteTM, washing with dichloromethane, and concentrated to give a residue that was purified by silica gel chromatography (0-50% EtOAc/hexanes) to give the title compound.
  • Step 4 (2S,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine
  • 6R -6-(trifluoromethyl)morpholin-3-one
  • LAH 11 mL, 22 mmol
  • the reaction mixture was heated to reflux for 1 hour, then cooled to rt.
  • the mixture was then diluted with ether, cooled to 0° C. and slowly treated with water (0.9 mL), followed by 15% aqueous sodium hydroxide (0.9 mL), and then water (2.7 mL).
  • Step 5 (2S,6R)-2-methyl-6-(trifluoromethyl)morpholine hydrochloride To a stirred solution of (2S,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine (0.30 g, 1.2 mmol) in DCE (1.2 mL) was added ACE-Cl (0.13 mL, 1.2 mmol). The mixture was heated to reflux for 16 hours, then cooled to rt and concentrated under reduced pressure to give a residue that was dissolved in MeOH (1.2 mL). The resulting mixture was heated to reflux for 4 hours. Then the mixture was cooled to ambient temperature and concentrated to give a residue that was triturated with Et 2 O:hexanes ( ⁇ 1:3) to give a solid. The solid was filtered, collected and dried under reduced pressure to give the title compound.
  • Step 1 N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)butanamide
  • 3-(benzylamino)-1,1,1-trifluoropropan-2-ol 1.2 g, 5.2 mmol
  • TEA 2.2 mL, 16 mmol
  • 2-bromobutanoyl chloride 1.0 g, 5.4 mmol
  • the mixture was stirred at 0° C. for 5 min then warmed to 15° C. for 1 hour.
  • the mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (18-25% ethyl acetate/petroleum ether) to give the title compound.
  • Step 2 4-benzyl-2-ethyl-6-(trifluoromethyl)morpholin-3-one To a stirred suspension of NaH (0.17 g, 4.2 mmol) in THF (10 mL) at 0° C. was added a solution of N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)butanamide (1.4 g, 3.8 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. and treated with MeOH (0.5 mL) until no more gas evolved. The mixture was concentrated under reduced pressure to a residue that was dissolved in water and extracted with EtOAc. The organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound.
  • Step 3 (2R,6S and 2S,6R)-4-benzyl-2-ethyl-6-(trifluoromethyl)morpholine
  • BH 3 .THF 21 mL, 21 mmol
  • MeOH MeOH
  • Step 4 (2R,6S and 2S,6R)-2-ethyl-6-(trifluoromethyl)morpholine hydrochloride
  • 2R,6S and 2S,6R -4-benzyl-2-ethyl-6-(trifluoromethyl)morpholine (0.40 g, 1.5 mmol) in THF (10 mL) under an atmosphere of nitrogen was added Pd/C (0.078 g, 0.073 mmol).
  • the mixture was degassed and backfilled with hydrogen (three times). Then the mixture was stirred under hydrogen (50 psi) at 20° C. for 12 hours.
  • the reaaction mixture was filtered, and the filtrate was treated with HCl/EtOAc and concentrated under reduced pressure to give the title compound.
  • Step 1 3-(benzyl(2-methylallyl)amino)-1,1,1-trifluoropropan-2-ol
  • K 2 CO 3 2.8 g, 20 mmol
  • 3-bromo-2-methylprop-1-ene 1.8 g, 13 mmol
  • the filtrate was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (5% ethyl acetate/petroleum ether) to give the title compound.
  • Step 2 4-benzyl-2,2-dimethyl-6-(trifluoromethyl)morpholine
  • THF 5 mL
  • water 5 mL
  • 3-(benzyl(2-methylallyl)amino)-1,1,1-trifluoropropan-2-ol 0.42 g, 1.5 mmol
  • the reaction mixture was stirred at 15° C. for 3 hours.
  • NaOH 1.2 mL, 3.1 mmol, 2.5 M in water
  • NaBH 4 67 mg, 1.8 mmol
  • the reaction mixture was stirred at 15° C. for 16 h, then extracted with EtOAc.
  • the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (3% ethyl acetate/petroleum ether) to give the title compound.
  • Step 3 2,2-dimethyl-6-(trifluoromethyl)morpholine hydrochloride To a solution of 4-benzyl-2,2-dimethyl-6-(trifluoromethyl)morpholine (0.25 g, 0.92 mmol) in THF (5 mL) under an atmosphere of nitrogen was added Pd/C (49 mg). The mixture was degassed and backfilled with hydrogen (three times). The reaction mixture was stirred under hydrogen (55 psi) at 15° C. for 12 hours, then filtered. The filtrate was treated with HCl/EtOAc (1 mL), and then concentrated under reduced pressure to give the title compound.
  • Step 1 3-bromo-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)pyridine
  • 3-bromo-2-chloro-5-(trifluoromethyl)pyridine 48 g, 180 mmol
  • 4,4-difluoropiperidine hydrochloride 36 g, 230 mmol
  • triethylamine 47 g, 460 mmol
  • the mixture was heated to 100° C. for 1 h, then cooled to rt and diluted in EtOAc.
  • the organic layer was washed with water, citric acid, then brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound.
  • Step 2 2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinonitrile
  • allylpalladium(II) chloride 1.3 g, 3.5 mmol
  • Xantphos 4.0 g, 7.0 mmol
  • potassium ferrocyanide 20 g, 46 mmol
  • Step 3 2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide
  • CU(OTf) 2 N,N-diethylhydroxylamine and trifluoromethanesulfonic acid.
  • the mixture was heated to 50° C. for 2 h, then quenched into water and extracted with DCM.
  • the organic layers were washed with citric acid then brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue that was slurried in 1:1 Et 2 O and petroleum ether and filtered to give the title compound.
  • Step 1 tert-butyl tert-butyl((4-(2-chloro-5-(trifluoromethyl)nicotinamido)pyridin-2-ylsulfonyl)carbamate
  • 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (0.81 g, 3.6 mmol)
  • tert-butyl (4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate 1.2 g, 3.6 mmol
  • POCl 3 (0.37 mL, 3.9 mmol
  • Step 2 2-chloro-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide
  • tert-butyl tert-butyl((4-(2-chloro-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate 1.7 g, 3.1 mmol
  • DCM 25 mL
  • TFA 6.3 mL
  • Step 1 Methyl 2-(4-oxopiperidin-1-yl)-5-(trifluoromethyl)nicotinate
  • Step 2 Methyl 2-(4,4-dichloropiperidin-1-yl)-5-(trifluoromethyl)nicotinate Tungsten(VI) chloride (1.2 g, 2.8 mmol) was added to a solution of methyl 2-(4-oxopiperidin-1-yl)-5-(trifluoromethyl)nicotinate (0.29 g, 0.95 mmol) in DCM (19 mL). The mixture was heated at 40° C. for 10 minutes, then diluted with DCM. The organic layer was separated, washed with saturated aqueous NaHCO 3 solution, dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound.
  • Step 3 2-(4,4-Dichloropiperidin-1-yl)-5-(trifluoromethyl)nicotinic acid
  • MeOH 3.9 mL
  • 1M NaOH 1.6 mL, 1.6 mmol
  • the mixture was heated at 100° C. for 5 minutes under microwave irradiation.
  • the mixture was quenched with hydrochloric acid (1M) and extracted with ethyl acetate.
  • the organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound.
  • Step 1 5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide
  • 2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide 1.3 g, 5.1 mmol
  • 1-bromopyrrolidine-2,5-dione 1.1 g, 6.1 mmol
  • the mixture was stirred at 11° C. for 2 hours, then diluted with water and extracted with EtOAc.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue which was purified by silica gel chromatography (0-22% EtOAc/petroleum ether) to give the title compound.
  • Step 2 N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide
  • 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide 150 mg, 0.45 mmol
  • Xantphos-Pd-G2 33 mg, 0.037 mmol
  • Cs 2 CO 3 365 mg, 1.1 mmol
  • Step 1 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinonitrile
  • K 2 CO 3 (0.11 g, 0.80 mmol
  • 4,4-difluoropiperidine hydrochloride 46 mg, 0.29 mmol
  • Step 2 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide
  • DMSO dimethyl sulfoxide
  • K 2 CO 3 a mixture of 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinonitrile (0.42 g, 1.6 mmol) in DMSO (4 mL)
  • K 2 CO 3 (0.65 g, 4.7 mmol) under nitrogen.
  • the mixture was stirred at 0° C. for 1 h, then hydrogen peroxide (0.53 g, 7.8 mmol) was added.
  • the mixture was stirred at 15° C. for 16 h, then dissolved in water and extracted with EtOAc.
  • Step 1 methyl 2,6-dichloronicotinate To a solution of 2,6-dichloronicotinic acid (5.0 g, 26 mmol) in DCM (50 mL) and MeOH (50 mL) was added (diazomethyl)trimethyl silane (39 mL, 78 mmol). The mixture was stirred at 25° C. for 13 h, then diluted with water and extracted with DCM. The organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue that was purified by silica gel chromatography (0-6% EtOAc/petroleum ether) to give the title compound.
  • Step 2 methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate
  • THF THF
  • DMF DMF
  • N-ethyl-N-isopropylpropan-2-amine 2.3 g, 17 mmol
  • 4,4-difluoroazepane hydrochloride 1.5 g, 8.7 mmol
  • the mixture was stirred at 70° C. for 11 h, then diluted with water and extracted with EtOAc.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue that was purified by silica gel chromatography (0-15% EtOAc/petroleum ether) to give the title compound.
  • Step 1 methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate
  • a mixture of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (0.30 g, 0.98 mmol), Pd(dppf)Cl 2 (72 mg, 0.098 mmol), potassium cyclopropyltrifluoroborate (0.36 g, 2.5 mmol) and K 2 CO 3 (0.41 g, 2.9 mmol) in dioxane (5 mL) and water (1 mL) was degassed and backfilled with nitrogen three times. The mixture was heated to 100° C. for 12 h. Then the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (PE:EtOAc 5:1) to give the title compound.
  • Step 2 methyl 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate
  • DMF 2.5 mL
  • NCS 0.111 g, 0.84 mmol
  • the mixture was stirred at 20° C. for 1 h, then heated to 30° C. for 12 h. The mixture was quenched with water and extracted with EtOAc.
  • Step 3 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid
  • Step 4 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide
  • oxalyl dichloride 0.13 g, 1.0 mmol
  • Step 1 methyl 2,5-dichloro-6-cyclobutylnicotinate To a mixture of sulfuric acid (0.78 mL, 15 mmol) and cyclobutanecarboxylic acid (2.8 mL, 29 mmol) in water (10 mL) was added methyl 2,5-dichloronicotinate (3.0 g, 15 mmol) followed by (nitrooxy)silver (0.74 g, 4.4 mmol). Then a solution of (NH 4 ) 2 S 2 O 8 (6.6 g, 29 mmol) in water (10 mL) was added. The reaction mixture was stirred at 20° C.
  • Step 2 2,5-dichloro-6-cyclobutylnicotinic acid
  • MeOH MeOH
  • water 3 mL
  • the resulting residue dissolved in water, acidified with 1N HCl to pH ⁇ 3, and extracted with EtOAc.
  • the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound.
  • Step 3 tert-butyl tert-butyl((4-(2,5-dichloro-6-cyclobutylnicotinamido)pyridin-2-yl)sulfonyl)-carbamate
  • a mixture of 2,5-dichloro-6-cyclobutylnicotinic acid (1.6 g crude) and tert-butyl ((4-aminopyridin-2-yl)sulfonyl)(tert-butyl)carbamate 2.1 g, 6.5 mmol
  • POCh 1.2 mL, 13 mmol
  • Step 4 2,5-dichloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide
  • a mixture of tert-butyl tert-butyl((4-(2,5-dichloro-6-cyclobutylnicotinamido)pyridin-2-yl)sulfonyl)carbamate (2.5 g crude) and TFA (3 mL) in dichloromethane (9 mL) was stirred at 20° C. for 2 h. Then the mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (petroleum ether:ethyl acetate 1:1) to give the title compound.
  • Step 1 2-chloro-6-cyclobutylnicotinonitrile
  • 2-chloronicotinonitrile 6.0 g, 43 mmol
  • cyclobutanecarboxylic acid 8.7 g, 87 mmol
  • AgNO 3 2.2 g, 13 mmol
  • (NH 4 ) 2 S 2 O 8 20 g, 87 mmol
  • Step 3 N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-6-cyclobutylnicotinamide
  • 2-chloro-6-cyclobutylnicotinamide (0.40 g, 1.9 mmol) in dioxane (20 mL) was added Cs 2 CO 3 (1.9 g, 5.7 mmol), 4-bromo-N,N-bis(2,4-dimethoxy-benzyl)pyridine-2-sulfonamide (1.1 g, 2.1 mmol) and XantPhos Pd G2 (0.17 g, 0.19 mmol).
  • Step 4 2-chloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide
  • N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-6-cyclobutylnicotinamide (0.67 g, 1.0 mmol) in dichloromethane (5 mL) was added TFA (5 mL). The mixture was stirred at 20° C. for 2 h. Then the mixture was concentrated under reduce pressure to give the title compound.
  • Step 1 methyl 2-chloro-6-(trifluoromethyl)nicotinate To a solution of 2-chloro-6-(trifluoromethyl)nicotinic acid (0.50 g, 2.2 mmol) in DCM (10 mL) and MeOH (1.1 mL) at 25° C. under an atmosphere of nitrogen was added dropwise (trimethylsilyl)diazomethane (1.8 mL, 3.6 mmol; 2 M in diethylether). The mixture was stirred at 25° C. for 1 h. Then the mixture was quenched with AcOH (76 ⁇ l, 1.3 mmol), and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc.
  • Step 2 methyl 2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate
  • methyl 2-chloro-6-(trifluoromethyl)nicotinate (0.28 g, 1.2 mmol) in N-methyl-2-pyrrolidinone (12 mL)
  • 4,4-difluoropiperidine (0.15 mL, 1.3 mmol)
  • K 2 CO 3 (0.32 g, 2.3 mmol
  • Step 3 methyl 5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate
  • acetonitrile 1.5 mL
  • NBS 66 mg, 0.37 mmol
  • Step 1 tert-butyl tert-butyl((4-(2-chloro-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate
  • 2-chloro-6-(trifluoromethyl)nicotinic acid 1.0 g, 4.4 mmol
  • tert-butyl (4-aminopyridin-2-yl)sulfonyl (tert-butyl)carbamate 1.5 g, 4.4 mmol
  • POCl 3 1.2 mL, 13 mmol

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