Pyridone compounds as TRPA1 inhibitors

Abstract

Compounds of formula (I) or pharma- ceutically acceptable salts thereof are described, wherein the substituents are as defined herein. Pharmaceutical compositions comprising same and methods of using same are also described for the treatment of medical conditions including pain, skin disorders, respiratory disorders, fibrotic disorders, inner ear disorders, fever or other disorders of temperature regulation. [Formula 1] TIFF2025515096000154.tif2672

Description

[Technical field]

[0001] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by any person of the patent document or patent disclosure as it appears in the U.S. Patent and Trademark Office patent files or records, but otherwise reserves any and all copyright rights whatsoever.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 338,181, filed May 4, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] Incorporation by Reference All documents cited herein are incorporated by reference in their entirety.

[0004] The present invention relates generally to the field of pharmacology. More specifically, the present invention relates to compounds and compositions useful as medicaments as potassium channel blockers. [Background technology]

[0005] Transient receptor potential channels (TRP channels) are a family of voltage-gated ion channels located primarily in the plasma membrane of mammalian cells. There are approximately 30 structurally related TRP channels, which are subdivided into several groups: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. Transient receptor potential ankyrin 1 (TRPA1), a member of the TRPA subfamily, is a cation-selective, calcium-permeable ion channel (Montell, C., 2005, Sci. STKE, 272:re3).

[0006] TRPA channels are structurally characterized by the presence of multiple N-terminal ankyrin repeats that form a large intracellular domain (Montell, C., 2005, Sci. STKE, 272:re3). Human TRPA1 has approximately 14 N-terminal ankyrin repeats. The TRPA1 protein is a homotetramer. Each subunit has six transmembrane helices that form a central pore that is surrounded by a voltage-sensor-like domain. The TRPA1 protein also contains a C-terminal extension (Terrett, JA et al., 2021, J. Med. Chem. 64, 7, 3843-3869).

[0007] TRPA1 is highly expressed in the plasma membrane of primary sensory neurons, where it functions as a polymodal sensor of exogenous and endogenous stimuli. These sensory neurons are located in the dorsal root and supraganglia and connect with the skin, lung, small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder, and several immune cells, including neutrophils, eosinophils, mast cells, dendritic cells, macrophages, and T and B lymphocytes (Naert, R. et al., 2021, Int. J. Mol. Sci. 22, 11460, 1-17). TRPA1 expression is most prevalent in small diameter sensory neurons, where it colocalizes with markers of peptidergic nociceptors such as TRPV1, calcitonin gene-related peptide (CGRP), and substance P (Kaneko, Y. et al., 2013, Curr. Top. Med. Chem. 13, 3, 241-243). TRPA1 is thought to function primarily as a sensor of environmental stimuli, giving rise to somatosensory modalities such as pain, cold, and itch.

[0008] TRPA1 is activated by a variety of endogenous and exogenous stimuli related to pain and inflammation. Specifically, TRPA1 can be activated by external irritants such as allyl isothiocyanate (AITC) and allicin. TRPA1 can also be activated by cinnamaldehyde, which functions as an agonist that activates the channel by covalent modification of cysteine ​​residues in the N-terminal ankyrin repeats (Terrett, JA et al., 2021, J. Med. Chem. 64, 7, 3843-3869). TRPA1 can also be activated by noxious stimuli including cold temperature and irritating natural compounds such as mustard, cinnamon, and garlic.

[0009] TRPA1 knockout (KO) mouse models suggest that this ion channel is involved in pain signaling. TRPA1 activity plays a role in several diseases in patients. Gain-of-function TRPA1 mutations in humans are associated with familial episodic pain syndrome (FEPS) (Kremeyer, B. et al., 2010, Neuron 66, 5, 671-680). The discovery of a human genetic association between TRPA1 and FEPS suggests that TRPA1 plays an important role in human pain. Patients with a single gain-of-function mutation in TRPA1 are known to experience debilitating upper body pain triggered by fasting, cold, and fatigue. Several anesthetic agents, including isoflurane, are known to be TRPA1 agonists (Matta, JA et al., 2008, PNAS 105, 25, 8784-8789), providing a rationale for TRPA1 inhibitors for postoperative pain relief.

[0010] TRPA1 activation has been implicated in the development of chronic respiratory diseases including asthma and cough (Caceres, AI et al., 2009, Proc. Natl. Acad. Sci. 106, 22, 9099-104; Reese, RM et al., 2020, Scientific Reports 10, 979, 1-11). Airway hyperresponsiveness, bronchoconstriction, and airway inflammation in asthma appear to be caused by the activity of TRPA1 expressed in airway smooth muscle cells, and sensory nervous system and clinical symptoms can be alleviated by TRPA1 antagonists (Balestrini, A. et al., 2021, J. Exp. Med. 218, 4, e20201637, 1-23; van den Berg, MPM et al., 2021, Respir. Res. 22, 48, 1-15; Terrett, JA et al., 2021, J. Med. Chem. 64, 7, 3843-3869). Coughing can be associated with asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Cough can also be post-viral, or chronic episodic, and in susceptible patients (Song, W.-J. and Chang, Y.-S., 2015, Clin. Transl. Allergy 5, 24, 1-10; Grace, MS and Belvisi, MG, 2011, Pulm. Pharmacol. Ther. 24, 3, 286-288), although a protective effect of TRPA in IPF has also been reported (Virk, HS et al., 2021, Br J Pharmacol. 178, 2948-2962).TRPA1 antagonists can inhibit calcium signaling, release of inflammatory mediators, and downregulation of antioxidant gene expression caused by cough inducers such as cigarette smoke extract (CSE) oxidative stress (Lin, Y.-J. et al., 2015, J. Appl. Physiol. 118, 273-281; ​​Wang, Z. et al., 2019, Front. Pharmacol. 10, 1253, 1-11).

[0011] TRPA1 is involved in dermatitis and itch. TRPA1 antagonists are effective in atopic dermatitis (Wilson, SR et al., 2013, J. Neurosci. 33, 22, 9283-9294), contact dermatitis (Liu, B. et al., 2013, FASEB J. 27, 9, 3549-3563), itch associated with psoriasis (Wilson, SR et al., 2013 J. Neurosci. 33, 22, 9283-9294), and IL-31-dependent itch (Cevikbas, F. et al., 2014, J. Allergy Clin. Immunol. 133, 2, 448-460). Direct clinical support has also been reported, with specific inhibition of TRPA1 alleviating AITC-induced itch (Balestrini, A. et al., 2021, J. Exp. Med. 218, 4, e20201637, 1-23). ​​Furthermore, TRPAl antagonists are effective in behavioral models of migraine-related allodynia (Edelmayer, RM et al., 2012, Pain 2012, 153, 9, 1949-1958).

[0012] TRPA1 expression is increased by inflammatory mediators and subsequent nerve injury, suggesting a role for TRPA1 activity in inflammation. For example, TRPA1 is required for the hypersensitivity observed in inflammatory pain models (Bautista, DM et al. 2013, Annu. Rev. Physiol. 75, 181-200; Julius, D. 2013, Annu. Rev. Cell Dev. Biol. 29, 355-384). Disease models of diabetes indicate that TRPA1 plays a role in the inflammatory pain associated with this metabolic disorder. TRPA1 may also have a role in the pathogenesis of cancer and other inflammatory diseases. Studies further suggest that TRPA1 is involved in migraine pain as a result of neurogenic inflammation (Edelmayer, RM et al., 2012, Pain 153, 9, 1949-1958). This may be due to activation of trigeminal TG neurons by intranasal application of TRPA1 activators.

[0013] TRPA1 also plays a role in arthritis and osteoarthritic pain (Horvath, A. et al., 2016, Arthritis Res. Ther. 18, 6, 1-14). Activation of TRPA1 has been shown to induce an inflammatory response in osteoarthritic chondrocytes (Nummenmaa, E. et al., 2016, Arthritis Res. Ther. 18, 185). This is supported by the observation that TRPA1 inhibition and genetic deletion reduces knee swelling, histopathological destruction, and inflammatory mediators in osteoarthritic mouse chondrocytes and mouse cartilage (Nummenmaa, E. et al., 2016, Arthritis Res. Ther. 18, 185, 1-11; Horvath, A. et al., 2016, Arthritis Res. Ther. 18, 6, 1-14). Additionally, TRPA1 KO mice have been shown to improve weight bearing in osteoarthritic limbs in a knee swelling model (Horvath, A. et al., 2016, Arthritis Res. Ther. 18, 6).

[0014] TRPA1 also has a role in colitis and visceral hypersensitivity, as well as in mediating gastrointestinal (GI) hypersensitivity to mechanical stimuli. TRPA1 expression is elevated in the inflamed mouse intestine (Cseko, K. et al., 2019, Pharmaceuticals 12, 48, 1-19; Izzo, A. et al., 2012, Br. J. Pharmacol. 166, 4, 1444-1460). Furthermore, dinitrobenzene sulfonic acid (DNBS)-induced colitis is attenuated after pharmacological blockade or genetic inactivation of TRPA1 (Engel, MA et al., 2011, Gastroenterology 141, 4, 1346-1358), suggesting that TRPA1 may be a target in inflammatory conditions in Gl, such as inflammatory bowel disease, Crohn's disease, and ulcerative colitis (Cseko, K. et al., 2019, Pharmaceuticals 12, 48, 1-19; Blackshaw, LA et al., 2013, The Open Pain Journal 6, (Suppl 1: M4) 23-30).

[0015] TRPA1 is highly expressed in sensory neurons innervating the bladder, suggesting that TRPA1 is a promising drug target for bladder disorders such as bladder instability, urinary incontinence, and cystitis (Streng, T. et al., 2008, Eur. Urol. 53, 391-399). TRPA1 is upregulated in the bladder mucosa of patients with bladder outlet obstruction (Du, S. et al., 2008, Urology 72, 2, 450-455).

[0016] Thus, there remains a need for the development of novel TRPA1 inhibitors as pharmaceutical agents for the treatment of several conditions, disorders, and diseases. Summary of the Invention

[0017] In one embodiment, a compound of formula I

[0018] [ka] Compounds useful as TRPA1 inhibitors are described having the structure: wherein the various substituents are defined herein. The compounds of formula I described herein block TRPA1 and can be used to treat various conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have several clinical applications, including as pharmacologic active agents and methods for treating pain, skin disorders, respiratory disorders, fibrotic disorders, inner ear disorders, heat or other disorders of thermoregulation, urinary disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, and cardiovascular disorders, or combinations thereof.

[0019] In one embodiment, compounds of formula I, or a pharma- ceutically acceptable salt or tautomer thereof, are described:

[0020] [ka] (In the formula, Y is N or CR 2 and; Z is N or CR 3 and; R 1 is H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, saturated heterocycle, CN, OR a , S.R. a , or N.R. a R b and; R 2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cycloalkyl halide, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C 1~4 Alkyl-CN, ORa , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b and; R 3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cycloalkyl halide, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C 1~4 Alkyl-CN, OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b, -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b and; R 4 is H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, aryl, heteroaryl, saturated heterocycle, CN, OR a , S.R. a , -C1-4 alkyl-ORa, or NR a R b and;

[0021] [ka] is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a is an aryl or heteroaryl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: L 1 is -(CR 5 R 6 ) n - and; R 5 each occurrence is independently H, D, alkyl, halogen, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , or -C 1~4 Alkyl-OR aand; R 6 each occurrence is independently H, D, alkyl, halogen, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , or -C 1~4 Alkyl-OR a and; n is 2 or 3; L 2 -CR 7 R 8 - and; R 7 is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C 1~4 Alkyl-OR a and; R 8 is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C 1~4 Alkyl-OR a and; R a and R b Each occurrence of is independently H, alkyl, (C=O)R x , (C=O)N(R x ) 2 , S.O. 2 R x , N.R. x (C=O)NR x2 , cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle containing 1 to 3 heteroatoms, aryl, or heteroaryl, each selected from the group consisting of N, O, and S; or alternatively, R a and R b together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or saturated heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; R, if applicable 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R a , or R b In the above, alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 1~2 OR x , N(R x ) 2 , -(CH 2 ) 1~2 N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo; R x each occurrence of R is independently H, D, alkyl, or an optionally substituted heterocycle; or alternatively, two R x groups, together with the nitrogen atom to which they are attached, optionally substituted with alkyl, form a heterocycle containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; However, when Z is N, R 4 is not OH).

[0022] In any one of the embodiments described herein, Y is CR 2 It is.

[0023] In any one of the embodiments described herein, Y is N.

[0024] In any one of the embodiments described herein, Z is CR 3 It is.

[0025] In any one of the embodiments described herein, Z is N.

[0026] In any one of the embodiments described herein, n is 2.

[0027] In any one of the embodiments described herein, R 5 Each occurrence of is independently cycloalkyl, halogenated cycloalkyl, -C 1~4 Alkyl-OR a , or CN.

[0028] In any one of the embodiments described herein, R 5 Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl.

[0029] In any one of the embodiments described herein, R 5 Each occurrence of is independently H, D, CH 3 , C.H. 2 CH 3 , OH, F, Cl, or Br.

[0030] In any one of the embodiments described herein, R 6 Each occurrence of is independently cycloalkyl, halogenated cycloalkyl, -C 1~4 Alkyl-OR a , or CN.

[0031] In any one of the embodiments described herein, R 6 Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl.

[0032] In any one of the embodiments described herein, R 6 Each occurrence of is independently H, D, CH 3 , C.H. 2CH 3 , OH, F, Cl, or Br.

[0033] In any one of the embodiments described herein, L 1 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -CH 2 -C(CH 3 ) 2 -, -CH(OH)-CH 2 -, -CH 2 -CH(OH)-,

[0034] [ka] is selected from the group consisting of:

[0035] In any one of the embodiments described herein, L 1 -CH 2 -CH 2 -,

[0036] [ka] is selected from the group consisting of:

[0037] In any one of the embodiments described herein, the compound has formula Ia, Ib, or Ic:

[0038] [ka] (In the formula, R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl. It has the structure:

[0039] In any one of the embodiments described herein, R 7 is cycloalkyl, halogenated cycloalkyl, CN, or -C 1~4 Alkyl-OR a It is.

[0040] In any one of the embodiments described herein, R 7 is H, D, alkyl, or fluorinated alkyl.

[0041] In any one of the embodiments described herein, R 7 are H, D, and CH 3 , or C.H. 2 CH 3 It is.

[0042] In any one of the embodiments described herein, R 8 is cycloalkyl, halogenated cycloalkyl, CN, or -C 1~4 Alkyl-OR a It is.

[0043] In any one of the embodiments described herein, R 8 is H, D, alkyl, or fluorinated alkyl.

[0044] In any one of the embodiments described herein, R 8 , H, CH 3 , or C.H. 2 CH 3 It is.

[0045] In any one of the embodiments described herein, the structural moiety L 2 -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 - and -CH(CH 2 CH 3 ).

[0046] In any one of the embodiments described herein, L 2 -CH 2 -It is.

[0047] In any one of the embodiments described herein,

[0048] [ka] is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , and -C 1~4 Alkyl-OR a and n is 1 to 5, optionally substituted with 1 to 5 substituents each independently selected from the group consisting of:

[0049] In any one of the embodiments described herein, the compound has formula IIa, IIb, or IIc:

[0050] [ka] (In the formula, R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 5bEach occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 11 each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 12 each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 13 each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 14each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 15 each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a is) It has the structure:

[0051] In any one of the embodiments described herein, R 11 , R 12 , R 14 , and R 15 is H;R 13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF 3 , OR a , S.R. a , N.R. a R b , or -C 1~4 Alkyl-OR a It is.

[0052] In any one of the embodiments described herein, R 13 is CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.H. 2 OCH 3 , C.F.3 , CN, C≡CH, or

[0053] [ka] It is.

[0054] In any one of the embodiments described herein,

[0055] [ka] teeth,

[0056] [ka] is selected from the group consisting of:

[0057] In any one of the embodiments described herein,

[0058] [ka] is H, halogen, alkyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , and -C 1~4 Alkyl-OR a and is a 5- or 6-membered heteroaryl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0059] In any one of the embodiments described herein,

[0060] [ka] teeth,

[0061] [ka] is selected from the group consisting of:

[0062] In any one of the embodiments described herein, R 1 is a cycloalkyl, a halogenated alkyl, or a halogenated cycloalkyl.

[0063] In any one of the embodiments described herein, R 1 is H, D, halogen, alkyl, CN, CF 3 , OR a , S.R. a , or N.R. a R b It is.

[0064] In any one of the embodiments described herein, R 1 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , and

[0065] [ka] is selected from the group consisting of:

[0066] In any one of the embodiments described herein, R 2 H, D, halogen, CN, CF 3 , OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-CN, -C1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b It is.

[0067] In any one of the embodiments described herein, R 2 is halogen, alkyl, CN, OR, if valence permits. x , -(CH 2 ) 1~2 OR x , N(R x ) 2 , -(CH 2 ) 1~2 N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo.

[0068] In any one of the embodiments described herein, R 2 is halogen, CN, OR, if valence permits. x , -(CH 2 ) 1~2 OR x , N(R x ) 2 , -(CH 2 ) 1~2 N(Rx ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo.

[0069] In any one of the embodiments described herein, R 2 is cycloalkyl, aryl, or alkylaryl, alkylheteroaryl.

[0070] In any one of the embodiments described herein, R 2 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, I, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , CH=CH 2 ,

[0071] [ka] is selected from the group consisting of:

[0072] In any one of the embodiments described herein, R 3 is H, D, halogen, alkyl, alkyl halide, heteroaryl, or CN.

[0073] In any one of the embodiments described herein, R 3 OR a , S.R. a , N.R. a R b , (C=O)NR a R b , -C 1~4 Alkyl-CN, -C1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , or -C 1~4 Alkyl-CONR a R b It is.

[0074] In any one of the embodiments described herein, R 3 is an alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, alkylaryl, alkylheteroaryl, NR b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b It is.

[0075] In any one of the embodiments described herein, R 3 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , C.N., C.H. 2 CN, CH=CH 2 , N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 ,

[0076] [ka] is selected from the group consisting of:

[0077] In any one of the embodiments described herein, R 4 is a cycloalkyl, a halogenated alkyl, or a halogenated cycloalkyl.

[0078] In any one of the embodiments described herein, R 4 is H, D, halogen, alkyl, CN, CF 3 , OR a , S.R. a , -C 1~4 Alkyl-OR a , or N.R. a R b It is.

[0079] In any one of the embodiments described herein, R 4 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , C.H. 2 OH,

[0080] [ka] is selected from the group consisting of:

[0081] In any one of the embodiments described herein, R a or R b At least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0082] In any one of the embodiments described herein, R a or R b At least one occurrence of may be independently selected from H, D, Me, Et, Pr, CH 2 CH 2 OH, phenyl, or

[0083] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C=O)C 1~4 Optionally substituted with alkyl.

[0084] In any one of the embodiments described herein, R a or R b At least one occurrence of is H, Me, phenyl,

[0085] [ka] It is.

[0086] In any one of the embodiments described herein, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0087] In any one of the embodiments described herein, R x Each occurrence of is independently H, alkyl, or a heterocycle optionally substituted with alkyl, halogen, or OH.

[0088] In any one of the embodiments described herein, R x is independently H or alkyl.

[0089] In any one of the embodiments described herein, R x is independently H or Me.

[0090] In any one of the embodiments described herein, the compound is selected from the group consisting of the compounds of Examples 2-5 and Tables 1-5.

[0091] In another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or diluent.

[0092] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the condition is selected from the group consisting of pain, a skin disorder, a respiratory disorder, a fibrotic disorder, an inner ear disorder, a heat or other disorder of temperature regulation, a urinary tract or bladder disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, and a cardiovascular disorder.

[0093] In any one of the embodiments described herein, the pain is acute pain, chronic pain, complex regional pain syndrome, inflammatory pain, neuropathic pain, post-operative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, hyperalgesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-associated neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, post stock pain, or pain associated with teeth and dental damage.

[0094] In any one of the embodiments described herein, the urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, bladder instability, or bladder outlet obstruction.

[0095] In any one of the embodiments described herein, the skin disorder is a burn, psoriasis, eczema, or pruritus.

[0096] In any one of the embodiments described herein, the skin disorder is atopic dermatitis or psoriasis-induced itch.

[0097] In any one of the embodiments described herein, the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, idiopathic pulmonary disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough.

[0098] In any one of the embodiments described herein, the ischemia is a disorder associated with CNS hypoxia or reduced blood flow to the CNS.

[0099] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis or multiple sclerosis.

[0100] In any one of the embodiments described herein, the central nervous system disorder is associated with neurodegeneration.

[0101] In any one of the embodiments described herein, the gastroenterological disorder is inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, emesis, or gastroduodenal ulcer.

[0102] In any one of the embodiments described herein, the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

[0103] In any one of the embodiments described herein, the mammalian species is human.

[0104] In yet another aspect, a method of inhibiting Transient Receptor Potential Ankyrin 1 (TRPA1) in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0105] In any one of the embodiments described herein, the mammalian species is human.

[0106] Any one of the embodiments disclosed herein may be appropriately combined with any other embodiment disclosed herein. The combination of any one of the embodiments disclosed herein with any other embodiment disclosed herein is expressly contemplated. In particular, the selection of one or more embodiments for one substituent may be appropriately combined with the selection of one or more specific embodiments for any other substituent. Such combinations may be made in any one or more embodiments of the present application described herein or in any formula described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] definition The following are definitions of terms used herein. The initial definition provided for a group or term herein applies to that group or term individually or as part of another group throughout the specification, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. It should be understood that the terminology used herein is only for the purpose of describing specific embodiments, and is not intended to be limiting.

[0108] The terms "alkyl" and "alk" refer to straight or branched chain alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. 1 ~C x ) alkyl" or "C 1~x The term "alkyl" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to x carbon atoms. For example, "(C 1 ~C 4The term "alkyl" refers to straight or branched chain alkane (hydrocarbon) groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl 3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R.d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached, R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0109] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. 2 ~C x alkenyl" or "C 2~x The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to x carbon atoms and at least one carbon-carbon double bond. For example, "C 2 ~C 6The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as, for example, ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, ( "Z" refers to pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., a single halogen substituent or CF 3 Or CCl 3 (alkyl groups with multiple halogen substituents such as phenyl, ... 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b Rc , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0110] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary groups include ethynyl. 2 ~C x alkynyl" or "C 2~xThe term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to x carbon atoms and at least one carbon-carbon triple bond. For example, "C 2 ~C 6 The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl 3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b Rc ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0111] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. 3 ~C 7 Cycloalkyl" or "C 3~7"Cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl 3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2 NRb R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-added or fused ring substituents, particularly spiro-added cycloalkyl, spiro-added cycloalkenyl, spiro-added heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, with the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves being optionally substituted.

[0112] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R aeach occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-added or fused ring substituents, particularly spiro-added cycloalkyl, spiro-added cycloalkenyl, spiro-added heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, with the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves being optionally substituted.

[0113] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. When containing more than one aromatic ring (e.g., bicyclic), the aromatic rings of the aryl group may be joined at one point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). A "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, where two adjacent aromatic rings have two carbon atoms in common. A "substituted aryl" refers to an aryl group substituted at any available point of attachment with one or more substituents, preferably one to three substituents. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl 3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , Rc , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused ring groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, with the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves being optionally substituted.

[0114] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the number of ring atoms of the heteroaryl ring and / or aryl ring is used to specify the size of the aryl or heteroaryl ring in the substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be similarly defined.

[0115] "Carbocycle" or "carbocyclic" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined hereinabove. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-added or fused ring substituents at any available point of attachment, particularly spiro-added cycloalkyl, spiro-added cycloalkenyl, spiro-added heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0116] The terms "heterocycle" and "heterocyclic" refer to fully saturated or partially or fully unsaturated containing aromatic (i.e., "heteroaryl") cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group may be independently saturated, partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, the nitrogen and sulfur heteroatoms being optionally oxidized, and the nitrogen heteroatom being optionally quaternized. (The term "heteroarylium" refers to a heteroaryl group having a quaternary nitrogen atom and thus a positive charge.) A heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl. , 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benz ...dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, benzo[b][1,4]dioxinyl, benzyl, Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0117] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl 3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e, P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R eEach occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-added or fused ring substituents at any available point of attachment, particularly spiro-added cycloalkyl, spiro-added cycloalkenyl, spiro-added heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, with the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents themselves being optionally substituted.

[0118] The term "oxo" means

[0119] [ka] It refers to a substituent, which may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring. When an oxo substituent is attached to a carbon ring atom on an aromatic group, e.g., an aryl or heteroaryl, the bonds on the aromatic ring may be rearranged to meet valence requirements. For example, a pyridine with a 2-oxo substituent is

[0120] [ka] which is its tautomeric form

[0121] [ka] Also includes.

[0122] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0123] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined herein. R and R' can be the same or different in the dialkylamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a ring structure. The resulting ring structure can be aromatic or non-aromatic. Examples of the resulting ring structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0124] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0125] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl group, or any other group disclosed herein) is substituted with one or more substituents, preferably 1 to 6 substituents, at any available point of attachment, where valence allows. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case CF 3 or CCl 3 (forming an alkyl group having the formula: ##STR00011##), cyano, nitro, oxo (i.e., ═O), CF 3 , OCF 3 , alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , N.R. b R c , N.R. b S(=O) 2 R e , N.R. b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b Rc , N.R. d S(=O) 2 NR b R c , N.R. d P(=O) 2 NR b R c , N.R. b C(=O)R a , or N.R. b P(=O) 2 R e and R a each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; b , R c , and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the foregoing exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group, or any other group disclosed herein) may or may not be substituted with one or more of the foregoing substituents.

[0126] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0127] The compounds of the present invention can form salts, which are also within the scope of the present invention. Reference to a compound of the present invention is understood to include reference to its salts, unless otherwise indicated. The term "salt" as used herein means acid salts and / or base salts formed with inorganic and / or organic acids and bases. Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a phenol or a carboxylic acid, a zwitterion ("internal salt") may be formed, which is included in the term "salt" as used herein. Although pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful, for example, in isolation or purification steps that may be used during preparation. Salts of the compounds of the present invention can be formed, for example, by reacting a compound described herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0128] Compounds of the present invention that contain a basic moiety, such as, but not limited to, an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, and the like. salts (e.g., 2-hydroxyethanesulfonate), lactate salts, maleate salts, methanesulfonate salts, naphthalenesulfonate salts (e.g., 2-naphthalenesulfonate), nicotinate salts, nitrate salts, oxalate salts, pectinates, persulfates, phenylpropionate salts (e.g., 3-phenylpropionate salt), phosphate salts, picrate salts, pivalate salts, propionate salts, salicylates, succinates, sulfate salts (such as those formed with sulfuric acid), sulfonate salts, tartrate salts, thiocyanate salts, toluenesulfonate salts such as tosylates, undecanoate salts, and the like.

[0129] The compounds of the present invention that contain an acidic moiety, such as, but not limited to, phenol or carboxylic acid, may form salts with various organic and inorganic bases.Exemplary base salts include alkali metal salts such as ammonium salt, sodium salt, lithium salt, and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and others.

[0130] The prodrug and solvate of the compound of the present invention are also contemplated herein.The term "prodrug" as used herein means a compound that, when administered to a subject, undergoes chemical conversion by metabolism or chemical process to produce the compound of the present invention or its salt and / or solvate.The solvate of the compound of the present invention includes, for example, hydrate.

[0131] The compounds of the present invention and their salts or solvates may exist in their tautomeric forms (e.g., as amides or imino ethers).All such tautomeric forms are contemplated herein as part of the present invention.As used herein, any depicted structure of a compound includes its tautomeric forms.

[0132] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomeric and diastereomeric forms, are contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having the specified activity), or may, for example, be racemic or admixed with all or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0133] The compounds of the invention, after their preparation, are preferably isolated and purified to obtain compositions containing an amount of the compound of 90% by weight or more, e.g., 95% by weight or more, 99% by weight or more ("substantially pure" compounds), which are then used or formulated as described herein. Such "substantially pure" compounds of the invention are also contemplated herein as part of the invention.

[0134] All configurational isomers of the compounds of the present invention are contemplated, in admixture or in pure or substantially pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) alkene isomers, and cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0135] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0136] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In the present specification, the general principles of organic chemistry are identified according to the principles of the present invention, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0137] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers and mixtures thereof are intended to be included in the present invention.

[0138] Isomeric mixtures containing any of a variety of isomeric ratios can be utilized according to the present invention. For example, when only two isomers are combined, mixtures containing isomeric ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomeric mixtures.

[0139] The present invention also includes isotopically labeled compounds identical to the compounds disclosed herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the invention, or enantiomers, diastereomers, tautomers, or pharma- ceutically acceptable salts or solvates thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, e.g., 3 H and 14 Those incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution assays. Tritium isotopes, i.e. 3 H(T), and carbon-14 isotopes, i.e. 14 C is particularly preferred due to its ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavier isotopes such as H(D) may be preferred in some circumstances since it may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0140] For example, if a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, a diastereomeric salt can be formed with a suitable optically active acid or base, and the diastereomers thus formed can then be resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0141] It will be understood that the compounds described herein may be substituted with any number of substituents or functional moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, and the substituents contained in the formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with a specified substituent group. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful, for example, in the treatment of proliferative disorders. As used herein, the term "stable" preferably refers to compounds that have sufficient stability to permit manufacture and maintain compound integrity for a period of time sufficient to be detected, preferably to be useful for the purposes detailed herein.

[0142] As used herein, the term "cancer" and equivalently "tumor" refers to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. Cancer can be malignant or non-malignant cancer. Cancer or tumor includes, but is not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. Cancer can be primary or metastatic. Diseases other than cancer may be associated with mutational changes in components of the Ras signaling pathway, and the compounds disclosed herein can be used to treat these non-cancer diseases. Such non-cancerous diseases include neurofibromatosis; Leopard syndrome; Noonan syndrome; Regius syndrome; Costello syndrome; cardio-facial-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arteriovenous malformation.

[0143] As used herein, "effective amount" refers to any amount necessary or sufficient to achieve or promote a desired outcome. In some cases, the effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular drug being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular drug without undue experimentation.

[0144] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, without limitation, non-human primates, laboratory animals, farm animals, race horses, domesticated animals, and non-domesticated animals.

[0145] compound Novel compounds are described as TRPA1 inhibitors.It is surprisingly found that the compounds disclosed herein exhibit TRPA1 inhibitory properties.Moreover, it is surprisingly found that the compounds disclosed herein selectively block TRPA1 and do not block hERG channel, and therefore have a desirable cardiovascular safety profile.

[0146] In one embodiment, the compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc

[0147] [ka] Compounds having the structure of, or a pharma- ceutically acceptable salt thereof, or a tautomer thereof, are described, and various substituents are defined herein. Compounds of formula I, Ia, Ib, Ic, IIa, IIb, or IIc described herein block or inhibit TRPA1 and can be used to treat various conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions comprising the compounds described herein and methods of using the compounds described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have several clinical applications, including as pharma- ceutical active agents and methods for treating pain, skin disorders, respiratory disorders, fibrotic disorders, inner ear disorders, heat or other disorders of thermoregulation, urinary disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, and cardiovascular disorders, or combinations thereof.

[0148] In one embodiment, compounds of formula I or a pharma- ceutically acceptable salt, or a tautomer thereof are described:

[0149] [ka] (In the formula, Y is N or CR 2 and; Z is N or CR 3 and; R 1 is H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, saturated heterocycle, CN, OR a , S.R. a , or N.R. a R b and; R 2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cycloalkyl halide, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C 1~4 Alkyl-CN, OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C.1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b and; R 3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cycloalkyl halide, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C 1~4 Alkyl-CN, OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b and; R 4 is H, D, halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkyl halide, cycloalkyl halide, saturated heterocycle, CN, OR a , S.R. a , -C 1~4 Alkyl-OR a , or N.R. a R b and;

[0150] [ka] is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a is an aryl or heteroaryl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: L 1 is -(CR 5 R 6 ) n - and; R 5 each occurrence is independently H, D, alkyl, halogen, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , or -C 1~4 Alkyl-OR a and; R 6 each occurrence is independently H, D, alkyl, halogen, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , or -C 1~4 Alkyl-OR a and; n is 2 or 3; L 2 -CR 7 R 8 - and; R 7 is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C 1~4 Alkyl-OR a and; R 8is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C 1~4 Alkyl-OR a and; R a and R b Each occurrence of is independently H, alkyl, (C=O)R x , (C=O)N(R x ) 2 , S.O. 2 R x , N.R. x (C=O)NR x2 , cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle containing 1 to 3 heteroatoms, aryl, or heteroaryl, each selected from the group consisting of N, O, and S; or alternatively, R a and R b together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or saturated heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; R, if applicable 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , or R b In the above, alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 1~2 OR x , N(R x ) 2 , -(CH 2 ) 1~2 N(R x ) 2 , (C=O)Rx , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo; R x each occurrence of R is independently H, D, alkyl, or an optionally substituted heterocycle; or alternatively, two R x groups, together with the nitrogen atom to which they are attached, optionally substituted with alkyl, form a heterocycle containing the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; However, when Z is N, R 4 is not OH).

[0151] In some embodiments, Y is CR 2 In some embodiments, Y is N. In some embodiments, Z is CR 3 In some embodiments, Z is N. In some embodiments, Y is CR 2 and Z is N. In some embodiments, Y is N and Z is CR 3 In some embodiments, Y is CR 2 and Z is CR 3 In some embodiments, Y is N and Z is N.

[0152] In some embodiments, n is 2. In some embodiments, n is 3.

[0153] In some embodiments, R 5 each occurrence is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , -C 1~4 Alkyl-OR a or halogen. In some embodiments, R 5Each occurrence of is independently cycloalkyl, halogenated cycloalkyl, or CN. 5 Each occurrence of is independently H, D, alkyl, halogen, OR a or fluorinated alkyl. In some embodiments, R 5 At least one occurrence of R is H or D. 5 At least one occurrence of OR a For example, OH, OMe, or OEt. In some embodiments, R 5 At least one occurrence of -C 1~4 Alkyl-OR a , e.g., C.H. 2 OH, CH 2 CH 2 OH, or CH 2 OCH 3 In some embodiments, R 5 At least one occurrence of is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 5 At least one occurrence of is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 5 At least one occurrence of is a halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R 5 At least one occurrence of is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3, CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 5 At least one occurrence of is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0154] [ka] In some embodiments, R 5 Each occurrence of is independently H, D, CH 3 , C.H. 2 CH 3 , OH, F, Cl, or Br.

[0155] In some embodiments, R 6 each occurrence is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , -C 1~4 Alkyl-OR a or halogen. In some embodiments, R 6 Each occurrence of is independently cycloalkyl, halogenated cycloalkyl, or CN. 6 Each occurrence of is independently H, D, alkyl, halogen, OR a or fluorinated alkyl. In some embodiments, R 6 At least one occurrence of R is H or D. 6 At least one occurrence of OR a For example, OH, OMe, or OEt. In some embodiments, R 6 At least one occurrence of -C 1~4 Alkyl-OR a , e.g., C.H. 2 OH, CH 2 CH2 OH, or CH 2 OCH 3 In some embodiments, R 6 At least one occurrence of is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 6 At least one occurrence of is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 6 At least one occurrence of is a halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R 6 At least one occurrence of is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 6 At least one occurrence of is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0156] [ka] In some embodiments, R 6 Each occurrence of is independently H, D, CH 3, C.H. 2 CH 3 , OH, F, Cl, or Br.

[0157] In some embodiments, L 1 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -CH 2 -C(CH 3 ) 2 -, -CH(OH)-CH 2 -, -CH 2 -CH(OH)-,

[0158] [ka] In some embodiments, the structural moiety L is selected from the group consisting of 1 -CH 2 -CH 2 -,

[0159] [ka] In some embodiments, L is selected from the group consisting of 1 -CH 2 -CH 2 -,

[0160] [ka] In some embodiments, L 1 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, and -CH 2 -C(CH 3 ) 2 In some embodiments, L1 -CH 2 -CH 2 In some embodiments, L 1 teeth,

[0161] [ka] In some embodiments, L 1 teeth,

[0162] [ka] In some embodiments, L 1 teeth,

[0163] [ka] In some embodiments, L 1 teeth,

[0164] [ka] It is.

[0165] In some embodiments, R 7 is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C 1~4 Alkyl-OR a In some embodiments, R 7 is cycloalkyl, halogenated cycloalkyl, or CN. In some embodiments, R 7 is H, D, alkyl, or fluorinated alkyl. In some embodiments, R 7 is H or D. In some embodiments, R 7 At least one occurrence of -C 1~4 Alkyl-OR a , e.g., C.H. 2 OH, CH 2 CH 2OH, or CH 2 OCH 3 In some embodiments, R 7 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 7 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 7 At least one occurrence of is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 7 At least one occurrence of is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0166] [ka] In some embodiments, R 7 , H, CH 3 , or C.H. 2 CH 3 It is.

[0167] In some embodiments, R 8is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C 1~4 Alkyl-OR a In some embodiments, R 8 is cycloalkyl, halogenated cycloalkyl, or CN. In some embodiments, R 8 is H, D, alkyl, or fluorinated alkyl. In some embodiments, R 8 is H or D. In some embodiments, R 8 At least one occurrence of -C 1~4 Alkyl-OR a , e.g., C.H. 2 OH, CH 2 CH 2 OH, or CH 2 OCH 3 In some embodiments, R 8 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 8 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 8 At least one occurrence of is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH3 In some embodiments, R 8 At least one occurrence of is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0168] [ka] In some embodiments, R 8 , H, CH 3 , or C.H. 2 CH 3 It is.

[0169] In some embodiments, L 2 -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 - and -CH(CH 2 CH 3 In some embodiments, the structural moiety L 2 -CH 2 -It is.

[0170] In some embodiments,

[0171] [ka] is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , and -C 1~4 Alkyl-OR a In some embodiments, the phenyl is optionally substituted with 1 to 5 substituents each independently selected from the group consisting of:

[0172] [ka] is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , and -C 1~4 Alkyl-OR a In some embodiments, the phenyl group is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of:

[0173] [ka] is CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.H. 2 OCH 3 , C.F. 3 , CN, C≡CH, and

[0174] [ka] In some embodiments, the phenyl group is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of:

[0175] [ka] is CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.H. 2 OCH 3 , C.F. 3 , CN, C≡CH, and

[0176] [ka] In some embodiments, the phenyl is substituted with at least one substituent selected from the group consisting of:

[0177] [ka] is phenyl substituted with at least one halogen. In some embodiments,

[0178] [ka] is phenyl substituted with one chlorine.

[0179] In some embodiments,

[0180] [ka] teeth,

[0181] [ka] is selected from the group consisting of:

[0182] In some embodiments,

[0183] [ka] is H, halogen, alkyl, cycloalkyl, cycloalkyl halide, alkyl halide, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , or -C 1~4 Alkyl-OR a In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of:

[0184] [ka] is an optionally substituted 5- or 6-membered heteroaryl containing 1-3 heteroatoms each selected from the group consisting of O and S. In a further embodiment,

[0185] [ka] is an optionally substituted thiophene or furan.

[0186] In some embodiments,

[0187] [ka] is a 5-membered heteroaryl, which is optionally substituted, where valences permit, by alkyl, halogen, OH, or oxo. Non-limiting examples of 5-membered heteroaryls include:

[0188] [ka] In some embodiments,

[0189] [ka] teeth,

[0190] [ka] is selected from the group consisting of:

[0191] In some embodiments,

[0192] [ka] is an optionally substituted 5- or 6-membered heteroaryl or phenyl. In some embodiments,

[0193] [ka] is an optionally substituted 5-membered heteroaryl.

[0194] [ka] teeth,

[0195] [ka] In some particular embodiments,

[0196] [ka] teeth,

[0197] [ka] is selected from the group consisting of:

[0198] In some embodiments,

[0199] [ka] is an optionally substituted 7-11 membered bicyclic or 8-16 membered tricyclic aryl or heteroaryl. Non-limiting examples of bicyclic or tricyclic rings include biphenyl, naphthyl, phenanthrenyl, benzothienyl, chromonyl, and coumarinyl.

[0200] In some embodiments,

[0201] [ka] is optionally replaced

[0202] [ka] is selected from the group consisting of:

[0203] In some embodiments, R 1 is a cycloalkyl, a halogenated alkyl, or a halogenated cycloalkyl. In some embodiments, R 1 is an alkyl or halogenated alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of halogenated alkyl include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 1 is cycloalkyl or halogenated cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 1 is a halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R 1 is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3, CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 1 is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0204] [ka] In some embodiments, R 1 is H or D. In some embodiments, R 1 CN, OR a , S.R. a , or N.R. a R b In some embodiments, R 1 is H, D, halogen, alkyl, CN, CF 3 , OR a , S.R. a , or N.R. a R b In some embodiments, R 1 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , and

[0205] [ka] In some embodiments, R 1 , H, CH 3, Cl, Br, NH 2 , and C.F. 3 The selection is made from a list consisting of:

[0206] In some embodiments, R 2 H, D, halogen, CN, CF 3 , OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b In some embodiments, R 2 is halogen, alkyl, CN, OR, if valence permits. x , -(CH 2 ) 1~2 OR x , N(R x ) 2 , -(CH 2 ) 1~2 N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R xIn some embodiments, R is a saturated heterocycle, a partially saturated heterocycle, or a heteroaryl, each optionally substituted with 1 to 3 substituents selected from the group consisting of: 2 is halogen, CN, OR, if valence permits. x , -(CH 2 ) 1~2 OR x , N(R x ) 2 , -(CH 2 ) 1~2 N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x In some embodiments, R is an alkyl, alkenyl, or alkynyl, each optionally substituted with 1 to 3 substituents selected from the group consisting of: 2 is cycloalkyl, aryl, or alkylaryl, alkylheteroaryl.

[0207] In some embodiments, R 2 is H, D, or alkyl, where alkyl is OH, oxo, or NH 2 Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 2 is alkenyl or alkynyl, where alkenyl and alkynyl are OH, oxo, or NH 2Non-limiting examples of alkenyl include ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. 2 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 2 is a halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R 2 is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 2is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0208] [ka] Examples include:

[0209] In some embodiments, R 2 OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b In some embodiments, R 2 OR a , S.R. a , or N.R. a R b In some embodiments, R 2 is (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , or (C=O)OR a In some embodiments, R2 -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , or -C 1~4 Alkyl-NR a COR b In some embodiments, R 2 is O.C. 1~4 Alkyl-R a or NR a -C 1~4 Alkyl-R b It is.

[0210] In some particular embodiments, R 2 NH 2 , C.H. 2 NH 2 , or C.H. 2 CH 2 NH 2 In other particular embodiments, R 2 OH, CH 2 OH, or CH 2 CH 2 It is OH.

[0211] In yet another embodiment, R 2 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1 to 3 heteroatoms, each selected from the group consisting of N, O, and S. In a further embodiment, R 2 teeth,

[0212] [ka] each of which, when valence permits, is selected from the group consisting of alkyl, OH, NH 2or oxo. In some embodiments, R 2 is an N-containing heterocycle, a partially saturated heterocycle, or a heteroaryl, each of which, when valences permit, is selected from alkyl, OH, NH 2 or oxo. Non-limiting examples of N-containing heterocycles, partially saturated heterocycles, and heteroaryls include:

[0213] [ka] Examples include:

[0214] In some embodiments, R 2 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, I, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , CH=CH 2 ,

[0215] [ka] In some embodiments, R 2 , H, CH 3 , Cl, OCH 3 , C.H. 2 OH, CN, CH 2 CN, NH 2 ,

[0216] [ka] , C.H. 2 NH 2 , CH=CH 2 ,

[0217] [ka] is selected from the group consisting of:

[0218] In some embodiments, R 3 is H, D, halogen, alkyl, halogenated alkyl, heteroaryl, or CN. 3 OR a , S.R. a , N.R. a R b , (C=O)NR a R b , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , or -C 1~4 Alkyl-CONR a R b In some embodiments, R 3 is an alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, alkylaryl, alkylheteroaryl, NR b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b It is.

[0219] In some embodiments, R 3 is H, D, or alkyl, where alkyl is OH, oxo, or NH 2Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 3 is alkenyl or alkynyl, where alkenyl and alkynyl are OH, oxo, or NH 2 Non-limiting examples of alkenyl include ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. 3 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 3 is a halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R 3 is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3, CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 3 is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0220] [ka] Examples include:

[0221] In some embodiments, R 3 OR a , S.R. a , N.R. a R b , (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b In some embodiments, R 3 OR a , S.R. a , N.R. a Rb , (C=O)NR a R b , -C 1~4 Alkyl-CN, -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , or -C 1~4 Alkyl-CONR a R b In some embodiments, R 3 OR a , S.R. a , or N.R. a R b In some embodiments, R 3 is (C=O)NR a R b , N.R. b (C=O)R a , (C=O)R a , or (C=O)OR a In some embodiments, R 3 -C 1~4 Alkyl-OR a , -C 1~4 Alkyl-SR a , -C 1~4 Alkyl-NR a R b , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-CONR a R b , or -C 1~4 Alkyl-NR a COR b In some embodiments, R 3 is O.C. 1~4 Alkyl-R a or NR a -C 1~4 Alkyl-R b It is.

[0222] In some particular embodiments, R 3 NH 2, C.H. 2 NH 2 , or C.H. 2 CH 2 NH 2 In other particular embodiments, R 3 OH, CH 2 OH, or CH 2 CH 2 It is OH.

[0223] In some particular embodiments, R 3 is an alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, alkylaryl, alkylheteroaryl, NR b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1~4 Alkyl-COOR a , -C 1~4 Alkyl-NR a COR b , O.C. 1~4 Alkyl-R a , or N.R. a -C 1~4 Alkyl-R b It is.

[0224] In yet another embodiment, R 3 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1 to 3 heteroatoms, each selected from the group consisting of N, O, and S. In a further embodiment, R 3 teeth,

[0225] [ka] each of which, when valence permits, is selected from the group consisting of alkyl, OH, NH 2 or oxo. In some embodiments, R 3is an N-containing heterocycle, a partially saturated heterocycle, or a heteroaryl, each of which, when valences permit, is selected from alkyl, OH, NH 2 or oxo. Non-limiting examples of N-containing heterocycles, partially saturated heterocycles, and heteroaryls include:

[0226] [ka] Examples include:

[0227] In some embodiments, R 3 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , C.N., C.H. 2 CN, CH=CH 2 , N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 ,

[0228] [ka] In some embodiments, R 3 H, NH 2 , C.H. 3 , C-N, Cl, Br,

[0229] [ka] , C.H. 2 CN, CH 2 OH,

[0230] [ka] is selected from the group consisting of:

[0231] In some embodiments, R 4is aryl, heteroaryl. In some embodiments, R 4 is an alkyl or halogenated alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of halogenated alkyl include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , and CHClCHClCH 3 In some embodiments, R 4 is cycloalkyl or halogenated cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 4 is a halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R 4 is an alkyl halide. Non-limiting examples of alkyl halides include CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3, and CHClCHClCH 3 In some embodiments, R 4 is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include:

[0232] [ka] In some embodiments, R 4 is H or D. In some embodiments, R 4 CN, OR a , S.R. a , or N.R. a R b In some embodiments, R 4 is H, D, halogen, alkyl, CN, CF 3 , OR a , S.R. a , -C 1~4 Alkyl-OR a , or N.R. a R b In some embodiments, R 4 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , C.H. 2 OH,

[0233] [ka] In some embodiments, R 4 are H, D, and CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.F. 3 , CN, NH 2 , N.H.C.H. 3 , N(CH3 ) 2 , C.H. 2 OH, and

[0234] [ka] In some embodiments, R 4 , H, CH 3 , N.H. 2 , C.H. 2 It is selected from the group consisting of OH, F, Br, and CN.

[0235] In some embodiments, R a or R b At least one occurrence of may be independently selected from H, D, Me, Et, Pr, CH 2 CH 2 OH, phenyl, or a heterocycle. In some embodiments, R a or R b At least one occurrence of is independently H, alkyl, alkenyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. a or R b At least one occurrence of is independently H, alkyl, or alkenyl. a or R b At least one occurrence of is independently H, Me, Et, Pr, or Bu. a or R b At least one occurrence of independently is (C=O)R x , (C=O)N(R x ) 2 , S.O. 2 R x , N.R. x (C=O)NR x2 , or (C=O)R x In some embodiments, R a or R b At least one occurrence of

[0236] [ka] and the heterocycle, when valence permits, is selected from the group consisting of alkyl, OH, oxo, or (C=O)C 1~4 In some embodiments, R a or R b At least one occurrence of is H, Me, phenyl,

[0237] [ka] In some embodiments, R a or R b At least one occurrence of is independently H or

[0238] [ka] It is.

[0239] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R a and R b together with the carbon atom to which they are attached, when valence permits, may be selected from alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x, and oxo. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted heterocycle containing a nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S, and such heterocycles may, where valences permit, be selected from alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. Non-limiting examples of heterocycles include:

[0240] [ka] Examples include:

[0241] In some embodiments, R 1 The alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, and heterocycle in the formula (I) are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R.x (C=O)R x and oxo. 2 In the above, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. 3 In the above, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. 4The alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, and heterocycle in the formula (I) are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. 5 The alkyl, halogenated alkyl, cycloalkyl, and halogenated cycloalkyl in are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. 6 The alkyl, halogenated alkyl, cycloalkyl, and halogenated cycloalkyl in are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R xand oxo. 7 The alkyl, halogenated alkyl, cycloalkyl, and halogenated cycloalkyl in are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. 8 The alkyl, halogenated alkyl, cycloalkyl, and halogenated cycloalkyl in are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x , N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo. a and R b The alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, and saturated heterocycles in are, where valence permits, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR x , -(CH 2 ) 0~2 OR x, N(R x ) 2 , (C=O)R x , (C=O)N(R x ) 2 , N.R. x (C=O)R x and oxo.

[0242] In some embodiments, R x Each occurrence of is independently H, alkyl, or a heterocycle optionally substituted with alkyl, OH, or alkoxy. x Each occurrence of is independently H or alkyl. In some embodiments, R x Each occurrence of R is a substituted heterocycle. x The groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms each selected from the group consisting of N, O, and S. In some particular embodiments, R x Each occurrence of is independently H or Me.

[0243] In some embodiments,

[0244] [ka] teeth,

[0245] [ka] It is.

[0246] In some embodiments, the compound has formula Ia, Ib, or Ic:

[0247] [ka] (In the formula, R5a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl. It has the structure:

[0248] In some embodiments, in formulas Ia, Ib, and Ic,

[0249] [ka] , R 1 , R 2、 R 3 , R 4 , R 7 , and R 8 are as defined above for compounds of formula I. The other substituents are defined herein.

[0250] In some embodiments, R 5a At least one occurrence of R is H or D. 5a At least one occurrence of OR a For example, OH or OMe. In some embodiments, R 5a At least one occurrence of R is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 5a At least one occurrence of is a halogen, e.g., F, Cl, Br, or I. In some embodiments, R 5aAt least one occurrence of is a fluorinated alkyl, e.g., CF 3 , C.H. 2 F, CHF 2 , C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , C.F. 2 CH 3 , or C.H. 2 CHF 2 It is.

[0251] In some embodiments, R 5b At least one occurrence of R is H or D. 5b At least one occurrence of OR a For example, OH or OMe. In some embodiments, R 5b At least one occurrence of R is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 5b At least one occurrence of is a halogen, e.g., F, Cl, Br, or I. In some embodiments, R 5b At least one occurrence of is a fluorinated alkyl, e.g., CF 3 , C.H. 2 F, CHF 2 , C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , C.F. 2 CH 3 , or C.H. 2 CHF 2 It is.

[0252] In some embodiments, R 6a At least one occurrence of R is H or D. 6a At least one occurrence of OR a For example, OH or OMe. In some embodiments, R 6aAt least one occurrence of R is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 6a At least one occurrence of is a halogen, e.g., F, Cl, Br, or I. In some embodiments, R 6a At least one occurrence of is a fluorinated alkyl, e.g., CF 3 , C.H. 2 F, CHF 2 , C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , C.F. 2 CH 3 , or C.H. 2 CHF 2 It is.

[0253] In some embodiments, R 6b At least one occurrence of R is H or D. 6b At least one occurrence of OR a For example, OH or OMe. In some embodiments, R 6b At least one occurrence of R is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 6b At least one occurrence of is a halogen, F, Cl, Br, or I. In some embodiments, R 6b At least one occurrence of is a fluorinated alkyl, e.g., CF 3 , C.H. 2 F, CHF 2 , C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , C.F. 2 CH 3 , or C.H. 2 CHF 2 It is.

[0254] In some embodiments, the compound has formula IIa, IIb, or IIc:

[0255] [ka] (In the formula, R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluorinated alkyl; R 11 each occurrence is independently selected from H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 12 each occurrence is independently selected from H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R13 each occurrence is independently selected from H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 14 each occurrence is independently selected from H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a and; R 15 each occurrence is independently selected from H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a is) It has the structure:

[0256] In some embodiments, R in formula IIa, IIb, and IIc 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as defined above for compounds of formula I. The other substituents are defined herein.

[0257] In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of R is not H. 11 , R 12 , R 13 , R 14 , and R 15 At least two of them are not H.

[0258] In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the following is H, alkyl, or CF 3 or halogen. In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of them is CN, CF 3 , OCF 3 , OR a , or S.R. a In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the groups is a halogen, NR a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the following is OR a , S.R. a , or N.R. a R b In some embodiments, R 11 , R12 , R 13 , R 14 , and R 15 At least one of R is H, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl. 11 , R 12 , R 13 , R 14 , and R 15 At least one of the 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.H. 2 OCH 3 , C.F. 3 , CN, C≡CH, or

[0259] [ka] In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the following is H, Me, Et, i-Pr, n-Bu, CF 2 H, C.F. 2 Cl, or CF 3 In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the following is OH, OCH 3 , C.H. 2 OCH 3 In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of R is halogen, e.g., Cl, F, Br, or I. In some embodiments, R 11 , R 12 , R 13 , R 14 , and R15 At least one of R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the alkyl halides is an alkyl halide, e.g., CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , or CHClCHClCH 3 In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of the groups is a halogenated cycloalkyl, e.g.

[0260] [ka] In some embodiments, R 11 , R 12 , R 13 , R 14 , and R 15 At least one of R is alkenyl, e.g., ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, or (E)-pent-1-enyl. 11 , R 12 , R 13 , R 14 , and R15 At least one of R is alkynyl, e.g., ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. 11 , R 12 , R 13 , R 14 , and R 15 At least one of R is CN. 11 , R 12 , R 13 , R 14 , and R 15 At least two of the 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.H. 2 OCH 3 , C.F. 3 , CN, C≡CH, or

[0261] [ka] are independently selected from the group consisting of:

[0262] In some embodiments, R 11 , R 12 , R 14 , and R 15 is H;R 13 is H, D, halogen, alkyl, cycloalkyl, CN, CF 3 , OR a , S.R. a , N.R. a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a In some embodiments, R 13 CN, CF 3 , OCF 3 , OR a , or S.R.a In some embodiments, R 13 is halogen, NR a R b , -C 1~4 Alkyl-SR a , or -C 1~4 Alkyl-OR a In some embodiments, R 13 OR a , S.R. a , or N.R. a R b In some embodiments, R 13 is H, halogen, fluorinated alkyl, or alkyl. In some embodiments, R 13 is CH 3 , C.H. 2 CH 3 , OH, F, Cl, Br, OCH 3 , C.H. 2 OCH 3 , C.F. 3 , CN, C≡CH, or

[0263] [ka] In some embodiments, R 13 is H, Me, Et, i-Pr, n-Bu, CF 2 H, C.F. 2 Cl, or CF 3 In some embodiments, R 13 OH, OCH 3 , C.H. 2 OCH 3 In some embodiments, R 13 is halogen, e.g., Cl, F, Br, or I. In some embodiments, R 13 is Cl. In some embodiments, R 13 is an alkyl halide, e.g., CF 3 , C.H. 2 F, C.H. 2 Cl, CH 2 CF 3 , CHFCH 3, CHFCH 2 F, C.F. 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , C.H. 2 CH 2 CF 3 , or CHClCHClCH 3 In some embodiments, R 13 represents a cycloalkyl halide, e.g.

[0264] [ka] In some embodiments, R 13 is CN. In some embodiments, R 13 is alkenyl, e.g., ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, or (E)-pent-1-enyl. 13 is ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.

[0265] In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc is any one of the compounds described herein. In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc is selected from the group consisting of the compounds of Examples 2-5 and Tables 1-5. In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc is selected from the group consisting of the compounds of Examples 2-5 and Tables 1, 2, and 3. In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc is selected from the group consisting of the compounds of Tables 4-5. In some embodiments, the compound of formula I, Ia, Ib, IIa, IIc is selected from the group consisting of the compounds of Examples 2-5 and Tables 1 and 3. In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc is selected from the group consisting of the compounds of Table 2. The compounds listed in Tables 1-5 are representative, non-limiting compounds of the embodiments disclosed herein.

[0266] [Table X]

[0267] Preparation method The following are general synthetic schemes for preparing the compounds of the present invention. These schemes are illustrative and are not meant to limit the techniques that a person skilled in the art may use to prepare the compounds disclosed herein. Different methods will be apparent to a person skilled in the art. In addition, various steps in the synthesis may be performed in alternative sequences or orders to obtain the desired compounds. All documents cited herein are incorporated by reference in their entirety. For example, the following reactions are illustrative, but not limiting, of the preparation of some of the starting materials and compounds disclosed herein.

[0268] Schemes 1-8 below illustrate synthetic routes that can be used to synthesize compounds of the invention, such as compounds having the structure of formula I, Ia, Ib, Ic, IIa, IIb, or IIc, or precursors thereof. Various modifications to these methods can be envisioned by those skilled in the art to achieve results similar to those of the inventions shown below. In the embodiments below, synthetic routes are described using compounds having the structure of formula I, Ia, Ib, Ic, IIa, IIb, or IIc, or precursors thereof, as examples. The general synthetic routes described in Schemes 1-8 and the examples described in the Examples section below illustrate the methods used to prepare the compounds described herein.

[0269] Compound I-3 shown in scheme 1 can be prepared by any method known in the art and / or is commercially available. X refers to a leaving group. Non-limiting examples of leaving groups include Cl, Br, or I. Other substituents are defined herein. As shown in scheme 1, compounds of formula I, such as I-1, can be prepared by alkylating appropriately substituted pyridazinone I-3 with halomethyloxadiazole I-2 in the presence of a base such as potassium carbonate, in a solvent such as DMF or NMP, and optionally with a catalyst such as sodium iodide.

[0270] [ka]

[0271] Compound I-4 as shown in Scheme 2 can be prepared by any method known in the art and / or is commercially available. The substituents as shown in Scheme 2 are defined herein. As shown in Scheme 2, oxadiazole I-2 can be prepared from nitrile I-4 as shown in Scheme 2. Nitrile I-4 is converted to amide oxime I-5 by heating with hydroxylamine hydrochloride and a base such as sodium bicarbonate in a solvent such as ethanol. Alternatively, a solution of hydroxylamine in water can be used without the addition of a base. The amide oxime is reacted with an α-haloacyl halide such as chloroacetyl chloride and a base such as triethylamine. The resulting intermediate is cyclized to chloromethyl oxadiazole by heating in toluene, for example, at 100°C.

[0272] [ka]

[0273] Compound I-3, as shown in Scheme 3, can be prepared by any method known in the art and / or is commercially available. The substituents shown in Scheme 3 are defined herein. As shown in Scheme 3, a second method of synthesizing compounds of formula I, such as I-1, is to construct an oxadiazole ring from pyridazine acetic acid and an amide oxime. An appropriately substituted pyridazinone I-3 is reacted with a haloacetate, such as ethyl bromoacetate, in the presence of a base, such as potassium carbonate, to give the ester I-6. The ester is then hydrolyzed, for example with lithium hydroxide, to give the carboxylic acid I-7. The acid I-7 and the amide oxime I-5 are reacted in a solvent, such as DCM, with a coupling agent, such as propanephosphonic anhydride, and a base, such as diisopropylethylamine. The formed adduct is then heated in a solvent, such as DMF, to cause cyclization to form the oxadiazole I-1.

[0274] [ka]

[0275] Many heterocycles I-3 are available, and R 1 , R 2 , R 3 , and R 4 One or more of the are halogens. These can be used to prepare alkyl, arylcyano, or other functionalized heterocycles by cross-coupling chemistry, e.g., Suzuki reaction. Such transformations can be performed on the heterocycle before reaction with I-2 to give I-1, or halogen-substituted heterocycles I-3 can be reacted with I-2 to then convert the halogens to other substituents. Similarly, heterocyclic carboxylic acids and esters I-3 can be used as precursors to amide, nitrile, alkoxymethyl, hydroxymethyl, and aminomethyl substituents. This chemistry can be performed before or after coupling I-3 with I-2 to give I-1.

[0276] Compound I-8 depicted in Scheme 4 can be prepared by any method known in the art and / or is commercially available. The substituents depicted in Scheme 4 are defined herein. 1 (S)-CH(OH)CH 2 Compounds of formula I, where: can be obtained from ketonitrile I-8. Reduction of the ketone with a suitable chiral reducing agent gives S-alcohol I-9. One such chiral reducing agent is [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-ruthenium (CAS[174813-81-1]) in a mixture of formic acid and triethylamine. Alcohol I-9 is then converted to amide oxime I-5a and chloromethyloxadiazole I-2a by the same method (similar to Scheme 2) used to prepare I-2.

[0277] [ka]

[0278] As shown in Scheme 5, heterocycle I-10, in which both X groups are halogen, can be reacted with Pd(dppf)Cl 2 and a base such as sodium carbonate in a solvent such as dioxane and water, 2 B(OH) 2 React with R 2 is aryl or vinyl to give I-11. NH is then protected with a suitable protecting group (PG) such as tetrahydropyranyl (THP) to form I-12. When PG is THP, it is introduced by treating I-11 with dihydropyran and an acid such as toluenesulfonic acid. PG may be added first by protecting I-10. I-12 can then be converted to I-13 by reaction with I-14 in the presence of a base such as potassium carbonate in a solvent such as dioxane and water to give I-15 as the free boronic acid. 1 B(OH) 2 , a boronic ester, or a boroxine and a palladium catalyst such as tetrakistriphenylphosphinepalladium. Deprotection of I-13 gives I-14, which can be converted to compound I-1 by either of the methods outlined in Scheme 1 or Scheme 3.

[0279] [ka]

[0280] As shown in Scheme 6, Y is CR 2 where Z is N and R 2 Compounds in which is an oxygen-containing substituent can be synthesized from pyrimidone ester I-15.

[0281] [ka]

[0282] R 1The group can be introduced, for example, by halogenation at C5 of I-15 with 1,3-dichloro-5,5-dimethylhydantoin in a solvent such as DMF. Reduction of the ester with a reducing agent such as sodium borohydride in methanol gives the hydroxymethylpyrimidinone I-17. I-16 can be converted to the amine R in a solvent such as dioxane. a R b Treatment with NH affords amide I-18. The chlorine atom at C5 in I-16, I-17, or I-18 can be converted to other R groups by standard methods such as the Suzuki reaction. 1 It can be converted to the group.

[0283] As shown in Scheme 7, Y is CR 2 where Z is N and R 4 Compounds in which is an oxygen-containing substituent can be obtained from 2,5-dichloro-4-methoxypyrimidine I-19.

[0284] [ka]

[0285] Palladium such as hydroxymethylstannane and bistriphenylphosphinepalladium dichloride in a solvent such as toluene II Catalytic Stille reaction of I-19 affords the hydroxymethylpyrimidine I-20. Hydrolysis with a base such as sodium hydroxide affords the pyrimidone I-21. The chlorine atom can be converted to other R groups by standard methods. 1 It can be converted to the group. As shown in Scheme 8, Y is CR 2 One method to prepare compounds where Z is CH is from pyridine boronic acid I-22.

[0286] [ka]

[0287] Boronic acid I-22 is reacted with aryl (or heteroaryl) halides R where X is Cl, Br, or I in a solvent such as dioxane and water. 2 X, Pd(dppf)Cl 2 and a base such as sodium carbonate to give R 2 where R is aryl or heteroaryl to give I-23. Hydrolysis with an acid such as HCl gives pyridine I-24.

[0288] Pharmaceutical Compositions The invention also provides pharmaceutical compositions comprising at least one of the compounds described herein or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or diluent.

[0289] In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of compounds of formula I, Ia, Ib, Ic, IIa, IIb, or IIc as described herein and a pharma- ceutically acceptable carrier or diluent.

[0290] In certain embodiments, the composition is in the form of a hydrate, solvate, or a pharma- ceutically acceptable salt.The composition can be administered to a subject by any suitable route of administration, including, without limitation, oral and parenteral.

[0291] The phrase "pharmaceutically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another in a subject. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can function as pharma- ceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. The term "carrier" refers to an organic or inorganic component, natural or synthetic, with which the active component is combined to facilitate application. The components of the pharmaceutical compositions can be commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0292] In certain embodiments, the compounds in the pharmaceutical composition may be provided in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" as used herein refers to relatively non-toxic, inorganic and organic acid salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. See, e.g., Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19, incorporated herein by reference in its entirety.

[0293] The pharma- ceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds from non-toxic organic or inorganic acids.For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, butionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid, etc.

[0294] In other cases, the compounds of the present invention may contain one or more acidic functional groups and therefore can form pharma-ceutically acceptable salts with pharma-ceutically acceptable bases. In these cases, the term "pharma-ceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharma-ceutically acceptable metal cation, ammonia, or a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative examples of alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, for example, Berge et al. (supra).

[0295] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0296] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0297] The method of preparing these formulations or compositions includes the step of combining the compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0298] Formulations of the present invention suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (using flavored bases, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using inert bases such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention can also be administered as a bolus, electuary, or paste.

[0299] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be combined with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; agar-agar, calcium carbonate, ginger, or tapioca; Disintegrating agents such as oka starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; dissolution retarders such as paraffin; absorption promoters such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions can also be used as fillers for soft-filled and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0300] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxybutylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0301] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to slow or controlled release the active ingredient therein, for example, using various proportions of hydroxybutylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to produce the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be of a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally delayed. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0302] The liquid dosage form for oral administration of the compound of the present invention includes pharma- ceutically acceptable emulsion, microemulsion, solution, suspension, syrup, and elixir.In addition to active ingredient, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition, cyclodextrin, such as hydroxybutyl-β-cyclodextrin, can be used to solubilize the compound.

[0303] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0304] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0305] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0306] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0307] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and butane.

[0308] Transdermal patches have the additional advantage of controlling the delivery of the compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the drug in a suitable medium. Absorption enhancers can also be used to increase the flux of the drug of the present invention across the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0309] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0310] Pharmaceutical compositions of this invention suitable for parenteral administration contain one or more compounds of the invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions; or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use and which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0311] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of the drug. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug thus depends on its rate of dissolution, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms can be accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for depot injections includes the use of polyethylene oxide-polypropylene oxide copolymers, whose vehicles are fluid at room temperature and solidify at body temperature.

[0312] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0313] When the compound of the present invention is administered to humans and animals as a pharmaceutical, it may be given as such or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0314] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, i.e., the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapeutic or medical procedures.The combination of specific therapies (treatments or procedures) for use in combination regimen takes into consideration the compatibility of the desired therapeutic and / or procedure and the desired therapeutic effect obtained.It will also be understood that the therapies used can achieve the desired effect on the same disorder (for example, the compounds of the present invention can be administered simultaneously with another anticancer drug).

[0315] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means.The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock, and farm animals), racehorses, birds, lizards, and any other organisms that can tolerate the compounds.

[0316] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, optionally accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, which notice reflects approval by the agency of the manufacture, use, or sale for human administration.

[0317] Administration to a Subject / Method of Treating a Condition In yet another aspect, the present invention provides a method for treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula I, Ia, Ib, Ic, IIa, IIb, or IIc, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing any one of the compounds or a pharma- ceutically acceptable salt thereof, wherein the condition is selected from the group consisting of pain, a skin disorder, a respiratory disorder, a fibrotic disorder, an inner ear disorder, a heat or other disorder of temperature regulation, a urinary tract or bladder disorder, an autoimmune disorder, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, and a cardiovascular disorder.

[0318] In some embodiments, the pain is acute pain, chronic pain, complex regional pain syndrome, inflammatory pain, neuropathic pain, post-operative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, hyperalgesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-associated neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, post-stock pain, or pain associated with teeth and dental damage.

[0319] In some embodiments, the urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, bladder instability, or bladder outlet obstruction. In some embodiments, the skin disorder is burns, psoriasis, eczema, or pruritus. In some embodiments, the skin disorder is atopic dermatitis or psoriasis-induced itch.

[0320] In some embodiments, the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, idiopathic pulmonary disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough.

[0321] In some embodiments, the ischemia is a disorder associated with CNS hypoxia or reduced blood flow to the CNS. In some embodiments, the autoimmune disease is rheumatoid arthritis or multiple sclerosis. In some embodiments, the central nervous system disorder is associated with neurodegeneration. In some embodiments, the gastroenterological disorder is inflammatory bowel disease, esophagitis, gastroesophageal reflux disease, irritable bowel syndrome, emesis, or gastroduodenal ulcer. In some embodiments, the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

[0322] In some embodiments, the mammalian species is human.

[0323] In yet another aspect, a method of inhibiting transient receptor potential ankyrin 1 (TRPA1) in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I, Ia, Ib, Ic, IIa, IIb, or IIc, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing any one of the compounds or pharma- ceutically acceptable salts thereof.

[0324] In some embodiments, the compounds described herein selectively inhibit TRPA1 and have minimal or no off-target inhibitory activity against potassium channels or against calcium or sodium channels. In some embodiments, the compounds described herein do not block hERG channels and therefore have a desirable cardiovascular safety profile.

[0325] Some aspects of the invention include administering to a subject an effective amount of a composition to achieve a particular outcome. Small molecule compositions useful according to the methods of the invention can therefore be formulated in any manner suitable for pharmaceutical use.

[0326] The formulations of the present invention are administered in pharma- ceutically acceptable solutions, which may routinely contain pharma- ceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0327] When used in therapy, an effective amount of the compound can be administered to a subject by any manner that allows the compound to be taken up by appropriate target cells. "Administering" the pharmaceutical composition of the present invention can be accomplished by any means known to those skilled in the art. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., by patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.). Injection can be a bolus injection or continuous infusion.

[0328] For example, pharmaceutical compositions according to the invention are often administered intravenously, intramuscularly, or by other parenteral means. They can also be administered by intranasal application, inhalation, topically, orally, or as implants, and can also be used rectally or vaginally. Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated with fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for implantation in the skin, or dried on a sharp object to be caught in the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations that release active compounds sustainedly, in which excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or dissolving agents, as described above, are commonly used. Pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief overview of this method for drug delivery, see Langer, R. (1990) Science 249:1527-33, which is incorporated herein by reference in its entirety.

[0329] The concentration of the compound contained in the composition used in the method of the present invention may range from about 1 nM to about 100 μM. Effective doses are believed to be in the range of about 10 picomoles / kg to about 100 micromoles / kg.

[0330] The pharmaceutical compositions are preferably prepared and administered in dose units. Liquid dose units are vials or ampoules for injection or other parenteral administration. Solid dose units are tablets, capsules, powders, and suppositories. For the treatment of a patient, different doses may be required depending on the activity of the compound, the method of administration, the purpose of the administration (i.e., prophylactic or therapeutic), the nature and severity of the disorder, the age and weight of the patient. The administration of a given dose can be carried out either by a single administration in the form of individual dose units, or by several smaller dose units. The administration of multiple doses repeatedly at specific intervals of days, weeks, or months is also contemplated by the present invention.

[0331] The composition can be administered as it is (as is) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt should be pharmaceutically acceptable, but pharmaceutically unacceptable salts can be conveniently used to prepare the pharmaceutically acceptable salt. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts can also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0332] Suitable buffering agents include, but are not limited to, acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0333] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that can be isotonic with the blood of recipients. Acceptable vehicles and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any non-irritating fixed mineral oil or non-mineral oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injections. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administration can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, which is incorporated herein by reference in its entirety.

[0334] The compounds useful in the present invention can be delivered in mixtures of three or more such compounds, which can further include one or more adjuvants in addition to the combination of compounds.

[0335] A variety of administration routes are available. The particular mode selected will of course depend on the particular compound selected, the age and general health of the subject, the particular condition being treated, and the dosage required for therapeutic effect. The method of the present invention can generally be practiced using any mode of administration that is medically acceptable, i.e., any mode that produces an effective level of response without causing medically unacceptable adverse effects. The preferred modes of administration are described above.

[0336] Composition is conveniently presented in unit dosage form and can be prepared by any method well known in the field of pharmacy.All methods include the step of mixing compound with carrier that constitutes one or more accessory ingredients.Generally, composition is prepared by mixing compound with liquid carrier, finely divided solid carrier, or both uniformly and intimately, and then shaping product if necessary.

[0337] Other delivery systems can include time-release, delayed release, or sustained release delivery systems. Such systems can avoid repeated administration of compounds and improve convenience for subjects and physicians. Many types of release delivery systems are available and known to those skilled in the art. They include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the aforementioned polymers containing drugs are described, for example, in U.S. Pat. No. 5,075,109. Drug delivery systems also include non-polymeric systems, i.e., lipids including sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral fats such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants, and the like. Specific examples include, but are not limited to, (a) erosion system, in which the agent of the present invention is contained in the form of a matrix, such as those described in U.S. Patent No. 4,452,775, 4,675,189 and 5,736,152, and (b) diffusion system, in which active ingredient permeates from polymer at controlled rate, such as those described in U.S. Patent No. 3,854,480, 5,133,974 and 5,407,686.Furthermore, pump-based hardware delivery system can be used, some of which are suitable for implantation.

[0338] Assay for efficacy of TRPA1 channel inhibitors In some embodiments, the compounds described herein are tested for their activity on TRPA1 channel.In some embodiments, the compounds described herein are tested for their TRPA1 channel electrophysiology.In some embodiments, the compounds described herein are tested for their hERG electrophysiology.

[0339] Equivalent The representative examples that follow are intended to help illustrate the present invention and are not intended to, and should not be construed to, limit the scope of the present invention. Indeed, in addition to those shown and described herein, various modifications of the present invention and many further embodiments thereof will become apparent to those skilled in the art from the entire contents of this document, including the examples that follow and references to the scientific and patent literature cited herein. It should be further understood that the contents of these cited references are incorporated herein by reference to help describe the state of the art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents. EXAMPLES

[0340] Example 1 (including Examples 1A-1F) describes exemplary intermediates used in the synthesis of representative compounds of Formula I, Ia, Ib, Ic, IIa, IIb, or IIc disclosed herein.

[0341] [Example 1A] Intermediate 1 ((1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol)

[0342] [ka]

[0343] Step A: To a stirred solution of 3-(4-chlorophenyl)-3-oxopropanenitrile (30.0 g, 167 mmol) and RuCl[(S,S)-Tsdpen](mesitylene) (0.426 g, 0.680 mmol) in ACN (300 mL) was added triethylamine formate complex (5:2) (24 mL) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in EA (200 mL) and water (300 mL) and extracted with EA (3×300 mL). The combined organic layers were washed with brine (2×300 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give (3S)-3-(4-chlorophenyl)-3-hydroxypropanenitrile as a brown oil (30.0 g, crude), which was used directly in the next step without purification: 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.50-7.37 (m, 4H), 6.03 (d, J = 4.6 Hz, 1H), 4.95-4.86 (m, 1H), 2.86 (m, 2H).

[0344] Step B: (3S)-3-(4-chlorophenyl)-3-hydroxypropanenitrile (30.0 g, 165 mmol) and NH in MeOH (300 mL). 2 A solution of OH (50% in water) (24 mL) was stirred at 75° C. for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give (3S)-3-(4-chlorophenyl)-N,3-dihydroxypropanimidamide as a brown oil (30.0 g, crude), which was used directly in the next step without purification: LCMS (ESI) C 9 H 11 ClN 2 O 2 [M + H] + Calculated values: 215, 217 (3 : 1) Measured values: 215, 217 (3 : 1); 1 H NMR (400 MHz, DMSO-d 6) δ 8.76 (s, 1H), 7.38-7.33 (m, 4H), 5.53-5.35 (m, 3H), 4.95-4.79 (m, 1H), 2.39-2.14 (m, 2H).

[0345] Step C: To a stirred solution of (3S)-3-(4-chlorophenyl)-N,3-dihydroxypropanimidamide (30.0 g, 140 mmol) and DIEA (45.2 g, 349 mmol) in NMP (300 mL) was added chloroacetyl chloride (17.4 g, 154 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h, heated to 95° C., stirred for 4 h, and cooled to room temperature. The mixture was diluted with EA (300 mL) and water (200 mL) and the layers were separated. The aqueous layer was further extracted with EA (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol as a yellow solid (15.0 g, 33.0% over three steps); LCMS (ESI) C 11 H 10 Cl 2 N 2 O 2 [M-H] - Calculated values: 271, 273 (3: 2) Measured values: 271, 273 (3: 2); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.53-7.23 (m, 4H), 5.67 (d, J = 4.9 Hz, 1H), 5.09 (s, 2H), 5.05-4.96 (m, 1H), 3.11-2.96 (m, 2H).

[0346] [Example 1B] Intermediate 2 (5-Methyl-6-(1H-pyrazol-4-yl)-3H-pyrimidin-4-one)

[0347] [ka]

[0348] Step A: Dioxane (8 mL) and H 2 To a stirred solution of 5,6-dichloro-3,4-dihydropyrimidin-4-one (0.500 g, 3.03 mmol) and 1-(tetrahydropyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.26 g, 4.55 mmol) in 2 mL of O was added Na 2 CO 3 (0.964 g, 9.09 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.247 g, 0.303 mmol) was added at room temperature. The reaction was degassed under reduced pressure, purged with nitrogen three times, and then stirred at 80° C. for 12 h. After cooling to room temperature, the resulting mixture was filtered and the filter cake was washed with MeOH (3×3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA (5 / 1) to give 5-chloro-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]-3H-pyrimidin-4-one as an off-white solid (0.450 g, 52.9%): LCMS (ESI) C 12 H 13 ClN 4 O 2 [M + H] + Calculated values: 281, 283 (3 : 1) Measured values: 281, 283 (3 : 1); 1 H NMR (300 MHz, DMSO-d 6) δ 8.63 (d, J = 0.7 Hz, 1H), 8.40-8.21 (m, 1H), 8.19 (d, J = 3.6 Hz, 1H), 5.54 (t, J = 9.8 Hz, 1H), 4.06-3.84 (m, 1H), 3.75-3.57 (m, 1H), 2.22-2.04 (m, 1H), 2.04-1.84 (m, 2H), 1.79-1.48 (m, 3H).

[0349] Step B: To a stirred mixture of 5-chloro-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]-3H-pyrimidin-4-one (0.450 g, 1.60 mmol) and DHP (0.337 g, 4.01 mmol) in THF (5 mL), TsOH H 2 O (76.2 mg, 0.401 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was quenched with water (30 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with PE / EA (1 / 1) to give 5-chloro-3-(tetrahydropyran-2-yl)-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyrimidin-4-one as a pale yellow oil (0.262 g, 44.8%): LCMS (ESI) C 17 H 21 ClN 4 O 3 [M + H] + Calculated value: 365, 367 (3 : 1) Measured value: 365, 367 (3 : 1); 1 H NMR (300 MHz, CDCl 3 ) δ 8.97-7.77 (m, 3H), 5.90-5.32 (m, 2H), 4.43-4.06 (m, 2H), 3.84-3.62 (m, 2H), 2.18-1.94 (m, 4H), 1.78-1.50 (m, 8H).

[0350] Step C: Dioxane (1.6 mL) and H 2 To a solution of 5-chloro-3-(tetrahydropyran-2-yl)-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyrimidin-4-one (0.160 g, 0.439 mmol) and trimethylboroxine (0.275 g, 2.19 mmol) in 20O (0.4 mL) was added Cs 2 CO 3 (0.429 g, 1.32 mmol) and Pd(PPh 3 ) 4 (50.7 mg, 0.0440 mmol) was added at room temperature. The reaction was degassed under reduced pressure and purged with nitrogen three times, then stirred at 100 °C for 4 h. After cooling to room temperature, the resulting mixture was filtered and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and purified by elution with 35% ACN in water (+10 mmol / L NH 4 HCO 3 ) to give 5-methyl-3-(tetrahydropyran-2-yl)-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyrimidin-4-one as a yellow oil (74.0 mg, 48.9%): LCMS (ESI) C 18 H 24 N 4 O 3 [M + H] + Calculated value: 345 Measured value: 345; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.35 (d, J = 5.7 Hz, 2H), 8.00 (s, 1H), 5.83-5.65 (m, 1H), 5.50 (t, J = 10.0 Hz, 1H), 4.15-3.89 (m, 2H), 3.69-3.61 (m, 2H), 2.18 (s, 3H), 2.03-1.44 (m, 12H).

[0351] Step D: A solution of 5-methyl-3-(tetrahydropyran-2-yl)-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyrimidin-4-one (74.0 mg, 0.215 mmol) and hydrochloric acid (0.2 mL, 6 M) in MeOH (0.8 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give 5-methyl-6-(1H-pyrazol-4-yl)-3H-pyrimidin-4-one as a yellow oil (46.0 mg, crude), which was used directly in the next step without further purification: LCMS (ESI) C 8 H 8 N 4 O[M+H] + Calculated value: 177, actual value 177.

[0352] [Example 1C] Intermediate 3 (5-chloro-6-(hydroxymethyl)pyrimidin-4(3H)-one)

[0353] [ka]

[0354] Step A: To a stirred mixture of methyl 6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.00 g, 6.49 mmol) in DMF (15 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.770 g, 3.89 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was purified by reverse phase chromatography, eluting with 20% ACN in water (+0.1% TFA) to give methyl 5-chloro-6-oxo-1,6-dihydropyrimidine-4-carboxylate as a pale yellow solid (0.700 g, 57.2%): LCMS (ESI) C 6 H 5 ClN 2 O 3 [M + H] + Calculated values: 189, 191 (3 : 1) Measured values: 189, 191 (3 : 1); 1 H NMR (300 MHz, DMSO-d6 ) δ 13.78 (s, 1H), 8.31 (s, 1H), 3.90 (s, 3H).

[0355] Step B: To a stirred mixture of methyl 5-chloro-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.300 g, 1.59 mmol) in THF (4 mL) and MeOH (1 mL) was added NaBH 4 (0.241 g, 6.36 mmol) was added at room temperature. The reaction was stirred at 70° C. under nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 1% ACN in water (+0.1% TFA) to give 5-chloro-6-(hydroxymethyl)pyrimidin-4(3H)-one as a light yellow solid (0.300 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 5 H 5 ClN 2 O 2 [M+H] + Calculated value: 161, 163 (3:1), actual value 161, 163 (3:1).

[0356] [Example 1D] Intermediate 4 (5-chloro-6-oxo-1H-pyrimidine-4-carboxamide)

[0357] [ka]

[0358] Step A: To a stirred solution of methyl 5-chloro-6-oxo-1H-pyrimidine-4-carboxylate (0.600 g, 3.18 mmol) in dioxane (1 mL) was added NH 3 H 22H 2 O (5 mL, 25%) was added at room temperature. The reaction was stirred at room temperature for 16 h. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 3% ACN in water (+0.05% TFA) to give 5-chloro-6-oxo-1H-pyrimidine-4-carboxamide as an off-white solid (0.240 g, 43.5%): LCMS (ESI) C 5 H 4 ClN 3 O 2 [M + H] + Calculated values: 174, 176 (3 : 1) Measured values: 174, 176 (3 : 1); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H).

[0359] [Example 1E] Intermediate 5 (5-chloro-2-(hydroxymethyl)-3H-pyrimidin-4-one)

[0360] [ka]

[0361] Step A: To a stirred solution of 2,5-dichloro-4-methoxypyrimidine (1.00 g, 5.59 mmol) and (tributylstannyl)methanol (2.69 g, 8.38 mmol) in toluene (10 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.390 g, 0.560 mmol) was added at room temperature. The reaction was degassed under reduced pressure and purged with nitrogen three times, then stirred at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and purified with 20% ACN in water (+10 mmol / L NH 4 HCO 3) to give (5-chloro-4-methoxypyrimidin-2-yl)methanol as an off-white solid (0.340 g, 34.9%); LCMS (ESI) C 6 H 7 ClN 2 O 2 [M + H] + Calculated values: 175, 177 (3 : 1) Measured values: 175, 177 (3 : 1); 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 4.90-4.87 (brs, 1H), 4.52 (s, 2H), 4.04 (s, 3H).

[0362] Step B: To a stirred solution of (5-chloro-4-methoxypyrimidin-2-yl)methanol (0.150 g, 0.860 mmol) in ACN (1 mL) was added H 2 NaOH (0.100 g, 2.58 mmol) in 2 mL of O was added at room temperature. The reaction was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was neutralized to pH 7 with hydrochloric acid (1 M) and then concentrated under reduced pressure to give 5-chloro-2-(hydroxymethyl)-3H-pyrimidin-4-one (0.300 g, crude), which was used directly in the next step without further purification: LCMS (ESI) C 5 H 5 ClN 2 O 2 [M-H] - Calculated values: 159, 161 (3 : 1) Measured values: 159, 161 (3 : 1); 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 5.85 (s, 1H), 4.33 (s, 2H).

[0363] [Example 1F] Intermediate 6 (3-chloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridin-2-ol)

[0364] [ka]

[0365] Step A: Dioxane (8 mL) and H 2 3-Chloro-2-methoxypyridin-4-ylboronic acid (0.800 g, 4.27 mmol) and Na in O (2 mL) 2 CO 3 (1.36 g, 12.8 mmol), 4-bromo-1-(tetrahydropyran-2-yl)pyrazole (0.990 g, 4.28 mmol) and Pd(dppf)Cl 2 (0.312 g, 0.427 mmol) was added at room temperature. The reaction was degassed under reduced pressure, purged with nitrogen three times and stirred at 80° C. for 16 h. The cooled mixture was diluted with water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA (2 / 1) to give 3-chloro-2-methoxy-4-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyridine as a pale yellow oil (0.900 g, 71.8%): LCMS (ESI) C 14 H 16 ClN 3 O 2 [M + H] + Calculated values: 294, 296 (3 : 1) Measured values: 294, 296 (3 : 1); 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.59 (d, J = 5.75 Hz, 1H), 8.15 (d, J = 5.85 Hz, 1H), 8.11-8.03 (m, 1H), 7.36-7.28 (m, 1H), 5.56-5.47 (m, 1H), 4.05-3.90 (m, 4H), 3.74-3.61 (m, 1H), 2.22-2.06 (m, 1H), 2.03-1.89 (m, 2H), 1.81-1.44 (m, 3H).

[0366] Step B: A solution of 3-chloro-2-methoxy-4-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyridine (0.400 g, 1.36 mmol) in hydrochloric acid (3 M, 4 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give 3-chloro-4-(1H-pyrazol-4-yl)pyridin-2-ol as a colorless oil (0.230 g, crude), which was used directly in the next step without purification: LCMS (ESI) C 8 H 6 ClN 3 O[M+H] + Calculated value: 196, 198 (3:1), actual value 196, 198 (3:1).

[0367] Step C: 3-Chloro-4-(1H-pyrazol-4-yl)pyridin-2-ol (0.230 g, 1.18 mmol) in DMF (2.5 mL) and K 2 CO 3 To a stirred mixture of (0.488 g, 3.53 mmol) was added SEMCl (0.196 g, 1.18 mmol) dropwise at room temperature. The reaction was stirred for 4 h, diluted with water (30 mL) and extracted with EA (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA (1 / 4) to give 3-chloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridin-2-ol as an off-white solid (0.160 g, 41.8%): LCMS (ESI) C 14 H 20 ClN 3 O 2 Si [M + H] + Calculated values: 326, 328 (3 : 1) Measured values: 326, 328 (3 : 1); 1 H NMR (300 MHz, DMSO-d 6) δ 11.99 (s, 1H), 8.70 (s, 1H), 8.20 (s, 1H), 7.42 (d, J = 6.91 Hz, 1H), 6.58 (d, J = 6.93 Hz, 1H), 5.53 (s, 2H), 3.68-3.61 (m, 2H), 0.90-0.84 (m, 2H), 0.00 (s, 9H).

[0368] Examples 2-5 describe the synthesis of representative compounds of Formula I, Ia, Ib, Ic, IIa, IIb, or IIc disclosed herein.

[0369] [Example 2] Compound 4 (1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methyl-6-oxopyridine-3-carboxamide)

[0370] [ka]

[0371] Step A: To a stirred solution of 5-(chloromethyl)-3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazole (0.200 g, 0.778 mmol) and 5-bromo-6-oxo-1H-pyridine-3-carbonitrile (0.232 g, 1.17 mmol) in DMF (2 mL) was added K 2 CO 3 (0.215 g, 1.56 mmol) was added at room temperature. The reaction mixture was stirred for 2 h, diluted with water (10 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and purified with 63% ACN in water (+10 mM NH 4 HCO 3) to give 5-bromo-1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-oxopyridine-3-carbonitrile as a brown solid (0.280 g, 85.8%): LCMS (ESI) C 17 H 12 BrClN 4 O 2 [M + H] + Calculated values: 419, 421, 423 (2 : 3 : 1), measured values: 419, 421, 423 (2 : 3 : 1); 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.83 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 7.35-7.26 (m, 2H), 7.26-7.18 (m, 2H), 5.50 (s, 2H), 3.06-2.87 (m, 4H).

[0372] Step B: 1,4-Dioxane (1 mL) and H 2 5-Bromo-1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-oxopyridine-3-carbonitrile (0.100 g, 0.238 mmol) and NaHCO in 2H2O (0.5 mL) 3 (40.0 mg, 0.476 mmol), 2,4,6-trimethylboroxine (0.179 g, 1.43 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (17.4 mg, 0.0240 mmol) was added at room temperature under nitrogen atmosphere. The reaction mixture was degassed under vacuum and purged with nitrogen three times, then heated to 80° C. for 16 h. The resulting mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and diluted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC with the following conditions: Column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 60% B, 60% B in 5 min; Wavelength: UV 210 nm; Retention time: 4.98 min. The fractions containing the desired product were collected and concentrated under reduced pressure to give 1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methyl-6-oxopyridine-3-carboxamide as a yellow solid (2.70 mg, 3.04%): LCMS (ESI) C 18 H 17 ClN 4 O 3 [M + H] + Calculated values: 373, 375 (3 : 1) Measured values: 373, 375 (3 : 1); 1 H NMR (300 MHz, CD 3 OD) δ 8.33 (d, J = 2.53 Hz, 1H), 7.92-7.87 (m, 1H), 7.27-7.19 (m, 2H), 7.18-7.08 (m, 2H), 5.45 (s, 2H), 3.02-2.98 (m, 4H), 2.14 (s, 3H).

[0373] [Example 3] Compound 29 (4-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-methyl-5-oxopyrazine-2-carboxamide)

[0374] [ka]

[0375] Step A: To a stirred mixture of methyl 5-chloro-6-methylpyrazine-2-carboxylate (2.00 g, 10.7 mmol) and LiOH (1.28 g, 53.6 mmol) in THF (14 mL) was added H2 HO (7 mL) was added dropwise at room temperature. The reaction mixture was stirred for 16 h, concentrated under reduced pressure and acidified to pH 5 with HCl (1 M). The precipitate was collected by filtration and washed with water (4×5 mL) to give 6-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylic acid as an off-white solid (1.50 g, 90.8%): LCMS (ESI) C 6 H 6 N 2 O 3 [M + H] + Calculated value: 155 Measured value: 155; 1 H NMR (300 MHz, DMSO-d 6 ) δ12.62-12.58 (brs, 2H), 7.93 (s, 1H), 2.28 (s, 3H).

[0376] Step B: To a stirred mixture of 5-hydroxy-6-methylpyrazine-2-carboxylic acid (0.500 g, 3.24 mmol) and oxalyl chloride (2.05 g, 16.2 mmol) in DCM (15 mL) was added dropwise at room temperature. The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL), stirred for 0.5 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 35% ACN in water (+0.05% TFA) to give methyl 6-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylate as a yellow solid (0.100 g, 18.3%): LCMS (ESI) C 7 H 8 N 2 O 3 [M + H] + Calculated value: 169 Measured value: 169; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.60 (s, 1H), 7.99 (s, 1H), 3.78 (s, 3H), 2.28 (s, 3H).

[0377] Step C: To a stirred solution of methyl 5-hydroxy-6-methylpyrazine-2-carboxylate (80.0 mg, 0.470 mmol) and (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol (0.150 g, 0.570 mmol) in DMF (3 mL) was added K 2 CO 3 (0.130 g, 0.950 mmol) and NaI (7.13 mg, 0.0500 mmol) were added at room temperature. The reaction mixture was stirred for 2 h, diluted with water (10 mL) and extracted with EA (4×20 mL). The combined organic layers were washed with brine (2×20 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and purified with 50% ACN in water (+10 mM NH 4 HCO 3 ) to give methyl 4-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-methyl-5-oxopyrazine-2-carboxylate as a yellow solid (0.150 g, 77.9%): LCMS (ESI) C 18 H 17 ClN 4 O 5 [M + H] + Calculated values: 405, 407 (3 : 1) Measured values: 405, 407 (3 : 1); 1 H NMR (300 MHz, CDCl 3 ) δ 8.14 (s, 1H), 7.35-7.31 (m, 4H), 5.32 (s, 2H), 5.16-5.12 (m, 1H), 3.96 (s, 3H), 3.17-3.10 (m, 2H), 2.56 (s, 3H).

[0378] Step D: Methyl 4-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-methyl-5-oxopyrazine-2-carboxylate (50.0 mg, 0.120 mmol) was dissolved in MeOH with NH 3 (7M, 1.5 mL) and the reaction mixture was stirred at 40° C. for 4 h and concentrated under reduced pressure. The crude product (50.0 mg) was purified by preparative HPLC under the following conditions: Column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (+0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 50% B, 50% B in 6.5 min; Wavelength: UV254 / 210 nm; Retention time: 5.68 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give 4-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-methyl-5-oxopyrazine-2-carboxamide as an off-white solid (29.0 mg, 60.2%). LCMS (ESI) C 17 H 16 ClN 5 O 4 [M + H] + Calculated values: 390, 392 (3 : 1) Measured values: 390, 392 (3 : 1); 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.45 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 7.37-7.32 (m, 4H), 5.56-5.51 (m, 3H), 4.95-4.92 (m, 1H), 3.05-2.90 (m, 2H), 2.37 (s, 3H).

[0379] [Example 4] Compound 33 ((S)-6-amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-methylpyrimidin-4(3H)-one)

[0380] [ka]

[0381] Step A: To a stirred mixture of 6-chloro-5-methylpyrimidin-4-amine (0.500 g, 3.48 mmol) in MeOH (8 mL) was added NaOMe (0.282 g, 5.22 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 24 h, cooled to room temperature, and concentrated under reduced pressure to give 6-methoxy-5-methylpyrimidin-4-amine as an off-white solid (0.500 g, crude), which was used directly in the next step without purification: LCMS (ESI) C 6 H 9 N 3 O[M+H] + Calculated value: 140, actual value 140.

[0382] Step B: A solution of 6-methoxy-5-methylpyrimidin-4-amine (0.500 g, 3.59 mmol) in HBr (5 mL, 33% in AcOH) was stirred at 100° C. for 1 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (1 / 1) to give 6-amino-5-methyl-3H-pyrimidin-4-one as a yellow solid (1.10 g, crude with silica), which was used directly in the next step without purification: LCMS (ESI) C 5 H 7 N 3 O[M+H] + Calculated value: 126, actual value 126.

[0383] Step C: To a stirred mixture of (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol (0.100 g, 0.366 mmol) and 6-amino-5-methyl-3H-pyrimidin-4-one (0.206 g, 1.65 mmol) in DMF (1 mL) was added K 2 CO 3(0.101 g, 0.732 mmol) was added at room temperature. The reaction mixture was stirred for 1 h, diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (5×2 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions: Column: X Bridge Prep OBD C18 column, 19×250 mm, 5 μm; Mobile phase A: water (+10 mM NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 28% B to 43% B, 43% B in 6 min; detector: UV254 / 220 nm; retention time: 5.41 min. Fractions containing the desired product were collected and concentrated under reduced pressure to give (S)-6-amino-3-((3-(2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-methylpyrimidin-4(3H)-one as an off-white solid (32.1 mg, 23.70%): LCMS (ESI) C 16 H 16 ClN 5 O 3 [M + H] + Calculated value: 362, 364 (3 : 1) Measured value: 362, 364 (3 : 1); 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.41-7.32 (m, 4H), 6.40 (s, 2H), 5.63 (d, J = 4.9 Hz, 1H), 5.26 (s, 2H), 5.02-4.92 (m, 1H), 3.04-2.89 (m, 2H), 1.73 (s, 3H).

[0384] [Example 5] Compound 63 (5-chloro-1-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-oxopyrimidine-4-carbonitrile)

[0385] [ka]

[0386] Step A: To a stirred solution of 5-chloro-1-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-oxopyrimidine-4-carboxamide (70.0 mg, 0.171 mmol) in pyridine (2 mL) was added TFAA (1 mL) dropwise at 0° C. The reaction was stirred under nitrogen at 25° C. for 2 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography and purified with 50% ACN in water (+10 mM NH 4 HCO 3 ) to give 5-chloro-1-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-oxopyrimidine-4-carbonitrile as a brown solid (26.0 mg, 38.9%); LCMS (ESI) C 16 H 11 Cl 2 N 5 O 3 [M-H] - Calculated values: 390, 392 (3 : 2), measured values: 390, 392 (3 : 2); 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 7.35-7.31 (m, 4H), 5.63 (d, J = 4.8 Hz, 1H), 5.55 (s, 2H), 4.98-4.92 (m, 1H), 3.05-2.94 (m, 2H).

[0387] The compounds in Table 1 below were prepared by using the procedures described in Schemes 1-8 or by methods analogous to those described for compounds 4, 29, 33, or 63 in Examples 2-5.

[0388] [Table 1-1]

[0389] [Table 1-2]

[0390] [Table 1-3]

[0391] [Table 1-4]

[0392] [Table 1-5]

[0393] [Table 1-6]

[0394] The compounds in Table 2 below can be prepared by using the procedures described in Schemes 1-8, or by methods analogous to those described for compounds 4, 29, 33, or 63 in Examples 2-5.

[0395] [Table 2-1]

[0396] [Table 2-2]

[0397] The compounds in Table 3 below can be prepared by using the procedures described in Schemes 1-8, or by methods analogous to those described for compounds 4, 29, 33, or 63 in Examples 2-5.

[0398] [Table 3-1]

[0399] [Table 3-2]

[0400] [Table 3-3]

[0401] [Example 6] Assessment of TRPA1 inhibitor activity This assay was used to evaluate the inhibitory activity of the disclosed compounds against the human TRPA1 channel.

[0402] cell culture CHO cells inducibly expressing human TRPA1 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, Zeocin (100 μg / ml), and blasticidin (10 μg / ml). Expression was induced by the addition of doxycycline (1 μg / ml) 24 hours prior to the experiment. Cells for use in electrophysiology were plated in plastic culture flasks and maintained at 4 °C in 5% CO according to ChanPharm's SOPs. 2 Grown in a humidified tissue culture incubator at 37° C. Stocks were maintained in cryogenic storage.

[0403] solution Cells were incubated in 80 mM NaCl, 60 mM NMDG, 4 mM KCl, 2 mM CaCl 2 , 6 mM MgCl 2The cells were bathed in an extracellular solution containing 5 mM glucose, 10 mM HEPES, 3 mM HEDTA; pH adjusted to 7.4 with NaOH; 305-310 mOsm. All compounds were dissolved in DMSO at 30 mM. The intracellular solution contained 10 mM CsCl, 110 mM CsF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES, 4 mM MgATP, 0.25 mM NaGTP, 4 mM BAPTA; pH adjusted to 7.2 with CsOH; 285-290 mOsm. Compound stock solutions were freshly diluted in the external solution to concentrations of 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, and 30 μM. The highest content of DMSO (0.1%) was present at 30 μM.

[0404] Patch clamp recordings and compound application All experiments were performed at room temperature. Each cell served as its own control. In preparation for the current recording session, the intracellular solution (see above) was loaded into the intracellular compartment of the automated patch clamp platform SyncroPatch (Nanion) chip, and the cell suspension was pipetted into the extracellular compartment. After establishment of the whole-cell configuration, membrane current recordings and compound application were enabled by SyncroPatch. TRPA1 currents were evoked by applying carvacrol (300 μM) at a constant holding potential of -60 mV (see Table A below).

[0405] [Table A]

[0406] Data analysis I C 50 To determine IC values, AUC and peak values ​​obtained in the presence of a given compound concentration were normalized to control values ​​in the absence of compound. IC values ​​were calculated by fitting the normalized data to the Hill equation using DataControl384 (proprietary software from Nanion). 50 derived the value.

[0407] [Example 7] Assessment of hERG activity This assay was used to evaluate the inhibitory activity of the disclosed compounds against the hERG channel.

[0408] cell culture CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium with glutamine containing 10% heat-inactivated FBS, 1% penicillin / streptomycin, hygromycin (100 μg / ml), and G418 (100 μg / ml). Cells for use in electrophysiology were plated in plastic culture flasks and incubated at 4 °C for 3 h at 20 °C for 1 h at 5% CO according to ChanPharm's SOPs. 2 Grown in a humidified incubator at 37° C. Stocks were maintained in cryogenic storage.

[0409] solution Cells were incubated in 140 mM NaCl, 4 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 The cells were bathed in an extracellular solution containing 10 mM KCl, 5 mM glucose, and 10 mM HEPES; pH adjusted to 7.4 with NaOH; 295-305 mOsm. The intracellular solution contained 10 mM KCl, 110 mM KF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 280-285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted in the external solution to concentrations of 50 μM and 100 μM. The highest content of DMSO (0.15%) was present at 50 μM.

[0410] Potential Protocol All experiments were performed at room temperature. Each cell served as its own control. In preparation for the recording session, the intracellular solution (see above) was loaded into the intracellular compartment of the automated patch clamp platform SyncroPatch (Nanion) chip, and the cell suspension was pipetted into the extracellular compartment. After establishment of the whole-cell configuration, membrane current recordings and compound application were enabled by SyncroPatch. hERG currents were evoked by repeating fixed amplitude voltage pulse patterns (depolarization: +20 mV amplitude, 300 ms duration; repolarization: -50 mV, 300 ms duration) at 3 s intervals from a holding potential of -80 mV.

[0411] Data analysis Data acquisition and analysis was performed using DataControl384 (proprietary software from Nanion). The last single pulse (i.e., repolarization step to -50 mV; tail current) in the pulse train at a given compound concentration was used to determine inhibition (percentage). AUC and peak values ​​obtained in the presence of compound were normalized to control values ​​in the absence of compound.

[0412] Table 4 provides a summary of the inhibitory activity of certain selected compounds of the invention against the TRPA1 and hERG channels.

[0413] [Table 4-1]

[0414] [Table 4-2]

[0415] [Table 4-3]

[0416] [Table 4-4]

[0417] Table 5 provides a summary of the inhibitory activity of certain selected compounds of the invention against the TRPA1 and hERG channels.

[0418] [Table 5-1]

[0419] [Table 5-2]

[0420] [Table 5-3]

[0421] [Table 5-4]

Claims

1. Compounds of formula I, or pharmaceutically acceptable salts thereof, or tautomers thereof: 【Chemistry 1】 (In the formula, Y is N or CR ２ And; Z is N or CR ３ And; R １ H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, saturated heterocycle, CN, OR ａ , SR ａ , or NR ａ R ｂ And; R ２ is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocyclic ring, partially saturated heterocyclic ring, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C １～４ alkyl-CN, OR ａ SR ａ NR ａ R ｂ (C=O)NR ａ R ｂ NR ｂ (C=O)R ａ (C=O)R ａ (C=O)OR ａ -C １～４ alkyl-OR ａ -C １～４ alkyl-SR ａ -C １～４ alkyl-NR ａ R ｂ -C １～４ alkyl-COOR ａ -C １～４ alkyl-CONR ａ R ｂ -C １～４ alkyl-NR ａ COR ｂ O-C １～４ alkyl-R ａ or NR ａ -C １～４ alkyl-R ｂ ; R ３ H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cycloalkyl halide, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C １～４ Alkyl-CN, OR ａ , SR ａ , NR ａ R ｂ (C=O)NR ａ R ｂ , NR ｂ (C=O)R ａ (C=O)R ａ (C=O) OR ａ , -C １～４ Alkyl-OR ａ , -C １～４ Alkyl-SR ａ , -C １～４ Alkyl-NR ａ R ｂ , -C １～４ Alkyl-COOR ａ , -C １～４ Alkyl-CONR ａ R ｂ , -C １～４ Alkyl-NR ａ COR ｂ O-C １～４ Alkyl-R ａ , or NR ａ -C １～４ Alkyl-R ｂ And; R ４ H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, aryl, heteroaryl, saturated heterocycle, CN, OR ａ , SR ａ , -C １～４ Alkyl-OR ａ , or NR ａ R ｂ And; 【Chemistry 2】 H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , or -C １～４ Alkyl-OR ａ Each aryl or heteroaryl is optionally substituted with one to five substituents independently selected from the group consisting of; L １ is -(CR ５ R ６ ) ｎ -; R ５ Each occurrence is independently H, D, alkyl, halogen, alkyl halogen, cycloalkyl, cycloalkyl halogen, CN, OR ａ , or -C １～４ Alkyl-OR ａ And; R ６ Each occurrence of R is, independently, H, D, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, CN, OR ａ , or -C １～４ alkyl-OR ａ ; n is either 2 or 3; L ２ is, -CR ７ R ８ - and; R ７ This includes H, D, alkyl, alkyl halogen, cycloalkyl, cycloalkyl halogen, CN, or -C １～４ Alkyl-OR ａ And; R ８ This includes H, D, alkyl, alkyl halogen, cycloalkyl, cycloalkyl halogen, CN, or -C １～４ Alkyl-OR ａ And; R ａ and R ｂ Each occurrence is independently H, alkyl, and (C=O)R. ｘ , (C=O)N(R ｘ ) ２ SO ２ R ｘ , NR ｘ (C=O)NR ｘ２ , a saturated heterocycle, aryl, or heteroaryl containing one to three heteroatoms selected from the group consisting of cycloalkyl, alkyl halide, heteroalkyl, heteroalkyl halide, cycloalkyl halide, N, O, and S; or alternatively, R ａ and R ｂ Together with the carbon or nitrogen atom to which they are bonded, they form a cycloalkyl group, or a saturated heterocycle comprising the nitrogen atom and 0 to 3 additional heteroatoms selected from the group consisting of N, O, and S; Where applicable, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ａ , or R ｂ The alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl are, wherever the valence allows, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, OR ｘ ,-(CH ２ ) １～２ OR ｘ , N(R ｘ ) ２ ,-(CH ２ ) １～２ N(R) ｘ ) ２ (C=O)R ｘ , (C=O)N(R ｘ ) ２ , NR ｘ (C=O)R ｘ They are optionally substituted by 1 to 4 substituents independently selected from the group consisting of , and oxo; R ｘ Each occurrence is independently a heterocycle substituted with H, D, alkyl, or of any choice; or alternatively, two R ｘ The groups, along with the nitrogen atoms to which they are bonded, are optionally substituted by alkyl groups, forming a heterocycle comprising the nitrogen atoms and 0 to 3 additional heteroatoms selected from the group consisting of N, O, and S; However, when Z is N, R ４ (This is not OH).

2. i) Y is a) CR ２ or b) N and / or, ii) Z is a) CR ３ or b) N The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a tautomer thereof.

3. i) n is 2, and / or, ii) R ５ Each occurrence is independently a) cycloalkyl, halogenated cycloalkyl, -C １～４ Alkyl-OR ａ , or CN, or b) H, D, alkyl, halogen, OR ａ , or fluorinated alkyl, or c) H, D, CH ３ ,CH ２ CH ３ , OH, F, Cl, or Br and / or, iii) R ６ Each occurrence is independently a) cycloalkyl, halogenated cycloalkyl, -C １～４ Alkyl-OR ａ , or CN, or b) H, D, alkyl, halogen, OR ａ , or fluorinated alkyl, or c) H, D, CH ３ ,CH ２ CH ３ , OH, F, Cl, or Br The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a tautomer thereof.

4. L １ However, the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a tautomer thereof, selected from the group consisting of the following. i)-CH ２ -CH ２ -、-CH(CH ３ )-CH ２ -、-CH ２ -CH(CH ３ )-、-CH ２ -C(CH ３ ) ２ -、-CH(OH)-CH ２ -、-CH ２ -CH(OH)-、 【Transformation 3】 or ii)-CH ２ -CH ２ -、 【Chemistry 4】

5. Formulas Ia, Ib, or Ic: 【Transformation 5】 (In the formula, R ５ａ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R ５ｂ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R ６ａ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R ６ｂ Each occurrence is independent of H, D, alkyl, halogen, OR ａ (or fluorinated alkyl) A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

6. i) R ７ a) cycloalkyl, halogenated cycloalkyl, CN, or -C １～４ Alkyl-OR ａ a) is H, D, alkyl, or fluorinated alkyl, or c) H, D, CH ３ , or CH ２ CH ３ That is, and / or, ii) R ８ a) cycloalkyl, halogenated cycloalkyl, CN, or -C １～４ Alkyl-OR ａ a) is H, D, alkyl, or fluorinated alkyl, or c) H, CH ３ , or CH ２ CH ３ That is, A compound according to any one of claims 1, 2, and 5, a pharmaceutically acceptable salt thereof, or a tautomer thereof.

7. L ２ but, i) -CH ２ -, -CH(CH ３ )-,-C(CH ３ ) ２ -, and -CH(CH ２ CH ３ Selected from the group consisting of ) or ii)-CH ２ - is, The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a tautomer thereof. 【Request Item 8】 【Transformation 6】 but, i) H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , and -C １～４ Alkyl-OR ａ A phenyl compound that is optionally substituted with 1 to 5 substituents independently selected from the group consisting of the following: ii) 【Chemistry 10】 Selected from the group consisting of, iii) H, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , and -C １～４ Alkyl-OR ａ A 5- or 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of the following: or iv) 【Chemistry 13】 A compound according to any one of claims 1, 2, and 5, selected from the group consisting of the above, a pharmaceutically acceptable salt thereof, or a tautomer thereof.

9. Formulas IIa, IIb, or IIc: 【Transformation 7】 (In the formula, R ５ａ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R ５ｂ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R ６ａ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R ６ｂ Each occurrence is independent of H, D, alkyl, halogen, OR ａ , or fluorinated alkyl; R １１ Each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , or -C １～４ Alkyl-OR ａ And; R １２ Each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , or -C １～４ Alkyl-OR ａ And; R １３ Each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , or -C １～４ Alkyl-OR ａ And; R １４ Each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , or -C １～４ Alkyl-OR ａ And; R １５ Each occurrence is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR ａ , SR ａ , NR ａ R ｂ , -C １～４ Alkyl-SR ａ , or -C １～４ Alkyl-OR ａ (is) Optional, R １１ , R １２ , R １４ , and R １５ However, it is H; R １３ However, H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF ３ , OR ａ , SR ａ , NR ａ R ｂ , or -C １～４ Alkyl-OR ａ That is, Optionally, R １３ However, CH ３ ,CH ２ CH ３ , OH, F, Cl, Br, OCH ３ ,CH ２ OCH ３ CF ３ , CN, C≡CH, or 【Transformation 8】 That is, The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a tautomer thereof.

10. i) R １ but, a) Cycloalkyl, alkyl halogen, or cycloalkyl halogen, b) H, D, halogen, alkyl, CN, CF ３ , OR ａ , SR ａ , or NR ａ R ｂ is, or, c) H, D, CH ３ ,CH ２ CH ３ , OH, F, Cl, Br, OCH ３ CF ３ , CN, NH ２ , NHCH ３ , N (CH ３ ) ２ , and 【Chemistry 14】 Selected from the group consisting of, and / or, ii) R ２ but, a) H, D, halogen, CN, CF ３ , OR ａ , SR ａ , NR ａ R ｂ (C=O)NR ａ R ｂ , NR ｂ (C=O)R ａ (C=O)R ａ (C=O) OR ａ , -C １～４ Alkyl-CN, -C １～４ Alkyl-OR ａ , -C １～４ Alkyl-SR ａ , -C １～４ Alkyl-NR ａ R ｂ , -C １～４ Alkyl-COOR ａ , -C １～４ Alkyl-CONR ａ R ｂ , -C １～４ Alkyl-NR ａ COR ｂ O-C １～４ Alkyl-R ａ , or NR ａ -C １～４ Alkyl-R ｂ That is, b) If the valence allows, halogens, alkyls, CNs, OR ｘ ,-(CH ２ ) １～２ OR ｘ , N(R ｘ ) ２ ,-(CH ２ ) １～２ N(R) ｘ ) ２ (C=O)R ｘ , (C=O)N(R ｘ ) ２ , NR ｘ (C=O)R ｘ A saturated heterocycle, a partially saturated heterocycle, or a heteroaryl molecule, each optionally substituted with one to three substituents selected from the group consisting of , and oxo. c) If valence allows, halogens, CN, OR ｘ ,-(CH ２ ) １～２ OR ｘ , N(R ｘ ) ２ ,-(CH ２ ) １～２ N(R) ｘ ) ２ (C=O)R ｘ , (C=O)N(R ｘ ) ２ , NR ｘ (C=O)R ｘ The alkyl, alkenyl, or alkynyl compounds are each optionally substituted with one to three substituents selected from the group consisting of , and oxo. d) Cycloalkyl, aryl, or alkylaryl, alkylheteroaryl, or e)H、D、CH ３ 、CH ２ CH ３ 、OH、F、Cl、Br、I、OCH ３ 、CF ３ 、CN、NH ２ 、NXCH ３ 、N (CH ３ ) ２ 、CH=CH ２ 、 【Chemistry 15】 Selected from the group consisting of, and / or, iii) R ３ but, a) H, D, halogen, alkyl, alkyl halide, heteroaryl, or CN b) OR ａ , SR ａ , NR ａ R ｂ (C=O)NR ａ R ｂ , -C １～４ Alkyl-CN, -C １～４ Alkyl-OR ａ , -C １～４ Alkyl-SR ａ , -C １～４ Alkyl-NR ａ R ｂ , or -C １～４ Alkyl-CONR ａ R ｂ That is, c) Alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, alkylaryl, alkylheteroaryl, NR ｂ (C=O)R ａ (C=O)R ａ (C=O) OR ａ , -C １～４ Alkyl-COOR ａ , -C １～４ Alkyl-NR ａ COR ｂ O-C １～４ Alkyl-R ａ , or NR ａ -C １～４ Alkyl-R ｂ is, or, HH、D、CH ３ 、CH ２ CH ３ 、OH、F、Cl、Br、OCH ３ 、CF ３ 、&N、CH ２ CN、CH=CH ２ 、NH ２ 、NXCH ３ 、N (CH ３ ) ２ 、 【Chemistry 16】 Selected from the group consisting of, and / or, iv) R ４ but, a) Cycloalkyl, alkyl halogen, or cycloalkyl halogen, b) H, D, halogen, alkyl, CN, CF ３ , OR ａ , SR ａ , -C １～４ Alkyl-OR ａ , or NR ａ R ｂ is, or, c)H、D、CH ３ 、CH ２ CH ３ 、OH、F、Cl、Br、OCH ３ 、CF ３ 、CN、NH ２ 、NXCH ３ 、N (CH ３ ) ２ 、CH ２ OH 【Chemistry 17】 Selected from the group consisting of, and / or, v) Regarding Ra and Rb, a) R ａ or R ｂ At least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocyclic, aryl, or heteroaryl. b) R ａ or R ｂ At least one occurrence of H, D, Me, Et, Pr, CH independently ２ CH ２ OH, phenyl, or [Chemistry 18] A heterocycle selected from the group consisting of; the heterocycle is alkyl, OH, oxo, or (C=O)C, wherever the valency allows. １～４ Optionally substituted with alkyl groups, c) R ａ or R ｂ The appearance of at least one of H, Me, phenyl, 【Chemistry 19】 is, or, d) R ａ and R ｂ However, together with the nitrogen atom to which they are bonded, they form an optionally substituted heterocycle containing the nitrogen atom and 0 to 3 additional heteroatoms selected from the group consisting of N, O, and S. and / or, vi) R ｘ Each occurrence is independent, a) A heterocycle optionally substituted with H, alkyl, or alkyl, halogen, or OH. b) It is H or alkyl, or c) It is H or Me, A compound according to any one of claims 1, 2, 5, and 9, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

11. A compound according to claim 1, selected from the group consisting of the compounds of Examples 2 to 5 and Tables 1 to 5, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

12. A pharmaceutical composition comprising at least one compound according to any one of claims 1, 2, 5, and 9, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, and a pharmaceutically acceptable carrier or diluent.

13. A pharmaceutical composition for use in a method of treating a condition in a mammalian species requiring the compound, comprising a compound according to any one of claims 1, 2, 5, and 9, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the method comprises administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof to the mammalian species, wherein the condition is selected from the group consisting of pain, skin disorders, respiratory diseases, fibrotic diseases, inner ear disorders, other disorders of heat or thermoregulation, urinary tract or bladder disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastroenterological disorders, and cardiovascular disorders.

14. i) The pain is acute pain, chronic pain, complex regional pain syndrome, inflammatory pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, hyperalgesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, nerve injury, post-stock pain, or pain associated with teeth and tooth injury. ii) The urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, unstable bladder, or subvesical urethral obstruction. iii) The skin disorder is a burn, psoriasis, eczema, or itching. iv) The skin disorder is atopic dermatitis or psoriasis-induced itching. v) The respiratory disease is an inflammatory airway disease, airway hypersensitivity, idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough. vi) The ischemia is a disorder related to CNS hypoxia or reduced blood flow to the CNS. vii) The autoimmune disease is rheumatoid arthritis or multiple sclerosis. viiii) The central nervous system disorder is related to neurodegeneration, ix) The gastrointestinal disorder is inflammatory bowel disease, esophagitis, gastroesophageal reflux disease, irritable bowel syndrome, vomiting, or gastric and duodenal ulcers. x) The cardiovascular disorder is a stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy, or xi) The mammalian species is human, The pharmaceutical composition according to claim 13.

15. A pharmaceutical composition for use in a therapeutic method for inhibiting transient receptor potential ankyrin 1 (TRPA1) in a mammalian species requiring it, comprising the compound according to any one of claims 1, 2, 5, and 9, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the method comprises administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof to the mammalian species, wherein the mammalian species is optionally human.

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