Pyridone compounds as TRPA1 inhibitors

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof is described, wherein the substituents are as defined herein. Also described are pharmaceutical compositions comprising the same and methods of using the same for treating medical conditions, including pain, skin disorders, respiratory tract disorders, fibrotic disorders, inner ear disorders, fever, or other body temperature regulation disorders. # imgabs0 #

Description

[0001] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the 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

[0003] 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.

[0004] Incorporated by Reference

[0005] All documents cited herein are hereby incorporated by reference in their entirety. Field of the Invention

[0006] The present invention relates generally to the field of pharmaceutical sciences. More specifically, the present invention relates to compounds and compositions useful as pharmaceuticals that are potassium channel blockers. Background Art

[0007] Transient receptor potential channels (TRP channels) are a family of voltage-gated ion channels that are primarily located on 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) is a member of the TRPA subfamily and is a cation-selective, calcium-permeable ion channel (Montell, C., 2005, Sci. STKE, 272: re3).

[0008] 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. TRPA1 protein is a homotetramer. Each subunit has six transmembrane helices that form a central pore surrounded by a voltage sensor-like domain. TRPA1 protein also contains a C-terminal extension (Terrett, JA et al., 2021, J. Med. Chem. 64, 7, 3843–3869).

[0009] TRPA1 is highly expressed in the plasma membrane of primary sensory neurons, where it plays the role of a multimodal sensor for exogenous and endogenous stimulation. These sensory neurons are located in dorsal root and nodose ganglion and are connected to 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 the most common in small diameter sensory neurons, and it is co-localized with markers of peptide-ergic 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 functions primarily as a sensor of environmental irritants and is thought to elicit somatic sensory patterns such as pain, cold, and itch.

[0010] TRPA1 is activated by a series of endogenous and exogenous pain and inflammatory stimuli. Specifically, TRPA1 can be activated by external stimuli such as allyl isothiocyanate (AITC) and allicin. TRPA1 can also be activated by cinnamaldehyde, which acts as an agonist to activate the channel by covalently modifying the cysteine ​​residues in the N-terminal ankyrin repeat sequence (Terrett, JA et al., 2021, J.Med.Chem.64,7,3843–3869). TRPA1 can also be activated by noxious stimuli, including cold temperatures and spicy natural compounds such as mustard, cinnamon and garlic.

[0011] TRPA1 knockout (KO) mouse models show that this ion channel is involved in pain signaling. TRPA1 activity plays a role in a variety of diseases in patients. Human gain-of-function TRPA1 mutations are associated with familial episodic pain syndrome (FEPS) (Kremeyer, B. et al., 2010, Neuron 66, 5, 671-680). The discovery of human genetic links between TRPA1 and FEPS suggests that TRPA1 plays an important role in human pain. It is known that patients carrying a single gain-of-function mutation in TRPA1 experience debilitating upper body pain triggered by fasting, cold and fatigue. Several anesthetics are known to be TRPA1 agonists, including isoflurane (Matta, JA et al., 2008, PNAS105, 25, 8784-8789), which provides a theoretical basis for the use of TRPA1 inhibitors to relieve postoperative pain.

[0012] TRPA1 activation is associated with 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 triggered by the activity of TRPA1 expressed in airway smooth muscle cells, and TRPA1 antagonists can relieve sensory neurological and clinical symptoms (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). Cough may be associated with asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Cough may also be a post-viral cough or a chronic idiopathic cough as well as a cough in sensitive 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), however, 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 triggered by cough triggering events such as cigarette smoke extract (CSE) oxidative stress, release of inflammatory mediators, and downregulated antioxidant gene expression (Lin, Y.-J. et al., 2015, J. Appl. Physiol. 118, 273–281; Wang, Z. et al., 2019, Front. Pharmacol. 10, 1253, 1-11).

[0013] TRPA1 is associated with dermatitis and pruritus. TRPA1 antagonists are effective for 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), psoriasis-related pruritus (Wilson, SR et al., 2013 J. Neurosci. 33, 22, 9283–9294) and IL-31-dependent pruritus (Cevikbas, F. et al., 2014, J. Allergy Clin. Immunol. 133, 2, 448–460). It is also reported that the pruritus induced by AITC after TRPA1 specific inhibition is relieved by direct clinical support (Balestrini, A. et al., 2021, J.Exp.Med.218,4, e20201637,1-23).In addition, TRPA1 antagonists are effective in the behavioral model of migraine-related allodynia (Edelmayer, RM et al., 2012, Pain 2012,153,9,1949-1958).

[0014] Inflammatory mediators and nerve damage increase TRPA1 expression, which shows the role of 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 show that TRPA1 plays a role in inflammatory pain associated with this metabolic disorder. TRPA1 may also play a role in the pathogenesis of cancer and other inflammatory diseases. Studies have further shown that TRPA1 is associated with migraine pain caused by neurogenic inflammation (Edelmayer, RM et al., 2012, Pain 153, 9, 1949-1958). This may be due to the activation of trigeminal TG neurons by nasal administration of TRPA1 activators.

[0015] TRPA1 also plays a role in arthritis and osteoarthritis pain (Horvath, A. et al., 2016, Arthritis Res. Ther. 18, 6, 1-14). It has been shown that activation of TRPA1 triggers an inflammatory response in osteoarthritis chondrocytes (Nummenmaa, E. et al., 2016, Arthritis Res. Ther. 18, 185). This is supported by the following observations: TRPA1 inhibition and gene deletion reduce knee swelling, histopathological destruction and inflammatory mediators in osteoarthritis mouse chondrocytes and murine 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 on osteoarthritic limbs in a knee swelling model (Horvath, A. et al., 2016, Arthritis Res. Ther. 18, 6).

[0016] TRPA1 also plays a role in colitis and visceral hypersensitivity, as well as in mediating gastrointestinal (GI) hypersensitivity to mechanical stimulation. 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). Additionally, colitis induced by dinitrobenzene sulfonic acid (DNBS) was attenuated following 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 GI inflammatory conditions 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).

[0017] TRPA1 is highly expressed in sensory neurons innervating the bladder, suggesting that TRPA1 is a potential 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).

[0018] Therefore, there remains a need to develop novel TRPAl inhibitors as agents for the treatment of a variety of conditions, disorders and diseases. Summary of the invention

[0019] In one aspect, compounds useful as TRPA1 inhibitors are described which have the formula I The structure of wherein the various substituents are defined herein. The compounds of Formula I described herein can block and inhibit TRPA1 and are used to treat a variety of conditions. Methods for synthesizing these compounds are also described herein. The pharmaceutical compositions described herein and methods for using these compositions can be used to treat conditions in vitro and in vivo. Such compounds, pharmaceutical compositions and methods of treatment have many clinical applications, including as pharmaceutically active agents and methods for treating pain, skin disorders, respiratory diseases, fibrotic diseases, inner ear disorders, fever or other body temperature regulation disorders, urinary tract disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders and cardiovascular disorders or combinations thereof.

[0020] In one aspect, a compound of Formula I or a pharmaceutically acceptable salt or tautomer thereof is described,

[0021]

[0022] in

[0023] Y is N or CR 2 ;

[0024] Z is N or CR 3 ;

[0025] R 1 is H, D, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, saturated heterocycle, CN, OR a , SR a or NR a R b ;

[0026] R 2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b ;

[0027] R 3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4Alkyl-R b ;

[0028] R 4 is H, D, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, saturated heterocycle, CN, OR a , SR a , -C1-4 alkyl-ORa or NR a R b ;

[0029] is aryl or heteroaryl, each optionally substituted by 1-5 substituents independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 ;

[0030] L 1 For –(CR 5 R 6 ) n –

[0031] R 5 Each occurrence of is independently H, D, alkyl, halogen, haloalkyl, cyclo

[0032] Alkyl, halocycloalkyl, CN, OR a or -C 1-4 Alkyl-OR a ;

[0033] R 6 Each occurrence of is independently H, D, alkyl, halogen, haloalkyl, cyclo

[0034] Alkyl, halocycloalkyl, CN, OR a or -C 1-4 Alkyl-OR a ;

[0035] n is 2 or 3;

[0036] L 2 For –CR 7 R 8 –

[0037] R 7 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4Alkyl-OR a ;

[0038] R 8 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4 Alkyl-OR a ;

[0039] R a and R b Each occurrence of is independently H, alkyl, (C=O)R x 、(C=O)N(R x ) 2 、SO 2 R x NR x (C=O)NR x2 , cycloalkyl, haloalkyl, heteroalkyl, haloheteroalkyl, halocycloalkyl, a saturated heterocycle containing 1-3 heteroatoms each selected from N, O and S, aryl or heteroaryl; or alternatively, R a and R b Together with the carbon or nitrogen atom to which they are attached, they form a cycloalkyl group or a saturated heterocyclic ring comprising the nitrogen atom and 0 to 3 additional heteroatoms each selected from N, O and S;

[0040] 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 groups in the formula (a) are optionally substituted with 1 to 4 substituents independently selected from the following groups when valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 and oxo; and

[0041] R x Each occurrence of is independently H, D, alkyl or optionally substituted heterocycle; or alternatively two R x The groups together with the nitrogen atom to which they are attached form a heterocyclic ring which is optionally substituted by an alkyl group and comprises the nitrogen atom and 0 to 3 further heteroatoms each selected from N, O and S;

[0042] The condition is that when Z is N, R 4 Not for OH.

[0043] In any of the embodiments described herein, Y is CR 2 .

[0044] In any of the embodiments described herein, Y is N.

[0045] In any of the embodiments described herein, Z is CR 3 .

[0046] In any of the embodiments described herein, Z is N.

[0047] In any of the embodiments described herein, n is 2.

[0048] In any of the embodiments described herein, R 5 Each occurrence of is independently cycloalkyl, halocycloalkyl, -C 1-4 Alkyl-OR a or CN.

[0049] In any of the embodiments described herein, R 5 Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group.

[0050] In any of the embodiments described herein, R 5 Each occurrence of is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl or Br.

[0051] In any of the embodiments described herein, R 6 Each occurrence of is independently cycloalkyl, halocycloalkyl, -C 1-4 Alkyl-OR a or CN.

[0052] In any of the embodiments described herein, R 6 Each occurrence of is independently H, D, alkyl, halogen, OR aor a fluoroalkyl group.

[0053] In any of the embodiments described herein, R 6 Each occurrence of is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl or Br.

[0054] In any of the embodiments described herein, L 1 Selected from –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)–,

[0055] In any of the embodiments described herein, L 1 Selected from –CH 2 –CH 2 –

[0056]

[0057] In any of the embodiments described herein, the compound has the structure of Formula Ia, Ib or Ic:

[0058]

[0059] in

[0060] R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0061] R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0062] R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group; and

[0063] R 6b Each occurrence of is independently H, D, alkyl, halogen, ORa or a fluoroalkyl group.

[0064] In any of the embodiments described herein, R 7 is cycloalkyl, halogenated cycloalkyl, CN or -C 1-4 Alkyl-OR a .

[0065] In any of the embodiments described herein, R 7 is H, D, alkyl or fluoroalkyl.

[0066] In any of the embodiments described herein, R 7 H, D, CH 3 or CH 2 CH 3 .

[0067] In any of the embodiments described herein, R 8 is cycloalkyl, halogenated cycloalkyl, CN or -C 1-4 Alkyl-OR a .

[0068] In any of the embodiments described herein, R 8 is H, D, alkyl or fluoroalkyl.

[0069] In any of the embodiments described herein, R 8 H, CH 3 or CH 2 CH 3 .

[0070] In any of the embodiments described herein, the moiety L 2 Selected from –CH 2 –, –CH(CH 3 )–、–C(CH 3 ) 2 – and –CH(CH 2 CH 3 ).

[0071] In any of the embodiments described herein, L 2 For –CH 2 –.

[0072] In any of the embodiments described herein, is phenyl, which is optionally substituted by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NRa R b , -C 1-4 Alkyl-SR a and -C 1-4 Alkyl-OR a .

[0073] In any of the embodiments described herein, the compound has the structure of Formula IIa, IIb, or IIc:

[0074]

[0075] in

[0076] R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0077] R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0078] R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0079] R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0080] R 11 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a ;

[0081] R 12 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a ;

[0082] R 13 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a ;

[0083] R 14 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, 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

[0084] R 15 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a .

[0085] In any of the embodiments described herein, R 11 , R 12 , R 14 and R 15 is H; and R 13 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 .

[0086] In any of the embodiments described herein, R 13 CH 3 , CH 2 CH3 , OH, F, Cl, Br, OCH 3 , CH 2 OCH 3 CF 3 , CN, C≡CH or

[0087] In any of the embodiments described herein, Selected from

[0088] In any of the embodiments described herein, is a 5- or 6-membered heteroaryl group, which is optionally substituted by 1-4 substituents each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b and -C 1-4 Alkyl-OR a .

[0089] In any of the embodiments described herein, Selected from

[0090] In any of the embodiments described herein, R 1 is cycloalkyl, haloalkyl or halocycloalkyl.

[0091] In any of the embodiments described herein, R 1 H, D, halogen, alkyl, CN, CF 3 , OR a , SR a or NR a R b .

[0092] In any of the embodiments described herein, R 1 Selected from 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

[0093] In any of the embodiments described herein, R2 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

[0094] In any of the embodiments described herein, R 2 is a saturated heterocycle, a partially saturated heterocycle or a heteroaryl group, each of which is optionally substituted by 1 to 3 substituents selected from the following groups when valence permits: halogen, alkyl, 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 and oxo.

[0095] In any of the embodiments described herein, R 2is alkyl, alkenyl or alkynyl, each of which is optionally substituted by 1-3 substituents selected from the following when valence permits: 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 and oxo.

[0096] In any of the embodiments described herein, R 2 It is a cycloalkyl group, an aryl group, an alkylaryl group, or an alkylheteroaryl group.

[0097] In any of the embodiments described herein, R 2 Selected from H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, I, OCH 3 CF 3 、CN、NH 2 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 ,

[0098]

[0099]

[0100] In any of the embodiments described herein, R 3 is H, D, halogen, alkyl, haloalkyl, heteroaryl or CN.

[0101] In any of the embodiments described herein, R 3 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 , -C1-4 Alkyl-SR a , -C 1-4 Alkyl-NR a R b or -C 1-4 Alkyl-CONR a R b .

[0102] In any of the embodiments described herein, R 3 is alkenyl, alkynyl, cycloalkyl, saturated heterocyclic ring, partially saturated heterocyclic ring, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

[0103] In any of the embodiments described herein, R 3 Selected from H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 CF 3 、CN、CH 2 CN, CH=CH 2 NH 2 NHCH 3 、N(CH 3 ) 2 ,

[0104] In any of the embodiments described herein, R 4 is cycloalkyl, haloalkyl or halocycloalkyl.

[0105] In any of the embodiments described herein, R 4 H, D, halogen, alkyl, CN, CF 3 , OR a , SR a , -C 1-4 Alkyl-OR a or NR a Rb .

[0106] In any of the embodiments described herein, R 4 Selected from 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 , CH 2 OH,

[0107] In any 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.

[0108] In any of the embodiments described herein, R a or R b At least one occurrence of is independently H, D, Me, Et, Pr, CH 2 CH 2 OH, phenyl or a heterocycle selected from:

[0109] The heterocyclic ring is optionally substituted with alkyl, OH, oxo or (C=O)C 1-4 Alkyl substituted.

[0110] In any of the embodiments described herein, R a or R b At least one occurrence of H, Me, phenyl,

[0111] In any of the embodiments described herein, R a and R b Together with the nitrogen atom to which they are attached they form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 further heteroatoms each selected from N, O and S.

[0112] In any of the embodiments described herein, R x Each occurrence of is independently H, alkyl, or heterocycle optionally substituted with alkyl, halogen, or OH.

[0113] In any of the embodiments described herein, R x are independently H or alkyl.

[0114] In any of the embodiments described herein, R x is independently H or Me.

[0115] In any of the embodiments described herein, the compound is selected from the compounds in Examples 2-5 and Tables 1-5.

[0116] In another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0117] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the condition is selected from pain, skin disorders, respiratory diseases, fibrotic diseases, inner ear disorders, fever or other temperature regulation disorders, urinary tract or bladder disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, and cardiovascular disorders.

[0118] In any of the embodiments described herein, 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, hyperesthesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve damage, post-stroke pain, or pain associated with teeth and dental damage.

[0119] In any of the embodiments described herein, the urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, bladder instability, or bladder outlet obstruction.

[0120] In any of the embodiments described herein, the skin disorder is a burn, psoriasis, eczema, or pruritus.

[0121] In any of the embodiments described herein, the skin disorder is pruritus caused by atopic dermatitis or psoriasis.

[0122] In any of the embodiments described herein, the respiratory disease is inflammatory airway disease, airway hyperresponsiveness, idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough or chronic cough.

[0123] In any of the embodiments described herein, ischemia is a lack of CNS oxygen or a condition associated with reduced blood flow to the CNS.

[0124] In any of the embodiments described herein, the autoimmune disease is rheumatoid arthritis or multiple sclerosis.

[0125] In any of the embodiments described herein, the central nervous system disorder is associated with neurodegeneration.

[0126] In any of the embodiments described herein, the gastrointestinal disorder is inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, vomiting, or gastroduodenal ulcer.

[0127] In any of the embodiments described herein, the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

[0128] In any of the embodiments described herein, the mammalian species is a human.

[0129] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In any of the embodiments described herein, the mammalian species is a human.

[0131] Any of the embodiments disclosed herein can be appropriately combined with any other embodiment disclosed herein. The combination of any of the embodiments disclosed herein with any other embodiment disclosed herein is clearly encompassed. Specifically, the selection of one or more embodiments of a substituent group can be appropriately combined with the selection of one or more specific embodiments of any other substituent group. Such a combination can be carried out in any one or more embodiments of the application described herein or any formula described herein. DETAILED DESCRIPTION

[0132] definition

[0133] The following are definitions of the terms used in this specification. Unless otherwise stated, the initial definitions provided for the groups or terms herein apply to the groups or terms throughout this specification alone or as part of another group. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art are generally understood. It should be understood that the terms used herein are only for the purpose of describing certain embodiments and are not intended to be limiting.

[0134] 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, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. The term "(C 1 -C x )alkyl" or "C 1-x "Alkyl" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to x carbon atoms. For example, the term "(C 1 -C 4 ") alkyl" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and isobutyl. "Substituted alkyl" refers to an alkyl group substituted at any available point of attachment by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 R e NR 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)Ra 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded, optionally form a heterocyclic ring, and 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 themselves may be optionally substituted.

[0135] The term "alkenyl" refers to a straight or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include vinyl or allyl. The term "C 2 -C x "Alkenyl" or "C 2-x "Alkenyl" refers to a straight or branched hydrocarbon group containing 2 to x carbon atoms and at least one carbon-carbon double bond. For example, the term "C 2 -C 6The term "alkenyl" refers to a straight or branched hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 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, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E) "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, but are not limited to, one or more of the following: hydrogen, halogen, alkyl, haloalkyl (i.e., with a single halogen substituent or multiple halogen substituents such as CF 3 or CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 R e NR 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 NRb C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bound, optionally form a heterocyclic ring; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents may themselves be optionally substituted.

[0136] 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. The term "C 2 -C x Alkynyl" or "C 2-x "Alkynyl" refers to a straight or branched hydrocarbon group containing 2 to x carbon atoms and at least one carbon-carbon triple bond. For example, the term "C 2 -C 6 "Alkynyl" refers to a straight or branched 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 at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and R c together with the N to which they are bound, optionally form a heterocyclic ring; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents may themselves be optionally substituted.

[0137] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings, each ring containing 3 to 8 carbons. 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 at any available point of attachment by one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 R e NR 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 Rc NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bound, optionally form a heterocyclic ring; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiral or fused cyclic substituents, especially spiral cycloalkyl, spiral cycloalkenyl, spiral heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0138] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings, each containing 3 to 8 carbons. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted by one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR a 、S(=O)Re 、S(=O) 2 R e 、P(=O) 2 R e 、S(=O) 2 OR e 、P(=O) 2 OR e NR b R c NR b S(=O) 2 R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bound, optionally form a heterocyclic ring; and R eEach occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiral or fused cyclic substituents, especially spiral cycloalkyl, spiral cycloalkenyl, spiral heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0139] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, especially a monocyclic or bicyclic group such as phenyl, biphenyl or naphthyl. When containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, wherein two adjacent aromatic rings have two common carbon atoms. "Substituted aryl" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available connection point. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bound, optionally form a heterocyclic ring; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0140] The term "biaryl" refers to two aryl groups connected by a single bond. The term "biaryl" refers to two heteroaryl groups connected by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group connected by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group connected by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl 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 connected to a 6-membered aryl group. Other combinations and ring sizes can be specified similarly.

[0141] The term "carbocycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings, each ring containing 3 to 8 carbons, or a cyclic aromatic hydrocarbon group with 1 to 5 aromatic rings, especially a monocyclic or bicyclic group, such as phenyl, biphenyl or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted by one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. 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-attached or fused cyclic substituents at any available point(s) of attachment, in particular spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0142] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated cyclic groups, including 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-containing ring. Each ring of the heterocyclic group may independently be saturated, or partially or fully unsaturated. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. (The term "heteroarylium" refers to a heteroaryl group with a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the rest 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, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepine Base, Aza Hexahydrodiazepine 1,3-dioxolanyl, 1,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzophenone, benzo[d][1,3]dioxolanyl, benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzo[d][1,3]dioxolanyl, benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzo[d][1,3]dioxolanyl, benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzo[b][1,4]dioxin ... oxazolidinyl, benzofuranyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furano[2,3-c]pyridinyl, furano[3,2-b]pyridinyl] or furano[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepine Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0143] "Substituted heterocycle" and "substituted heterocyclic" 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, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3 , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 Re NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bound, optionally form a heterocyclic ring; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. Exemplary substituents themselves can be optionally substituted. Exemplary substituents also include spiral connection or fused cyclic substituents at any available one or more attachment points, especially spiral connection cycloalkyl, spiral connection cycloalkenyl, spiral connection heterocycle (not including heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves can be optionally substituted.

[0144] The term "oxo" refers to Substituent groups may be attached to carbon ring atoms on a carbocyclic or heterocyclic ring. When an oxo substituent group is attached to a carbon ring atom on an aromatic group (e.g., aryl or heteroaryl), the bonds on the aromatic ring may be rearranged to satisfy valence requirements. For example, a pyridine having a 2-oxo substituent group may have the structure It also includes its tautomeric forms

[0145] The term "alkylamino" refers to a group having the structure -NHR', wherein 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, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0146] The term "dialkylamino" refers to a group having the structure -NRR', wherein 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. In the dialkylamino moiety, R and R' may be the same or different. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)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, etc. In certain embodiments, R and R' are connected to form a ring structure. The resulting ring structure may be aromatic or non-aromatic. Examples of resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0147] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0148] The term "substituted" refers to embodiments in which a molecule, a molecular moiety, or a substituent group (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl group, or any other group disclosed herein) is substituted at any available point of attachment as valence permits with one or more substituents, preferably 1 to 6 substituents. Exemplary substituents include, but are not limited to, one or more of the following: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case forming a group such as CF 3 or with CCl 3 alkyl groups), cyano, nitro, oxo (ie, =O), CF 3 、OCF 3, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , SR 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 NR b R c NR b S(=O) 2 R e NR 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 NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a or NR b P(=O) 2 R e , where R a Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R b , R c and R d Each occurrence of is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R band R c together with the N to which they are bound, optionally form a heterocyclic ring; and R e Each occurrence of is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl themselves can be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, a molecular moiety or a substituent group (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl group or any other group disclosed herein) may or may not be substituted by one or more of the aforementioned substituents.

[0149] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0150] The compounds of the present invention may form salts, which are also within the scope of the present invention. Unless otherwise indicated, reference to the compounds of the present invention should be understood to include reference to their salts. As used herein, the term "salt" means an acidic and / or basic salt formed with inorganic and / or organic acids and bases. In addition, when the compounds of the present invention contain both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, phenol or carboxylic acid), zwitterions ("inner salts") may be formed and included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts may also be available, for example, in separation or purification steps that may be used during the preparation process. The salts of the compounds of the present invention may be formed, for example, by reacting the compounds described herein with an amount of acid or base (such as an equal amount of acid or base) in a medium such as a salt in which it will precipitate or in an aqueous medium, and then lyophilizing.

[0151] The compounds of the invention containing a basic moiety (such as, but not limited to, an amine or a pyridine or imidazole ring) can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide. Salts such as succinates, isethionates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates (such as methanesulfonate), undecanoates, and the like.

[0152] Compounds of the invention containing an acidic moiety (such as, but not limited to, phenol or carboxylic acid) can form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts (such as sodium, lithium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts with organic bases (e.g., organic amines) (such as benzathine penicillin, dicyclohexylamine, hybamine salts (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-imidazolebisamide, tert-butylamine) and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can 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, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0153] Prodrugs and solvates of the compounds of the present invention are also encompassed herein. As used herein, the term "prodrug" refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound of the present invention or a salt and / or solvate thereof after administration to a subject. Solvates of the compounds of the present invention include, for example, hydrates.

[0154] 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 compound structure includes its tautomeric forms.

[0155] All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomeric and diastereomeric forms, are encompassed within the scope of the present invention. The various 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 with a specific activity), or may be mixed, for example, as a racemate or mixed with all other or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 recommendations. The racemic form may be separated by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Various optical isomers may be obtained from the racemate by any suitable method, including but not limited to conventional methods, such as forming a salt with an optically active acid, followed by crystallization.

[0156] The compounds of the present invention are preferably isolated and purified after their preparation to obtain a composition containing an amount of equal to or greater than 90%, such as equal to or greater than 95%, equal to or greater than 99% by weight of the compound ("substantially pure" compound), which is then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also encompassed herein as part of the present invention.

[0157] All configurational isomers of the compounds of the present invention are contemplated, either 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) olefin isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0158] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0159] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, inside the back cover of the Handbook of Chemistry and Physics, 75th edition, 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.

[0160] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds are encompassed by the present invention, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof and other mixtures thereof, all falling within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0161] According to the present invention, isomer mixtures containing any of a variety of isomer ratios may be used. For example, in the case of combining only two isomers, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1 or 100:0 isomer ratios are all encompassed by the present invention. One of ordinary skill in the art will readily appreciate that similar ratios are encompassed for more complex isomer mixtures.

[0162] The present invention also includes isotopically labeled compounds which are identical to the compounds disclosed herein but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually 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, such as 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 their enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts or solvates containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, radioactive isotopes such as 3 H and 14 Those having C incorporated therein can be used in drug and / or substrate tissue distribution assays. 3 H(T)) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2H(D)) may offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the following schemes and / or in the Examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0163] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, diastereomeric salts are formed with an appropriate optically active acid or base, and the diastereomers so formed are then resolved by fractional crystallization or chromatographic means well known in the art, and the pure enantiomers are subsequently recovered.

[0164] It should be understood that compounds as described herein can be substituted by any number of substituents or functional moieties. In general, the term "substituted" (whether or not there is the term "optionally" in front) and the substituents contained in the formula of the present invention refer to the group in which the hydrogen group in a given structure is replaced by a specified substituent. When more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. As used herein, the term "substituted" is intended to include all allowed substituents of organic compounds. In a broad sense, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any allowed substituents of the organic compounds described herein that satisfy the valence of heteroatoms. In addition, the present invention is not intended to be limited in any way by the allowed substituents of organic compounds. The combination of substituents and variables envisioned by the present invention is preferably those that lead to the formation of stable compounds that can be used to treat, for example, proliferative disorders. As used herein, the term "stable" preferably refers to a compound that possesses stability sufficient to allow manufacture and to maintain the integrity of the compound for a period of time sufficient to be detected and preferably to be useful for the purposes detailed herein.

[0165] As used herein, the term "cancer" and equivalently "tumor" refers to a condition in which there is a detectable amount of abnormally replicated cells of host origin in a subject. Cancer can be malignant or non-malignant cancer. Cancer or tumors include, but are not limited to, biliary cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (gastric / stomach) cancer, intraepithelial neoplasia, leukemia, lymphoma, liver cancer, lung cancer (e.g., small cells and non-small cells), melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (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 mutations 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 may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardio-facial-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformations-arteriovenous malformations.

[0166] As used herein, "effective amount" refers to any amount necessary to achieve or promote a desired result or any amount sufficient to achieve or promote a desired result. In some cases, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary to promote or achieve a desired biological response of a subject or any amount sufficient to promote or achieve a desired biological response of a subject. The effective amount for any particular application may vary with factors such as the disease or condition being treated, the specific agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can determine the effective amount of a specific agent empirically without excessive experimentation.

[0167] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including but not limited to non-human primates, laboratory animals, livestock, racehorses, domestic animals, and non-domestic animals.

[0168] Compound

[0169] Novel compounds that are TRPA1 inhibitors are described. It has been surprisingly found that the compounds disclosed herein exhibit TRPA1 inhibitory properties. In addition, it has been surprisingly found that the compounds disclosed herein selectively block TRPA1 without blocking hERG channels and therefore have a desired cardiovascular safety profile.

[0170] In one aspect, a compound having a structure of Formula I, Ia, Ib, Ic, IIa, IIb or IIc is described (

[0171]

[0172] ) or a pharmaceutically acceptable salt or tautomer thereof, wherein various substituents are defined herein. The compounds of Formula I, Ia, Ib, Ic, IIa, IIb or IIc described herein can block or inhibit TRPA1 and are used to treat a variety of conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions comprising the compounds described herein and methods for using these compositions described herein can be used to treat conditions in vitro and in vivo. Such compounds, pharmaceutical compositions and methods of treatment have many clinical applications, including as pharmaceutically active agents and methods for treating pain, skin disorders, respiratory diseases, fibrotic diseases, inner ear disorders, fever or other body temperature regulation disorders, urinary tract disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders and cardiovascular disorders or combinations thereof.

[0173] In one aspect, a compound of Formula I or a pharmaceutically acceptable salt or tautomer thereof is described,

[0174]

[0175] in

[0176] Y is N or CR 2 ;

[0177] Z is N or CR 3 ;

[0178] R 1 is H, D, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, saturated heterocycle, CN, OR a , SR a or NR a R b ;

[0179] R 2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, 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 Rb 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b ;

[0180] R 3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, 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 , OC 1-4Alkyl-R a or NR a -C 1-4 Alkyl-R b ;

[0181] R 4 is H, D, halogen, alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, halocycloalkyl, saturated heterocycle, CN, OR a , SR a , -C 1-4 Alkyl-OR a or NR a R b ;

[0182] is aryl or heteroaryl, each optionally substituted by 1-5 substituents independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 ;

[0183] L 1 For –(CR 5 R 6 ) n –

[0184] R 5 Each occurrence of is independently H, D, alkyl, halogen, haloalkyl, cyclo

[0185] Alkyl, halocycloalkyl, CN, OR a or -C 1-4 Alkyl-OR a ;

[0186] R 6 Each occurrence of is independently H, D, alkyl, halogen, haloalkyl, cyclo

[0187] Alkyl, halocycloalkyl, CN, OR a or -C 1-4 Alkyl-OR a ;

[0188] n is 2 or 3;

[0189] L 2 For –CR 7 R 8 –

[0190] R 7 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4 Alkyl-OR a ;

[0191] R 8 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4 Alkyl-OR a ;

[0192] R a and R b Each occurrence of is independently H, alkyl, (C=O)R x 、(C=O)N(R x ) 2 、SO 2 R x NR x (C=O)NR x2 , cycloalkyl, haloalkyl, heteroalkyl, haloheteroalkyl, halocycloalkyl, a saturated heterocycle containing 1-3 heteroatoms each selected from N, O and S, aryl or heteroaryl; or alternatively, R a and R b Together with the carbon or nitrogen atom to which they are attached, they form a cycloalkyl group or a saturated heterocyclic ring comprising the nitrogen atom and 0 to 3 additional heteroatoms each selected from N, O and S;

[0193] 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 groups in the formula (a) are optionally substituted with 1 to 4 substituents independently selected from the following groups when valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 and oxo; and

[0194] R x Each occurrence of is independently H, D, alkyl or optionally substituted heterocycle; or alternatively two R x The groups together with the nitrogen atom to which they are attached form a heterocyclic ring which is optionally substituted by an alkyl group and comprises the nitrogen atom and 0 to 3 further heteroatoms each selected from N, O and S;

[0195] The condition is that when Z is N, R 4 Not for OH.

[0196] 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.

[0197] In some embodiments, n is 2. In some embodiments, n is 3.

[0198] In some embodiments, R 5 Each occurrence of is independently H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN, OR a , -C 1-4 Alkyl-OR a In some embodiments, R 5 Each occurrence of is independently cycloalkyl, halocycloalkyl, or CN. 5 Each occurrence of is independently H, D, alkyl, halogen, OR a In some embodiments, R 5 At least one occurrence of is H or D. In some embodiments, R 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 , for example, CH 2 OH, CH 2 CH 2 OH or CH2 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, isobutyl, 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 halogens include F, Cl, Br, and I. In some embodiments, R 5 At least one occurrence of is a haloalkyl. Non-limiting examples of haloalkyl include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 5 At least one occurrence of is a halocycloalkyl. Non-limiting examples of halocycloalkyl include In some embodiments, R 5 Each occurrence of is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl or Br.

[0199] In some embodiments, R 6 Each occurrence of is independently H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN, OR a , -C 1-4 Alkyl-OR a In some embodiments, R 6 Each occurrence of is independently cycloalkyl, halocycloalkyl, or CN. 6 Each occurrence of is independently H, D, alkyl, halogen, OR a In some embodiments, R6 At least one occurrence of is H or D. In some embodiments, R 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 , for example, CH 2 OH, CH 2 CH 2 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, isobutyl, 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 halogens include F, Cl, Br, and I. In some embodiments, R 6 At least one occurrence of is a haloalkyl. Non-limiting examples of haloalkyl include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 6 At least one occurrence of is a halocycloalkyl. Non-limiting examples of halocycloalkyl include In some embodiments, R 6 Each occurrence of is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl or Br.

[0200] In some embodiments, L 1Selected from –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)–,

[0201]

[0202] In some embodiments, the moiety L 1 Selected from –CH 2 –CH 2 –

[0203] In some embodiments, L 1 For –CH 2 –CH 2 – In some embodiments, L 1 Selected from –CH 2 –CH 2 –, –CH(CH 3 )–CH 2 –, –CH 2 –CH(CH 3 )– and –CH 2 –C(CH 3 ) 2 In some embodiments, L 1 For –CH 2 –CH 2 In some embodiments, L 1 for In some embodiments, L 1 for In some embodiments, L 1 for In some embodiments, L 1 for

[0204] In some embodiments, R 7 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4 Alkyl-OR aIn some embodiments, R 7 is cycloalkyl, halocycloalkyl or CN. In some embodiments, R 7 is H, D, alkyl or fluoroalkyl. 7 is H or D. In some embodiments, R 7 At least one occurrence of -C 1-4 Alkyl-OR a , for example, CH 2 OH, CH 2 CH 2 OH or CH 2 OCH 3 In some embodiments, R 7 is an alkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 7 is a cycloalkyl group. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 7 At least one occurrence of is a haloalkyl. Non-limiting examples of haloalkyl include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 7 At least one occurrence of is a halocycloalkyl. Non-limiting examples of halocycloalkyl include

[0205] In some embodiments, R 7 H, CH 3 or CH 2 CH 3 .

[0206] In some embodiments, R 8 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C1-4 Alkyl-OR a In some embodiments, R 8 is cycloalkyl, halocycloalkyl or CN. In some embodiments, R 8 is H, D, alkyl or fluoroalkyl. 8 is H or D. In some embodiments, R 8 At least one occurrence of -C 1-4 Alkyl-OR a , for example, CH 2 OH, CH 2 CH 2 OH or CH 2 OCH 3 In some embodiments, R 8 is an alkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R 8 is a cycloalkyl group. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 8 At least one occurrence of is a haloalkyl. Non-limiting examples of haloalkyl include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 8 At least one occurrence of is a halocycloalkyl. Non-limiting examples of halocycloalkyl include

[0207] In some embodiments, R 8 H, CH 3 or CH 2 CH 3 .

[0208] In some embodiments, L 2Selected from –CH 2 –, –CH(CH 3 )–、–C(CH 3 ) 2 – and –CH(CH 2 CH 3 )-. In some embodiments, the moiety L 2 For –CH 2 –.

[0209] In some embodiments, is phenyl, which is optionally substituted by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a and -C 1-4 Alkyl-OR a In some embodiments, is phenyl, which is optionally substituted by 1-3 substituents each independently selected from the group consisting of H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a and -C 1-4 Alkyl-OR a In some embodiments, is phenyl, which is optionally substituted by 1-3 substituents each independently selected from the following: CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 , CH 2 OCH 3 CF 3 , CN, C≡CH and In some embodiments, is phenyl, which is substituted by at least one substituent selected from the group consisting of: CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 , CH 2 OCH 3 CF 3 , CN, C≡CH and In some embodiments, is phenyl, which is substituted by at least one halogen. It is a phenyl group substituted with one chlorine.

[0210] In some embodiments, Selected from

[0211] In some embodiments, is a 5- or 6-membered heteroaryl group, which is optionally substituted by 1-4 substituents each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b or -C 1-4 Alkyl-OR a In some embodiments, is an optionally substituted 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms each selected from O and S. In a further embodiment, is optionally substituted thiophene or furan.

[0212] In some embodiments, is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted with alkyl, halogen, OH or oxo when valence permits. Non-limiting examples of 5-membered heteroaryl include In some embodiments, Selected from

[0213] In some embodiments, is an optionally substituted 5- or 6-membered heteroaryl or phenyl. In some embodiments, is an optionally substituted 5-membered heteroaryl group. Selected from In some specific embodiments, Selected from

[0214] In some embodiments, is an optionally substituted 7- to 11-membered bicyclic or 8- to 16-membered tricyclic aryl or heteroaryl. Non-limiting examples of bicyclic or tricyclic rings include biphenyl, naphthyl, phenanthrenyl, benzothienyl, chromonyl and coumarinyl.

[0215] In some embodiments, Selected from optionally substituted

[0216] In some embodiments, R 1 is cycloalkyl, haloalkyl or halocycloalkyl. 1 is an alkyl group or a haloalkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of haloalkyl groups include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 1 is a cycloalkyl or a 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 halogens include F, Cl, Br, and I. In some embodiments, R 1 is a haloalkyl group. Non-limiting examples of haloalkyl groups include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 1 Is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include In some embodiments, R 1 is H or D. In some embodiments, R 1 CN, OR a , SR a or NR a R b In some embodiments, R 1 H, D, halogen, alkyl, CN, CF 3 , OR a , SR a or NR a R b In some embodiments, R 1 Selected from 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 In some embodiments, R 1 Selected from H, CH 3 、Cl、Br、NH 2 and CF 3 .

[0217] In some embodiments, R 2 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-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-NRa COR b , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b In some embodiments, R 2 is a saturated heterocycle, a partially saturated heterocycle or a heteroaryl group, each of which is optionally substituted by 1 to 3 substituents selected from the following groups when valence permits: halogen, alkyl, 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 In some embodiments, R 2 is alkyl, alkenyl or alkynyl, each of which is optionally substituted by 1-3 substituents selected from the following when valence permits: 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 In some embodiments, R 2 It is a cycloalkyl group, an aryl group, an alkylaryl group, or an alkylheteroaryl group.

[0218] In some embodiments, R 2 is H, D or alkyl, wherein the alkyl is optionally substituted with OH, oxo or NH 2 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. 2 is alkenyl or alkynyl, wherein the alkenyl and alkynyl are optionally substituted with OH, oxo or NH 2Non-limiting examples of alkenyl include ethenyl, 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, (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 a cycloalkyl group. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 2 is a halogen. Non-limiting examples of halogens include F, Cl, Br, and I. In some embodiments, R 2 is a haloalkyl group. Non-limiting examples of haloalkyl groups include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 2 Is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0219] In some embodiments, R 2 OR a , SR a NR a R b 、(C=O)NR a R b NR b (C=O)R a 、(C=O)Ra 、(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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b In some embodiments, R 2 OR a , SR a or NR a R b In some embodiments, R 2 (C=O)NR a R b NR b (C=O)R a 、(C=O)R a OR (C=O)OR a In some embodiments, R 2 For -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 For OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

[0220] In some specific embodiments, R 2 For NH 2 , CH 2 NH 2 or CH 2 CH 2 NH 2 In other specific embodiments, R 2 OH, CH 2 OH or CH 2 CH 2 OH.

[0221] In yet other embodiments, R 2 is an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring, partially saturated heterocyclic ring or heteroaryl ring, each containing 1 to 3 heteroatoms each selected from N, O and S. In a further embodiment, R 2 Selected from

[0222] Wherein each is optionally replaced by an alkyl group, OH, NH 2 In some embodiments, R 2 is an N-containing heterocyclic ring, a partially saturated heterocyclic ring or a heteroaryl group, each of which is optionally substituted with an alkyl group, OH, NH 2 Non-limiting examples of N-containing heterocycles, partially saturated heterocycles and heteroaryls include

[0223] In some embodiments, R 2 Selected from H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, I, OCH 3 CF 3 、CN、NH 2 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 ,

[0224]

[0225] In some embodiments, R 2 Selected from H, CH 3 、Cl、OCH 3 , CH 2 OH, CN, CH2 CN、NH 2 , CH 2 NH 2 、CH=CH 2 ,

[0226] In some embodiments, R 3 is H, D, halogen, alkyl, haloalkyl, heteroaryl or CN. 3 OR a , SR a NR 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 alkenyl, alkynyl, cycloalkyl, saturated heterocyclic ring, partially saturated heterocyclic ring, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

[0227] In some embodiments, R 3 is H, D or alkyl, wherein the alkyl is optionally substituted with OH, oxo or NH 2 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. 3 is alkenyl or alkynyl, wherein the alkenyl and alkynyl are optionally substituted with OH, oxo or NH 2Non-limiting examples of alkenyl include ethenyl, 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, (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 a cycloalkyl group. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R 3 is a halogen. Non-limiting examples of halogens include F, Cl, Br, and I. In some embodiments, R 3 is a haloalkyl group. Non-limiting examples of haloalkyl groups include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 3 Is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0228] In some embodiments, R 3 OR a , SR a NR a R b 、(C=O)NR a R b NR b (C=O)R a 、(C=O)Ra 、(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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b In some embodiments, R 3 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 In some embodiments, R 3 OR a , SR a or NR a R b In some embodiments, R 3 (C=O)NR a R b NR b (C=O)R a 、(C=O)R a OR (C=O)OR a In some embodiments, R 3 For -C 1-4 Alkyl-OR a , -C 1-4 Alkyl-SR a , -C 1-4Alkyl-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 For OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

[0229] In some specific embodiments, R 3 For NH 2 , CH 2 NH 2 or CH 2 CH 2 NH 2 In other specific embodiments, R 3 OH, CH 2 OH or CH 2 CH 2 OH.

[0230] In some specific embodiments, R 3 is alkenyl, alkynyl, cycloalkyl, saturated heterocyclic ring, partially saturated heterocyclic ring, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

[0231] In yet other embodiments, R 3 is an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring, partially saturated heterocyclic ring or heteroaryl ring, each containing 1 to 3 heteroatoms each selected from N, O and S. In a further embodiment, R 3 Selected from

[0232] Wherein each is optionally replaced by an alkyl group, OH, NH 2 In some embodiments, R 3 is an N-containing heterocyclic ring, a partially saturated heterocyclic ring or a heteroaryl group, each of which is optionally substituted with an alkyl group, OH, NH 2 Non-limiting examples of N-containing heterocycles, partially saturated heterocycles and heteroaryls include

[0233]

[0234] In some embodiments, R 3 Selected from H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 CF 3 、CN、CH 2 CN, CH=CH 2 NH 2 NHCH 3 、N(CH 3 ) 2 ,

[0235] In some embodiments, R 3 Selected from H, NH 2 , CH 3 、CN、Cl、Br、 CH 2 CN, CH 2 OH,

[0236] In some embodiments, R 4 is aryl, heteroaryl. In some embodiments, R 4 is an alkyl group or a haloalkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of haloalkyl groups include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 4 is a cycloalkyl or a 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 halogens include F, Cl, Br, and I. In some embodiments, R 4 is a haloalkyl group. Non-limiting examples of haloalkyl groups include CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 and CHClCHClCH 3 In some embodiments, R 4 Is a halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0237] In some embodiments, R 4 is H or D. In some embodiments, R 4 CN, OR a , SR a or NR a R b In some embodiments, R 4 H, D, halogen, alkyl, CN, CF 3 , OR a , SR a , -C 1-4 Alkyl-OR a or NR a R b In some embodiments, R 4 Selected from H, D, CH 3 , CH2 CH 3 , OH, F, Cl, Br, OCH 3 CF 3 、CN、NH 2 NHCH 3 、N(CH 3 ) 2 , CH 2 OH, In some embodiments, R 4 Selected from 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 , CH 2 OH and In some embodiments, R 4 Selected from H, CH 3 NH 2 , CH 2 OH, F, Br and CN.

[0238] In some embodiments, R a or R b At least one occurrence of is independently H, D, Me, Et, Pr, CH 2 CH 2 OH, phenyl or 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. In some embodiments, R a or R b At least one occurrence of is independently (C=O)R x 、(C=O)N(R x ) 2 、SO 2 R x NR x (C=O)NR x2 or (C=O)R xIn some embodiments, R a or R b At least one occurrence of is independently a heterocycle selected from:

[0239] The heterocyclic ring is optionally substituted with alkyl, OH, oxo or (C=O)C 1-4 In some embodiments, R a or R b At least one occurrence of H, Me, phenyl, In some embodiments, R a or R b At least one occurrence of is independently H or

[0240] In some embodiments, R a and R b Together with the nitrogen atom to which they are attached, they form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S. In some embodiments, R a and R b Together with the carbon atom to which they are attached, they form a cycloalkyl group, which is optionally substituted, when valence permits, with 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR 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, they form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S, which are optionally substituted, when valence permits, by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x、(C=O)N(R x ) 2 NR x (C=O)R x Non-limiting examples of heterocycles include

[0241] In some embodiments, R 1 The alkyl, haloalkyl, cycloalkyl, halocycloalkyl and heterocycle in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when the valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 2 The alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl and alkylheteroaryl in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 3 The alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl and alkylheteroaryl in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)Rx 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 4 The alkyl, haloalkyl, cycloalkyl, halocycloalkyl and heterocycle in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when the valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 5 The alkyl, haloalkyl, cycloalkyl and halocycloalkyl in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when the valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 6 The alkyl, haloalkyl, cycloalkyl and halocycloalkyl in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when the valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 7The alkyl, haloalkyl, cycloalkyl and halocycloalkyl in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when the valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R 8 The alkyl, haloalkyl, cycloalkyl and halocycloalkyl in the group are optionally substituted by 1 to 4 substituents independently selected from the following groups when the valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR x (C=O)R x In some embodiments, R a and R b The alkyl, cycloalkyl, haloalkyl, heteroalkyl, haloheteroalkyl, halocycloalkyl and saturated heterocycle in the group are optionally substituted by 1-4 substituents independently selected from the following groups when valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH 2 ) 0-2 OR x 、N(R x ) 2 、(C=O)R x 、(C=O)N(R x ) 2 NR 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.x Each occurrence of is a substituted heterocycle. In some embodiments, two R x The groups together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring including the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S. In some specific embodiments, R x Each occurrence of is independently H or Me.

[0243] In some embodiments, for

[0244] In some embodiments, the compound has the structure of Formula Ia, Ib, or Ic:

[0245]

[0246] in

[0247] R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0248] R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0249] R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group; and

[0250] R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group.

[0251] In some embodiments, in Formulas Ia, Ib and Ic R 1 , R 2 , R 3 , R 4 , R 7 and R 8 is as defined above for compounds of formula I. Other substituents are defined herein.

[0252] In some embodiments, R 5a At least one occurrence of is H or D. In some embodiments, R 5a At least one occurrence of OR a , for example, OH or OMe. In some embodiments, R 5aAt least one occurrence of is alkyl, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 5a At least one occurrence of is a halogen, for example, F, Cl, Br, or I. In some embodiments, R 5a At least one occurrence of is a fluoroalkyl group, for example, CF 3 , CH 2 F. CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 CF 2 CH 3 or CH 2 CHF 2 .

[0253] In some embodiments, R 5b At least one occurrence of is H or D. In some embodiments, R 5b At least one occurrence of OR a , for example, OH or OMe. In some embodiments, R 5b At least one occurrence of is alkyl, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 5b At least one occurrence of is a halogen, for example, F, Cl, Br, or I. In some embodiments, R 5b At least one occurrence of is a fluoroalkyl group, for example, CF 3 , CH 2 F. CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 CF 2 CH 3 or CH 2 CHF 2 .

[0254] In some embodiments, R 6a At least one occurrence of is H or D. In some embodiments, R 6a At least one occurrence of OR a , for example, OH or OMe. In some embodiments, R 6a At least one occurrence of is alkyl, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 6aAt least one occurrence of is a halogen, for example, F, Cl, Br, or I. In some embodiments, R 6a At least one occurrence of is a fluoroalkyl group, for example, CF 3 , CH 2 F. CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 CF 2 CH 3 or CH 2 CHF 2 .

[0255] In some embodiments, R 6b At least one occurrence of is H or D. In some embodiments, R 6b At least one occurrence of OR a , for example, OH or OMe. In some embodiments, R 6b At least one occurrence of is alkyl, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. 6b is halogen, F, Cl, Br or I. In some embodiments, R 6b At least one occurrence of is a fluoroalkyl group, for example, CF 3 , CH 2 F. CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 CF 2 CH 3 or CH 2 CHF 2 .

[0256] In some embodiments, the compound has the structure of Formula IIa, IIb, or IIc:

[0257]

[0258] in

[0259] R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0260] R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0261] R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0262] R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl;

[0263] R 11 Each occurrence of is independently H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 ;

[0264] R 12 Each occurrence of is independently H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 ;

[0265] R 13 Each occurrence of is independently H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 ;

[0266] R 14 Each occurrence of is independently H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR aor -C 1-4 Alkyl-OR a ;and

[0267] R 15 Each occurrence of is independently H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 .

[0268] In some embodiments, R in Formula IIa, IIb and IIc is 1 , R 2 , R 3 , R 4 , R 7 and R 8 is as defined above for compounds of formula I. Other substituents are defined herein.

[0269] In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least one of is not H. In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least two of them are not H.

[0270] In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least one of them is H, alkyl, CF 3 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 SR a In some embodiments, R 11 , R 12 , R 13 , R 14and R 15 At least one of them is 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 them is OR a , SR a or NR a R b In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least one of is H, halogen, fluoroalkyl, alkyl, alkenyl, or alkynyl. 11 , R 12 , R 13 , R 14 and R 15 At least one of them is CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 , CH 2 OCH 3 CF 3 , CN, C≡CH or In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least one of H, Me, Et, i-Pr, n-Bu, CF 2 H.CF 2 Cl or CF 3 In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least one of OH, OCH 3 , CH 2 OCH 3 In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15At least one of is a halogen, for example, Cl, F, Br or I. In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 and R 15 At least one of them is a halogenated alkyl group, for example, CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 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 is a halogenated cycloalkyl group, for example,

[0271] In some embodiments, R 11 , R 12 , R 13 , R 14 and R 15 At least one of R is alkenyl, for example, ethenyl, 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 R 15At least one of R is alkynyl, for example, 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 In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 and R 15 At least two of which are independently selected from CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 , CH 2 OCH 3 CF 3 , CN, C≡CH or

[0272] In some embodiments, R 11 , R 12 , R 14 and R 15 is H; and R 13 H, D, halogen, alkyl, cycloalkyl, CN, CF 3 , OR a , SR a NR 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 SR a In some embodiments, R 13 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 , SR a or NR a R b In some embodiments, R13 is H, halogen, fluoroalkyl or alkyl. 13 CH 3 , CH 2 CH 3 , OH, F, Cl, Br, OCH 3 , CH 2 OCH 3 CF 3 , CN, C≡CH or In some embodiments, R 13 For H, Me, Et, i-Pr, n-Bu, CF 2 H.CF 2 Cl or CF 3 In some embodiments, R 13 OH, OCH 3 , CH 2 OCH 3 In some embodiments, R 13 is halogen, for example, Cl, F, Br or I. In some embodiments, R 13 In some embodiments, R 13 is a haloalkyl group, for example, CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F. CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 or CHClCHClCH 3 In some embodiments, R 13 is a halogenated cycloalkyl group, for example,

[0273] In some embodiments, R 13 In some embodiments, R 13is alkenyl, for example, ethenyl, 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. In some embodiments, R 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.

[0274] In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb or IIc is any of the compounds described herein. In some embodiments, the compound of formula I, Ia, Ib, Ic, IIa, IIb or IIc is selected from the compounds in 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 compounds in 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 compounds in Tables 4-5. In some embodiments, the compound of formula I, Ia, Ib, IIa, IIc is selected from the compounds in 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 compounds in Table 2. The compounds listed in Tables 1-5 are representative and non-limiting compounds of the embodiments disclosed herein.

[0275] abbreviation

[0276] CAN Acetonitrile

[0277] DCM Dichloromethane

[0278] DIEA N,N-Diisopropylethylamine

[0279] DMF Dimethylformamide

[0280] DMSO Dimethyl sulfoxide

[0281] EA Ethyl acetate

[0282] MeOH Methanol

[0283] NMP N-Methyl-2-pyrrolidone

[0284] PE Petroleum Ether

[0285] TFA Trifluoroacetic acid

[0286] THF Tetrahydrofuran

[0287] Preparation method

[0288] The following is a general synthesis scheme for making the compounds of the present invention. These schemes are schematic and are not intended to limit the possible techniques that a person skilled in the art can use to make the compounds disclosed herein. Different methods will be apparent to those skilled in the art. In addition, the various steps in the synthesis can be carried out in an alternating order or sequence to obtain the desired compound. All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrative and do not limit the preparation of some starting materials and compounds disclosed herein.

[0289] The following schemes 1-8 describe synthetic routes that can be used to synthesize compounds of the present invention, such as compounds having structures of Formula I, Ia, Ib, Ic, IIa, IIb or IIc, or their precursors. Those skilled in the art can envision making various modifications to these methods to achieve results similar to the invention given below. In the following embodiments, synthetic routes are described using compounds having structures of Formula I, Ia, Ib, Ic, IIa, IIb or IIc, or their precursors, as examples. The general synthetic routes described in Schemes 1-8 and the examples described in the Examples section below illustrate methods for preparing the compounds described herein.

[0290] Compound 1-3 as 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 1-1, can be prepared by alkylating a suitably substituted pyridazinone 1-3 with a halomethyl oxadiazole 1-2 in the presence of a base such as potassium carbonate, optionally using a catalyst such as sodium iodide in a solvent such as DMF or NMP.

[0291]

[0292] Solution 1

[0293] Compound 1-4 as shown in Scheme 2 can be prepared and / or commercially available by any method known in the art. The substituents shown in Scheme 2 are defined herein. As shown in Scheme 2, oxadiazole 1-2 can be prepared from nitrile 1-4 as shown in Scheme 2. Nitrile 1-4 is converted to amide oxime 1-5 by heating with hydroxylamine hydrochloride and a base such as sodium bicarbonate in a solvent such as ethanol. Alternatively, an aqueous solution of hydroxylamine can be used without adding a base. Amide oxime reacts with α-haloacyl halides such as chloroacetyl chloride and a base such as triethylamine. The resulting intermediate is cyclized to chloromethyl oxadiazole in toluene by, for example, heating at 100°C.

[0294]

[0295] Solution 2

[0296] Compound I-3 as shown in Scheme 3 can be prepared and / or commercially available by any method known in the art. The substituents shown in Scheme 3 are defined herein. As shown in Scheme 3, a second method for synthesizing compounds of Formula I such as I-1 is to construct an oxadiazole ring from pyridazineacetic acid and amidoxime. Appropriately substituted pyridazinone I-3 is reacted with a haloacetic acid ester such as ethyl bromoacetate in the presence of a base such as potassium carbonate to obtain ester I-6. The ester is then hydrolyzed, for example, with lithium hydroxide to obtain carboxylic acid I-7. Acid I-7 and amidoxime I-5 are reacted together with a coupling agent such as propanephosphonic anhydride and a base such as diisopropylethylamine in a solvent such as DCM. The formed adduct is then heated in a solvent such as DMF to cause cyclization to form oxadiazole I-1.

[0297]

[0298] Solution 3

[0299] There are many heterocyclic rings I-3 available, where R 1 , R 2 , R 3 and R 4 One or more of is halogen. They can be used to prepare alkyl, aryl cyano or other functionalized heterocycles by cross-coupling chemical reaction (for example, Suzuki reaction). Such conversion can be carried out on heterocycle before heterocycle and I-2 are reacted to obtain I-1, or halogen-substituted heterocycle I-3 and I-2 can be reacted, and then halogen is converted into other substituents. Similarly, heterocyclic carboxylic acid and ester I-3 can be used as precursors of amides, nitrile, alkoxymethyl, methylol and aminomethyl substituents. Chemical reaction can be carried out before or after I-3 and I-2 are coupled to obtain I-1.

[0300] Compound 1-8 as shown in Scheme 4 can be prepared by any method known in the art and / or is commercially available. The substituents shown in Scheme 4 are defined herein. 1 (S)-CH(OH)CH 2Compounds of formula I 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-methylbenzenesulfonamido-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 chloromethyl oxadiazole I-2a by the same method as used to prepare I-2 (as shown in Scheme 2).

[0301]

[0302] Solution 4

[0303] The heterocyclic ring I-10 in which both X groups are halogens is combined with an aryl or vinyl boronic acid or boronic ester R 2 B(OH) 2 In the presence of a palladium catalyst such as Pd(dppf)Cl 2 and a base such as sodium carbonate in a solvent such as dioxane and water to give 2 I-11 is an aryl or vinyl group, as shown in Scheme 5. 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 can also be added by first protecting I-10. I-12 is then reacted with R in a solvent such as dioxane and water in the presence of a base such as potassium carbonate. 1 B(OH) 2 (as free boronic acid, boronic ester or boroxane) and a palladium catalyst such as tetrakis(triphenylphosphine)palladium. Deprotection of 1-13 affords 1-14, which can be converted to compound 1-1 by the methods outlined in Scheme 1 or Scheme 3.

[0304]

[0305] Solution 5

[0306] Where Y is CR 2 , Z is N and R 2 Compounds containing oxygen substituents can be synthesized from pyrimidinone ester 1-15 as shown in Scheme 6.

[0307]

[0308] Solution 6

[0309] R can be introduced by halogenating 1-15 at C5 with, for example, 1,3-dichloro-5,5-dimethylhydantoin in a solvent such as DMF. 1 Reduction of the ester with a reducing agent such as sodium borohydride in methanol affords the hydroxymethylpyrimidone I-17. Treatment of I-16 with an amine RaRbNH in a solvent such as dioxane affords the 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 Group.

[0310] Where Y is CR 2 , Z is N and R 4 Compounds containing oxygen substituents are obtained from 2,5-dichloro-4-methoxypyrimidine 1-19 as shown in Scheme 7.

[0311]

[0312] Solution 7

[0313] Reaction of I-19 with hydroxymethylstannane and a palladium II catalyst such as bis(triphenylphosphine)palladium dichloride in a solvent such as toluene yields the hydroxymethylpyrimidine I-20. Hydrolysis with a base such as sodium hydroxide yields the pyrimidone I-21. The chlorine atom can be converted to other R 1 Group.

[0314] A preparation wherein Y is CR 2 and compounds where Z is CH are prepared starting from the pyridine boronic acid 1-22 as shown in Scheme 8.

[0315]

[0316] Solution 8

[0317] Boronic acid I-22 and aryl (or heteroaryl) halide R 2 X (wherein X is Cl, Br or I), a palladium catalyst such as Pd(dppf)Cl 2 and a base such as sodium carbonate in a solvent such as dioxane and water to give 2 I-23 is aryl or heteroaryl. Hydrolysis with an acid such as HCl provides the pyridine I-24.

[0318] Pharmaceutical composition

[0319] The present invention also provides a pharmaceutical composition comprising at least one compound as described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or diluent.

[0320] In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from the compounds of Formula I, Ia, Ib, Ic, IIa, IIb or IIc as described herein and a pharmaceutically acceptable carrier or diluent.

[0321] In certain embodiments, the composition is in the form of a hydrate, a solvate, or a pharmaceutically acceptable salt.The composition can be administered to a subject by any suitable route of administration, including but not limited to oral and parenteral administration.

[0322] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle involved in carrying or delivering the subject agent from one organ or body part to another, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable", i.e., compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can be used as pharmaceutically 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 waxes; 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 glycerol, 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; ethanol; phosphate buffered saline; and other nontoxic compatible substances employed in pharmaceutical preparations. The term "carrier" refers to an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate application. The components of the pharmaceutical compositions are also capable of being mixed with the compounds of the invention and with each other in a manner such that there is no interaction that would significantly impair the desired pharmaceutical efficiency.

[0323] In certain embodiments, the compound in the pharmaceutical composition can be provided in the form of a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to the relatively nontoxic inorganic and organic acid salts of the compound of the present invention. These salts can be prepared in situ during the final separation and purification of the compound of the present invention, or by reacting the purified compound of the present invention in the form of its free alkali with a suitable organic or inorganic acid alone and separating the salt so formed. Representative salts include hydrobromate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate (napthylate), mesylate, glucoheptonate, lactobionate and lauryl sulfonate etc. See, for example, Berge et al., (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19 (incorporated herein by reference as a whole).

[0324] Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as salts from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those 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, butyric 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc.

[0325] In other cases, the compound of the present invention may contain one or more acidic functional groups and thus be able to form a pharmaceutically acceptable salt with a pharmaceutically acceptable base. In these cases, the term "pharmaceutically acceptable salt" refers to the relatively nontoxic inorganic and organic base addition salts of the compound of the present invention. These salts can also be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound in its free acid form with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate, with ammonia or with a pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine separately to prepare. Representative alkali metal salts or alkaline earth metal salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. See, for example, Berge et al. (ibid.).

[0326] 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 compositions.

[0327] The preparations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The preparations can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary with the host treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, in 100%, the amount will be in the range of about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0328] The method for preparing these preparations or compositions includes the step of bringing the compound of the present invention into association with a carrier and optionally one or more auxiliary ingredients. Generally, the preparation is prepared by uniformly and intimately bringing the compound of the present invention into association with a liquid carrier or a finely divided solid carrier or both and then shaping the product if necessary.

[0329] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and gum arabic 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 a pastille (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the invention as the active ingredient. The compounds of the invention may also be administered as a bolus, electuary, or paste.

[0330] In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders and granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; Wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate and sodium starch glycolate; dissolution retardants such as paraffin; absorption promoters such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glyceryl monostearate and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffer. A similar type of solid composition may also be used as a filler in soft or hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0331] Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxybutyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a powdered compound mixture moistened with an inert liquid diluent in a suitable machine.

[0332] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention (such as sugar pills, capsules, pills and granules) may optionally be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the art of pharmaceutical formulation). They may also be formulated to provide slow or controlled release of the active ingredients therein using, for example, hydroxybutyl methylcellulose, other polymer matrices, liposomes and / or microspheres in different proportions to provide the desired release properties. They may be sterilized, for example, by filtering through a bacterial retention 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 before use. These compositions may also optionally contain an emulsifier and may be a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

[0333] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (such as ethanol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol), oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition, cyclodextrins such as hydroxybutyl-β-cyclodextrin may be used to solubilize the compound.

[0334] 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.

[0335] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0336] Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.

[0337] 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, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0338] In addition to the compounds of this invention, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and butane.

[0339] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the agent of the present invention through the skin. The rate of such flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or a gel.

[0340] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of this invention.

[0341] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions; or sterile powders which can be reconstituted into sterile injectable solutions or dispersions before use, which sterile powders may contain antioxidants, buffers, bacteriostats, or solutes which render the preparation isotonic with the blood of the intended recipient, or suspending agents or thickening agents.

[0342] In some cases, in order to prolong the effect of the drug, it is desirable to slow down the absorption of the drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. So the absorption rate of the drug just depends on its dissolution rate, and the dissolution rate can depend on crystal size and crystalline form. Alternatively, the delayed absorption of the drug form for parenteral administration is achieved by dissolving or suspending the drug in an oil vehicle. A strategy for reservoir injection includes the use of polyethylene oxide-polypropylene oxide copolymers, wherein the vehicle is fluid at room temperature and solidifies at body temperature.

[0343] Injectable reservoir forms are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled according to the ratio of the drug to the polymer and the properties of the specific polymer adopted. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by embedding the drug in a liposome or microemulsion compatible with body tissues.

[0344] When the compounds of the present invention are administered as medicines to humans or animals, they can 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 pharmaceutically acceptable carrier.

[0345] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, that is, the compounds and pharmaceutical compositions can be administered simultaneously with, before, or after one or more other desired therapies or medical procedures. The specific combination of therapies (therapies or procedures) to be employed in the combination regimen will take into account the compatibility of the desired therapies and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapies employed can achieve the desired effect on the same condition (e.g., a compound of the present invention can be administered simultaneously with another anticancer agent).

[0346] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally or in other acceptable ways. The compounds can be used to treat arthritic conditions in mammals (e.g., humans, livestock and domestic animals), racehorses, birds, lizards and any other organisms that can tolerate the compounds.

[0347] The present invention also provides a pharmaceutical pack or kit comprising one or more containers containing one or more ingredients of the pharmaceutical composition of the present invention. Optionally, such containers may be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of drugs or biological products, which notice reflects the agency's approval of the manufacture, use or sale for human administration.

[0348] Methods of administering to a subject / treating a condition

[0349] In yet another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from a compound of Formula I, Ia, Ib, Ic, IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of said compounds or pharmaceutically acceptable salts thereof, wherein the condition is selected from pain, skin disorders, respiratory diseases, fibrotic diseases, inner ear disorders, fever or other temperature regulation disorders, urinary tract or bladder disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders and cardiovascular disorders.

[0350] In some embodiments, 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, hyperesthesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve damage, post-stroke pain, or pain associated with teeth and dental damage.

[0351] 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 itching caused by psoriasis.

[0352] In some embodiments, the respiratory disease is inflammatory airway disease, airway hyperresponsiveness, idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough.

[0353] In some embodiments, ischemia is CNS hypoxia or a condition associated with 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 gastrointestinal disorder is inflammatory bowel disease, esophagitis, gastroesophageal reflux disease, irritable bowel syndrome, vomiting, or gastroduodenal ulcer. In some embodiments, the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

[0354] In some embodiments, the mammalian species is human.

[0355] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of said compounds or pharmaceutically acceptable salts thereof.

[0356] In some embodiments, the compounds described herein selectively inhibit TRPA1 with minimal or no off-target inhibitory activity on potassium channels or on calcium or sodium channels. In some embodiments, the compounds described herein do not block hERG channels and thus have a desirable cardiovascular safety profile.

[0357] Some aspects of the invention involve administering to a subject an effective amount of a composition to achieve a particular result.Thus, small molecule compositions useful according to the methods of the invention may be formulated in any manner suitable for pharmaceutical use.

[0358] The formulations of the present invention are administered in pharmaceutically acceptable solutions, which may generally contain pharmaceutically acceptable concentrations of salt, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0359] For use in treatment, an effective amount of the compound can be administered to a subject by any mode that allows the compound to be absorbed 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., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.) or mucosal (intranasal, intratracheal, inhalation, rectal, intravaginal, etc.). Injection can be a push injection or a continuous infusion.

[0360] For example, the pharmaceutical composition according to the present invention is usually applied intravenously, intramuscularly or by other parenteral means. They can also be applied intranasally, inhaled, topically, orally or as an implant; even rectal or vaginal use. Suitable liquid or solid pharmaceutical preparations are in the form of aqueous or saline solutions, microencapsulated, encochleated, coated on tiny gold particles, contained in liposomes, atomized, aerosols, pellets for implantation into the skin, or dried to a sharp object to be scraped into the skin, for example, for injection or inhalation. The pharmaceutical composition also includes granules, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with extended release of active compounds, in which excipients and additives and / or adjuvants such as disintegrants, binders, coatings, expanders, lubricants, flavorings, sweeteners or solubilizers as described above are usually used. The pharmaceutical composition is suitable for various drug delivery systems. For a brief review of current drug delivery methods, see Langer, R. (1990) Science 249: 1527-33, which is incorporated herein by reference in its entirety.

[0361] The compounds contained in the compositions used in the methods of the present invention may be present in concentrations ranging from about 1 nM to about 100 μM. Effective dosages are believed to be in the range of about 10 pmoles / kg to about 100 micromoles / kg.

[0362] The pharmaceutical composition is preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders and suppositories. For the treatment of patients, different dosages may be required, depending on the activity of the compound, the mode of administration, the purpose of administration (i.e., preventive or therapeutic), the nature and severity of the disease, and the age and weight of the patient. The administration of a given dose can be carried out in a single administration in the form of a single dosage unit, or in several smaller dosage units. The present invention also encompasses repeated and multiple administrations of dosages at specific intervals separated by a few days, weeks or months.

[0363] The composition can be applied in the form of its own (pure) or pharmaceutically acceptable salt. When used in medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can also be conveniently used to prepare its pharmaceutically acceptable salt. Such salts include but are not limited to those prepared by 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. In addition, such salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts of carboxylic acid groups.

[0364] Suitable buffers 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).

[0365] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that can be isotonic with the blood of the recipient. Acceptable vehicles and solvents include water, Ringer's solution, phosphate buffered saline, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are generally used as solvents or suspension media. For this reason, any mild non-volatile mineral oil or non-mineral oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be 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; it is incorporated herein by reference in its entirety.

[0366] The compounds useful in the present invention may be delivered as a mixture of more than two such compounds.In addition to the combination of compounds, the mixture may also contain one or more adjuvants.

[0367] There are multiple routes of administration available. Of course, the specific mode selected will depend on the specific compound selected, the age and general health of the subject, the specific condition being treated, and the dosage required for therapeutic efficacy. In general, the methods of the present invention can be practiced using any medically acceptable mode of administration, which means any mode that produces an effective response level without causing clinically unacceptable adverse reactions. Preferred modes of administration are discussed above.

[0368] The composition can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical field. All methods include the step of associating the compound with a carrier that constitutes one or more auxiliary ingredients. Generally, the composition is prepared by uniformly and intimately associating the compound with a liquid carrier, a finely divided solid carrier, or both and then shaping the product if necessary.

[0369] Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administration of compounds, thereby increasing convenience for subjects and doctors. Many types of release delivery systems are available and known to those of ordinary skill 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 in, for example, U.S. Patent No. 5,075,109. Delivery systems also include non-polymer systems, which are: lipids, including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as monoglycerides, diglycerides and triglycerides; hydrogel release systems; silicone rubber 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 systems in which the agent of the invention is contained in an intramatrix form, such as described in U.S. Pat. Nos. 4,452,775, 4,675,189 and 5,736,152, and (b) diffusion systems in which the active component permeates from a polymer at a controlled rate, such as described in U.S. Pat. Nos. 3,854,480, 5,133,974 and 5,407,686. In addition, pump-based hardware delivery systems may be used, some of which are suitable for implantation.

[0370] Effectiveness assay of TRPA1 channel inhibitors

[0371] In some embodiments, the compounds as described herein are tested for their activity on the TRPA1 channel. In some embodiments, the compounds as described herein are tested for their TRPA1 channel electrophysiology. In some embodiments, the compounds as described herein are tested for their hERG electrophysiology.

[0372] Equivalent

[0373] The following representative examples are intended to help illustrate the present invention, and are not intended to nor should be construed as limiting the scope of the present invention. In fact, except those shown and described herein, from the full content of this document (including the following examples and the references to the science and patent documentation cited herein), various modifications of the present invention and many further embodiments thereof will be apparent to those skilled in the art. It should also be understood that the contents of these cited references are incorporated herein by reference to help illustrate the prior art. The following examples contain important additional information, examples and guidance, which may be applicable to the practice of various embodiments of the present invention and equivalents thereof.

[0374] Example

[0375] 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.

[0376] Example 1A. Intermediate 1 ((1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol)

[0377]

[0378] Step a:

[0379] To a stirred solution of 3-(4-chlorophenyl)-3-oxopropionitrile (30.0 g, 167 mmol) and RuCl[(S,S)-Tsdpen](mesitylene) (0.426 g, 0.680 mmol) in ACN (300 mL) was added formic acid triethylamine complex (5:2) (24 mL) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved in EA (200 mL) and water (300 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give (3S)-3-(4-chlorophenyl)-3-hydroxypropionitrile (30.0 g, crude product) as a brown oil, which was used directly in the next step without purification: 1 H NMR (400 MHz, DMSO-d 6 )δ7.50-7.37(m,4H),6.03(d,J=4.6Hz,1H),4.95-4.86(m,1H),2.86(m,2H).

[0380] Step b:

[0381] (3S)-3-(4-chlorophenyl)-3-hydroxypropionitrile (30.0 g, 165 mmol) and NH 2 A solution of OH (50% in water) (24 mL) in MeOH (300 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-dihydroxypropionimideamide (30.0 g, crude) as a brown oil, which was used directly in the next step without purification: LCMS (ESI): C 9 H 11 C1N 2 O 2 [M+H] +Calculated value: 215,217 (3:1), Measured value: 215,217 (3:1); 1 H NMR (400 MHz, DMSO-d 6 )δ8.76(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).

[0382] Step c:

[0383] To a stirred solution of (3S)-3-(4-chlorophenyl)-N,3-dihydroxypropionimide amide (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 hours, heated to 95°C, stirred for 4 hours 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 extracted with more EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL) and purified by 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 (15.0 g, 33.0%, three steps) as a yellow solid; LCMS (ESI) C 11 H 10 Cl 2 N 2 O 2 [MH] - Calculated value: 271,273 (3:2) Measured value: 271,273 (3:2); 1 H NMR (300 MHz, DMSO-d 6 )δ7.53-7.23(m,4H),5.67(d,J=4.9Hz,1H),5.09(s,2H),5.05-4.96(m,1H),3.11-2.96(m,2H).

[0384] Example 1B. Intermediate 2 (5-methyl-6-(1H-pyrazol-4-yl)-3H-pyrimidin-4-one)

[0385]

[0386] Step a:

[0387] 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) were added to a mixture of dioxane (8 mL) and H 2 O at room temperature. 2 To the stirred solution in O (2 mL) 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). The reaction was degassed under reduced pressure and purged with nitrogen three times, then stirred at 80 ° C for 12 hours. After cooling to room temperature, the resulting mixture was filtered and the filter cake was washed with MeOH (3 x 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 (0.450 g, 52.9%) as an off-white solid: LCMS (ESI) C 12 H 13 C1N 4 O 2 [M+H] + Calculated value: 281,283 (3:1) Measured value: 281,283 (3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ8.63(d,J=0.7Hz,1H),8.40-8.21(m,1H),8.19(d,J=3.6Hz,1H),5.54(t,J=9.8Hz,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).

[0388] Step b:

[0389] 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) was added TsOH·H 2O (76.2 mg, 0.401 mmol). The resulting mixture was stirred at 70 ° C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was quenched with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and purified by 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 (0.262 g, 44.8%) as a pale yellow oil: LCMS (ESI) C 17 H 21 C1N 4 O 3 [M+H] + Calculated value: 365,367 (3:1) Measured value: 365,367 (3:1); 1 H NMR (300 MHz, CDCl 3 )δ8.97-7.77(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).

[0390] Step c:

[0391] 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 trimethylcyclotriboroxane (0.275 g, 2.19 mmol) in dioxane (1.6 mL) and H2O at room temperature was added 1% ethyl acetate (0.140 g, 0.439 mmol). 2 Cs was added to the solution in O (0.4 mL) 2 CO 3 (0.429 g, 1.32 mmol) and Pd(PPh 3 ) 4 (50.7 mg, 0.0440 mmol). The reaction was degassed under reduced pressure and purged with nitrogen three times, then stirred at 100 ° C for 4 hours. After cooling to room temperature, the resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and washed with 35% ACN / water (plus 10 mmol / L NH 4 HCO 3) was eluted to give 5-methyl-3-(tetrahydropyran-2-yl)-6-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyrimidin-4-one (74.0 mg, 48.9%) as a yellow oil: 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 )δ8.35(d,J=5.7Hz,2H),8.00(s,1H),5.83-5.65(m,1H),5.50(t,J=10.0Hz, 1H),4.15-3.89(m,2H),3.69-3.61(m,2H),2.18(s,3H),2.03-1.44(m,12H).

[0392] Step d:

[0393] 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 aqueous HCl (0.2 mL, 6 M) in MeOH (0.8 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 5-methyl-6-(1H-pyrazol-4-yl)-3H-pyrimidin-4-one (46.0 mg, crude) as a yellow oil, 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 Measured value: 177.

[0394] Example 1C. Intermediate 3 (5-chloro-6-(hydroxymethyl)pyrimidin-4(3H)-one)

[0395]

[0396] Step a:

[0397] To a stirred mixture of methyl 6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.00 g, 6.49 mmol) in DMF (15 mL) at room temperature was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.770 g, 3.89 mmol). The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was purified by reverse phase chromatography, eluting with 20% ACN / water (plus 0.1% TFA) to give methyl 5-chloro-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.700 g, 57.2%) as a light yellow solid: LCMS (ESI) C 6 H 5 C1N 2 O 3 [M+H] + Calculated value: 189,191 (3:1) Measured value: 189,191 (3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ13.78(s,1H),8.31(s,1H),3.90(s,3H).

[0398] Step b:

[0399] 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). The reaction was stirred at 70 °C for 4 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 1% ACN / water (plus 0.1% TFA) to give 5-chloro-6-(hydroxymethyl)pyrimidin-4(3H)-one (0.300 g, crude) as a pale yellow solid, which was used directly in the next step without further purification: LCMS (ESI): C 5 H 5 C1N 2 O 2 [M+H] + Calculated value: 161,163 (3:1) Measured value: 161,163 (3:1).

[0400] Example 1D. Intermediate 4 (5-chloro-6-oxo-1H-pyrimidine-4-carboxamide)

[0401]

[0402] Step a:

[0403] 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 2 O (5 mL, 25%). The reaction was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 3% ACN / water (plus 0.05% TFA) to give 5-chloro-6-oxo-1H-pyrimidine-4-carboxamide (0.240 g, 43.5%) as an off-white solid: LCMS (ESI) C 5 H 4 C1N 3 O 2 [M+H] + Calculated value: 174,176 (3:1) Measured value: 174,176 (3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ10.54(s,1H),8.24(s,1H),8.01(s,1H),7.79(s,1H).

[0404] Example 1E. Intermediate 5 (5-chloro-2-(hydroxymethyl)-3H-pyrimidin-4-one)

[0405]

[0406] Step a:

[0407] 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). The reaction was degassed under reduced pressure and purged with nitrogen three times, then stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and washed with 20% ACN / water (plus 10 mmol / L NH 4 HCO 3 ) was eluted to give (5-chloro-4-methoxypyrimidin-2-yl)methanol (0.340 g, 34.9%) as an off-white solid; LCMS (ESI): C 6 H 7 C1N 2 O 2 [M+H] + Calculated value: 175,177 (3:1) Measured value: 175,177 (3:1);1 H NMR (400 MHz, DMSO-d 6 )δ8.64(s,1H),4.90-4.87(brs,1H),4.52(s,2H),4.04(s,3H).

[0408] Step b:

[0409] To a stirred solution of (5-chloro-4-methoxypyrimidin-2-yl)methanol (0.150 g, 0.860 mmol) in ACN (1 mL) was added 4% paraformaldehyde in H 2 0 (2 mL) in NaOH (0.100 g, 2.58 mmol). The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. The resulting mixture was neutralized with aqueous HCl (1 M) to pH 7 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 C1N 2 O 2 [MH] - Calculated value: 159,161 (3:1) Measured value: 159,161 (3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ8.14(s,1H),5.85(s,1H),4.33(s,2H).

[0410] Example 1F. Intermediate 6 (3-chloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridin-2-ol)

[0411]

[0412] Step a:

[0413] To 3-chloro-2-methoxypyridin-4-ylboronic acid (0.800 g, 4.27 mmol) and Na 2 CO 3 (1.36 g, 12.8 mmol) in dioxane (8 mL) and H 2 To the stirred mixture in 2 mL of 4-bromo-1-(tetrahydropyran-2-yl)pyrazole (0.990 g, 4.28 mmol) and Pd(dppf)Cl 2(0.312 g, 0.427 mmol). The reaction was degassed under reduced pressure, purged with nitrogen three times, and stirred at 80 °C for 16 hours. The cooled mixture was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and washed with anhydrous Na 2 SO 4 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 (0.900 g, 71.8%) as a pale yellow oil: LCMS (ESI): C 14 H 16 C1N 3 O 2 [M+H] + Calculated value: 294,296 (3:1) Measured value: 294,296 (3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ8.59(d,J=5.75Hz,1H),8.15(d,J=5.85Hz,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).

[0414] Step b:

[0415] A solution of 3-chloro-2-methoxy-4-[1-(tetrahydropyran-2-yl)pyrazol-4-yl]pyridine (0.400 g, 1.36 mmol) in aqueous HCl (3 M, 4 mL) was stirred at 80° C. for 16 hours. 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 (0.230 g, crude) as a colorless oil, which was used directly in the next step without purification: LCMS (ESI): C 8 H 6 C1N 3 O[M+H] + Calculated value: 196,198 (3:1) Measured value: 196,198 (3:1).

[0416] Step c:

[0417] 3-Chloro-4-(1H-pyrazol-4-yl)pyridin-2-ol (0.230 g, 1.18 mmol) and K 2 CO3 To a stirred mixture of 1,4-dihydro- ... 2 SO 4 The residue was purified by silica gel chromatography using PE / EA (1 / 4) as eluent to give 3-chloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridin-2-ol (0.160 g, 41.8%) as an off-white solid: LCMS (ESI): C 14 H 20 C1N 3 O 2 Si[M+H] + Calculated value: 326,328 (3:1) Measured value: 326,328 (3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ11.99(s,1H),8.70(s,1H),8.20(s,1H),7.42(d,J=6.91Hz,1H),6.58(d,J= 6.93Hz,1H),5.53(s,2H),3.68-3.61(m,2H),0.90-0.84(m,2H),0.00(s,9H).

[0418] Examples 2-5 describe the synthesis of representative compounds of Formula I, Ia, Ib, Ic, Ha, lib or lib disclosed herein.

[0419] Example 2. Compound 4 (1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methyl-6-oxopyridine-3-carboxamide)

[0420]

[0421] Step a:

[0422] 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). The reaction mixture was stirred for 2 h, diluted with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using 63% ACN / water (plus 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 (0.280 g, 85.8%) as a brown solid: LCMS (ESI): C 17 H 12 BrClN 4 O 2 [M+H] + Calculated value: 419,421,423 (2:3:1), Measured value: 419,421,423 (2:3:1); 1 H NMR (300 MHz, DMSO-d 6 )δ8.83(d,J=2.3Hz,1H),8.43(d,J=2.2Hz,1H),7.35-7.26(m,2H),7.26-7.18(m,2H),5.50(s,2H),3.06-2.87(m,4H).

[0423] Step b:

[0424] To 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 was added at room temperature under nitrogen atmosphere. 3 (40.0 mg, 0.476 mmol) in 1,4-dioxane (1 mL) and H 2 To the stirred mixture in 2% O (0.5 mL) were added 2,4,6-trimethylcyclotriboroxane (0.179 g, 1.43 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (17.4 mg, 0.0240 mmol). The reaction mixture was vacuum degassed and purged with nitrogen three times, then heated to 80 ° C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL) and washed with anhydrous Na 2 SO 4Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18OBD column, 19x 150mm, 5μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 20mL / min; gradient: 35% B to 60% B, 60% B in 5 minutes; wavelength: UV 210nm; retention time: 4.98min. 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 (2.70mg, 3.04%) as a yellow solid: LCMS (ESI) C 18 H 17 C1N 4 O 3 [M+H] + Calculated value: 373,375 (3:1) Measured value: 373,375 (3:1); 1 H NMR (300MHz, CD 3 OD)δ8.33(d,J=2.53Hz,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).

[0425] 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)

[0426]

[0427] Step a:

[0428] 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 H 2 O dropwise at room temperature. 2 O (7 mL). The reaction mixture was stirred for 16 hours, concentrated under reduced pressure and acidified to pH 5 with HCl (1 M). The precipitate was collected by filtration and washed with water (4 x 5 mL) to give 6-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylic acid (1.50 g, 90.8%) as an off-white solid: 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).

[0429] Step b:

[0430] 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 DMF (0.1 mL) dropwise at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL), stirred for 0.5 hours and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 35% ACN / water (plus 0.05% TFA) to give methyl 6-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylate (0.100 g, 18.3%) as a yellow solid: 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 )δ12.60(s,1H),7.99(s,1H),3.78(s,3H),2.28(s,3H).

[0431] Step c:

[0432] 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). The reaction mixture was stirred for 2 hours, diluted with water (10 mL) and extracted with EA (4 x 20 mL). The combined organic layers were washed with brine (2 x 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 using 50% ACN / water (plus 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 (0.150 g, 77.9%) as a yellow solid: LCMS (ESI): C 18 H 17 C1N 4 O 5 [M+H] + Calculated value: 405,407 (3:1) Measured value: 405,407 (3:1); 1 H NMR (300 MHz, CDCl 3 )δ8.14(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).

[0433] Step d:

[0434] To NH in MeOH 3 4-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-methyl-5-oxopyrazine-2-carboxylic acid methyl ester (50.0 mg, 0.120 mmol) was added to 1% 4-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-methyl-5-oxopyrazine-2-carboxylic acid methyl ester (50.0 mg, 0.120 mmol) (7M, 1.5 mL), the reaction mixture was stirred at 40°C for 4 hours and concentrated under reduced pressure. The crude product (50.0 mg) was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19 x 150 mm, 5 μm; mobile phase A: water (with 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 50% B, 50% B in 6.5 minutes; wavelength: UV 254 / 210 nm; retention time: 5.68 min. The 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 (29.0 mg, 60.2%) as an off-white solid: LCMS (ESI): C 17 H 16 C1N 5 O 4 [M+H] + Calculated value: 390,392 (3:1) Measured value: 390,392 (3:1); 1 H NMR (300 MHz, DMSO-d 6)δ8.45(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).

[0435] 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)

[0436]

[0437] Step a:

[0438] 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 (0.500 g, crude) as an off-white solid, which was used directly in the next step without purification: LCMS (ESI): C 6 H 9 N 3 O[M+H] + Calculated value: 140, measured value: 140.

[0439] Step b:

[0440] 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 hour, 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 (1.10 g, crude product with silica) as a yellow solid, which was used directly in the next step without purification: LCMS (ESI): C 5 H 7 N 3 O[M+H] + Calculated value: 126, measured value: 126.

[0441] Step c:

[0442] 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). The reaction mixture was stirred for 1 hour, diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (5 x 2 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: X Bridge Prep OBD C18 column, 19 x 250 mm, 5 μm; mobile phase A: water (plus 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 minutes; detector: UV 254 / 220 nm; retention time: 5.41 min. The 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 (32.1 mg, 23.70%) as an off-white solid: LCMS (ESI) C 16 H 16 C1N 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 )δ8.18(s,1H),7.41-7.32(m,4H),6.40(s,2H),5.63(d,J=4.9Hz,1H),5.26(s,2H),5.02-4.92(m,1H),3.04-2.89(m,2H),1.73(s,3H).

[0443] 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)

[0444]

[0445] Step a:

[0446] 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 at 25°C under nitrogen for 2 hours and concentrated under reduced pressure. The residue was purified by reverse phase chromatography and washed with 50% ACN / water (plus 10 mM NH 4 HCO 3 ) was eluted to give 5-chloro-1-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-6-oxopyrimidine-4-carbonitrile (26.0 mg, 38.9%) as a brown solid; LCMS (ESI): C 16 H 11 Cl 2 N 5 O 3 [MH] - Calculated value: 390,392 (3:2), Measured value: 390,392 (3:2); 1 H NMR (300 MHz, DMSO-d 6 )δ8.81(s,1H),7.35-7.31(m,4H),5.63(d,J=4.8Hz,1H),5.55(s,2H),4.98-4.92(m,1H),3.05-2.94(m,2H).

[0447] The compounds in Table 1 below were prepared by using the procedures described in Schemes 1-8 or in a manner analogous to that described for Compounds 4, 29, 33 or 63 in Examples 2-5.

[0448] Table 1

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] The compounds in Table 2 below can be prepared by using the procedures described in Schemes 1-8 or in a manner analogous to that described for Compounds 4, 29, 33 or 63 in Examples 2-5.

[0465] Table 2

[0466]

[0467]

[0468]

[0469] The compounds in Table 3 below can be prepared by using the procedures described in Schemes 1-8 or in a manner analogous to that described for Compounds 4, 29, 33 or 63 in Examples 2-5.

[0470] Table 3

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477] Example 6. Evaluation of TRPA1 inhibitor activity

[0478] This assay is used to evaluate the inhibitory activity of disclosed compounds on human TRPA1 channels.

[0479] Cell culture

[0480] CHO cells 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 adding doxycycline (1 μg / ml) 24 hours before the experiment. Cells for electrophysiology were seeded in plastic culture flasks and incubated at 5% CO according to ChanPharm SOP. 2 -Grow in a humidified tissue culture incubator at 37°C. Store stocks at low temperatures.

[0481] Solution

[0482] The cells were immersed in an extracellular solution containing 80 mM NaCl, 60 mM NMDG, 4 mM KCl, 2 mM CaCl 2 、6mM MgCl 2 , 5mM glucose, 10mM HEPES, 3mM HEDTA; pH adjusted to 7.4 with NaOH; 305-310mOsm. All compounds were dissolved in DMSO at 30mM. The internal solution contained 10mM CsCl, 110mM CsF, 10mM NaCl, 10mM EGTA, 10mM HEPES, 4mM MgATP, 0.25mM NaGTP, 4mM BAPTA; pH adjusted to 7.2 with CsOH; 285-290mOsm. Compound stock solutions were freshly diluted with external solution to concentrations of 3nM, 10nM, 30nM, 100nM, 300nM, 1μM, 3μM, 10μM, and 30μM. The highest level of DMSO (0.1%) was present at 30μM.

[0483] Patch clamp recordings and compound application

[0484] 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 establishing the whole-cell configuration, membrane current recording and compound application were achieved with the aid of SyncroPatch. TRPA1 currents were induced by applying carvacrol (300 μM) at a constant holding potential of -60 mV (see Table A below).

[0485] Table A

[0486]

[0487] Data analysis

[0488] To determine IC 50 The AUC and peak values ​​obtained in the presence of a given compound concentration were normalized to the control values ​​in the absence of the compound. IC values ​​were derived by fitting the normalized data to the Hill equation using DataControl 384 (Nanion's proprietary software). 50 value.

[0489] Example 7. Evaluation of hERG activity

[0490] This assay is used to evaluate the inhibitory activity of disclosed compounds on the hERG channel.

[0491] Cell culture

[0492] 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 electrophysiology were seeded in plastic culture flasks and incubated at 5% CO according to ChanPharm SOP. 2 -Grow in a humidified incubator at 37°C. Store stocks at low temperature.

[0493] Solution

[0494] The cells were immersed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 5 mM glucose and 10 mM HEPES; pH adjusted to 7.4 with NaOH; 295-305 mOsm. The internal 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 with external solution to concentrations of 50 μM and 100 μM. The highest level of DMSO (0.15%) was present at 50 μM.

[0495] Voltage scheme

[0496] All experiments were performed at room temperature. Each cell served as its own control. When preparing the recording session, the intracellular solution (see above) was loaded into the intracellular compartment of the automatic patch clamp platform SyncroPatch (Nanion) chip and the cell suspension was pipetted into the extracellular compartment. After setting up the full-cell configuration, membrane current recording and compound application were realized by means of SyncroPatch. The hERG current was triggered by a voltage pulse mode with a fixed amplitude (depolarization: +20mV amplitude, 300ms duration; repolarization: -50mV, 300ms duration), with a 3-second interval from the holding potential of -80mV repeated.

[0497] Data analysis

[0498] Data acquisition and analysis were performed using DataControl384 (Nanion's proprietary software). To determine (percent) inhibition, the last single pulse in the pulse train at a given compound concentration was used (i.e., repolarization step to -50 mV; tail current). The AUC and peak values ​​obtained in the presence of the compound were normalized based on control values ​​in the absence of the compound.

[0499] Table 4 provides a summary of the inhibitory activity of certain selected compounds of the present invention on TRPAl channels and hERG channels.

[0500] Table 4. IC values ​​of some exemplary compounds for TRPA1 channel and hERG channel 50 (μM) value

[0501]

[0502]

[0503]

[0504]

[0505]

[0506] *Not detected (ND)

[0507] Table 5 provides a summary of the inhibitory activity of certain selected compounds of the present invention on TRPAl channels and hERG channels.

[0508] Table 5. IC values ​​of some exemplary compounds for TRPA1 channel and hERG channel 50 (μM) value

[0509]

[0510]

[0511]

[0512]

[0513]

[0514] *Not yet measured (ND)

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or a tautomer thereof: in Y is N or CR2; Z is N or CR3; R1 is H, D, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, saturated heterocycle, CN, OR a , SR a or NR a R b ; R2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b ; R3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b ; R4 is H, D, halogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, saturated heterocycle, CN, OR a , SR a , -C 1-4 Alkyl-OR a or NR a R b ; is aryl or heteroaryl, each optionally substituted by 1-5 substituents independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 ; L1 is –(CR5R6)–; Each occurrence of R5 is independently H, D, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, CN, OR a or -C 1-4 Alkyl-OR a ; Each occurrence of R6 is independently H, D, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, CN, OR a or -C 1-4 Alkyl-OR a ; n is 2 or 3; L2 is –CR7R8–; R7 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4 Alkyl-OR a ; R8 is H, D, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, CN or -C 1-4 Alkyl-OR a ; R a and R b Each occurrence of is independently H, alkyl, (C=O)R x 、(C=O)N(R x 2. SO2R x NR x (C=O)NR x2 , cycloalkyl, haloalkyl, heteroalkyl, haloheteroalkyl, halocycloalkyl, a saturated heterocycle containing 1-3 heteroatoms each selected from N, O and S, aryl or heteroaryl; or alternatively, R a and R b Together with the carbon or nitrogen atom to which they are attached, they form a cycloalkyl group or a saturated heterocyclic ring comprising the nitrogen atom and 0 to 3 additional heteroatoms each selected from N, O and S; R1, R2, R3, R4, R5, R6, R7, R8, R a or R b The alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl and alkylheteroaryl groups in the formula (a) are optionally substituted with 1 to 4 substituents independently selected from the following groups when valence permits: alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, OR x 、-(CH2) 1-2 OR x 、N(R x )2, -(CH2) 1-2 N(R x )2、(C=O)R x 、(C=O)N(R x )2. NR x (C=O)R x and oxo; and R x Each occurrence of is independently H, D, alkyl or optionally substituted heterocycle; or alternatively two R x The groups together with the nitrogen atom to which they are attached form a heterocyclic ring which is optionally substituted by an alkyl group and comprises the nitrogen atom and 0 to 3 further heteroatoms each selected from N, O and S; Provided that when Z is N, R4 is not OH.

2. The compound according to claim 1, wherein Y is CR2.

3. The compound according to claim 1, wherein Y is N.

4. A compound according to any one of claims 1 to 3, wherein Z is CR3.

5. The compound according to any one of claims 1 to 3, wherein Z is N.

6. The compound according to any one of claims 1 to 5, wherein n is 2.

7. A compound according to any one of claims 1-6, wherein each occurrence of R5 is independently cycloalkyl, halocycloalkyl, -C 1-4 Alkyl-OR a or CN.

8. A compound according to any one of claims 1-6, wherein each occurrence of R5 is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group.

9. The compound of claim 8, wherein each occurrence of R5 is independently H, D, CH3, CH2CH3, OH, F, Cl or Br.

10. according to the compound described in any one of claims 1-9, wherein each occurrence of R6 is independently cycloalkyl, halocycloalkyl, -C 1-4 Alkyl-OR a or CN.

11. A compound according to any one of claims 1-9, wherein each occurrence of R6 is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group.

12. The compound of claim 11, wherein each occurrence of R6 is independently H, D, CH3, CH2CH3, OH, F, Cl or Br.

13. The compound according to any one of claims 1 to 5, wherein L1 is selected from -CH2-CH2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-C(CH3)2-, -CH(OH)-CH2-, -CH2-CH(OH)-, 14. The compound according to any one of claims 1 to 5, wherein L1 is selected from -CH2-CH2-, 15. The compound of claim 1, wherein the compound has a structure of Formula Ia, Ib or Ic: in R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl; R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl; R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group; and R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or a fluoroalkyl group.

16. The compound according to any one of claims 1 to 15, wherein R7 is cycloalkyl, halogenated cycloalkyl, CN or -C 1-4 Alkyl-OR a .

17. The compound according to any one of claims 1-15, wherein R7 is H, D, alkyl or fluoroalkyl.

18. The compound according to claim 17, wherein R7 is H, D, CH3 or CH2CH3.

19. The compound according to any one of claims 1 to 18, wherein R8 is cycloalkyl, halogenated cycloalkyl, CN or -C 1-4 Alkyl-OR a .

20. The compound according to any one of claims 1-18, wherein R8 is H, D, alkyl or fluoroalkyl.

21. The compound of claim 20, wherein R8 is H, CH3 or CH2CH3.

22. The compound of any one of claims 1-14, wherein L2 is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, and -CH(CH2CH3).

23. The compound according to any one of claims 1-14, wherein L2 is -CH2-.

24. A compound according to any one of claims 1 to 23, wherein is phenyl, which is optionally substituted by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a and -C 1-4 Alkyl-OR a .

25. The compound of claim 1, wherein the compound has a structure of Formula IIa, IIb or IIc: in R 5a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl; R 5b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl; R 6a Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl; R 6b Each occurrence of is independently H, D, alkyl, halogen, OR a or fluoroalkyl; R 11 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a ; R 12 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a ; R 13 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a ; R 14 Each occurrence of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, 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 of is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b , -C 1-4 Alkyl-SR a or -C 1-4 Alkyl-OR a .

26. The compound according to claim 25, wherein R 11 , R 12 , R 14 and R 15 is H; and R 13 H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, OR a , SR a NR a R b or -C 1-4 Alkyl-OR a .

27. The compound according to claim 26, wherein R 13 is CH3, CH2CH3, OH, F, Cl, Br, OCH3, CH2OCH3, CF3, CN, C≡CH or 28. A compound according to any one of claims 1 to 24, wherein Selected from 29. A compound according to any one of claims 1 to 23, wherein is a 5- or 6-membered heteroaryl group, which is optionally substituted by 1-4 substituents each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, aryl, heteroaryl, CN, OR a , SR a NR a R b and -C 1-4 Alkyl-OR a .

30. The compound according to claim 29, wherein Selected from 31. The compound according to any one of claims 1 to 30, wherein R1 is cycloalkyl, haloalkyl or halocycloalkyl.

32. A compound according to any one of claims 1 to 30, wherein R1 is H, D, halogen, alkyl, CN, CF3, OR a , SR a or NR a R b .

33. A compound according to any one of claims 1-30, wherein R1 is selected from H, D, CH3, CH2CH3, OH, F, Cl, Br, OCH3, CF3, CN, NH2, NHCH3, N(CH3)2 and 34. according to the compound described in any one of claims 1-33, wherein R2 is H, D, halogen, CN, CF3, 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

35. A compound according to any one of claims 1 to 33, wherein R2 is a saturated heterocycle, a partially saturated heterocycle or a heteroaryl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, alkyl, CN, OR x 、-(CH2) 1-2 OR x 、N(R x )2, -(CH2) 1-2 N(R x )2、(C=O)R x 、(C=O)N(R x )2. NR x (C=O)R x and oxo.

36. A compound according to any one of claims 1-33, wherein R2 is alkyl, alkenyl or alkynyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, OR x 、-(CH2) 1-2 OR x 、N(R x )2, -(CH2) 1-2 N(R x )2、(C=O)R x 、(C=O)N(R x )2. NR x (C=O)R x and oxo.

37. A compound according to any one of claims 1 to 33, wherein R2 is cycloalkyl, aryl or alkylaryl, alkylheteroaryl.

38. A compound according to any one of claims 1-33, wherein R2 is selected from H, D, CH3, CH2CH3, OH, F, Cl, Br, I, OCH3, CF3, CN, NH2, NHCH3, N(CH3)2, CH=CH2, 39. A compound according to any one of claims 1-38, wherein R3 is H, D, halogen, alkyl, haloalkyl, heteroaryl or CN.

40. A compound according to any one of claims 1-38, wherein R3 is 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 .

41. A compound according to any one of claims 1-38, wherein R3 is 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 , OC 1-4 Alkyl-R a or NR a -C 1-4 Alkyl-R b .

42. A compound according to any one of claims 1-38, wherein R3 is selected from H, D, CH3, CH2CH3, OH, F, Cl, Br, OCH3, CF3, CN, CH2CN, CH=CH2, NH2, NHCH3, N(CH3)2, 43. A compound according to any one of claims 1-42, wherein R4 is cycloalkyl, haloalkyl or halocycloalkyl.

44. according to the compound described in any one of claims 1-42, wherein R4 is H, D, halogen, alkyl, CN, CF3, OR a , SR a , -C 1-4 Alkyl-OR a or NR a R b .

45. A compound according to any one of claims 1-42, wherein R4 is selected from H, D, CH3, CH2CH3, OH, F, Cl, Br, OCH3, CF3, CN, NH2, NHCH3, N(CH3)2, CH2OH, 46. ​​A compound according to any one of claims 1-45, wherein R a or R b At least one occurrence of is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

47. The compound according to claim 46, wherein R a or R b At least one occurrence of is independently H, D, Me, Et, Pr, CH2CH2OH, phenyl, or a heterocycle selected from: The heterocyclic ring is optionally substituted with alkyl, OH, oxo or (C=O)C 1-4 Alkyl substituted.

48. The compound according to claim 47, wherein R a or R b At least one occurrence of H, Me, phenyl, 49. A compound according to any one of claims 1-45, wherein R a and R b Together with the nitrogen atom to which they are attached they form an optionally substituted heterocyclic ring comprising said nitrogen atom and 0-3 further heteroatoms each selected from N, O and S.

50. A compound according to any one of claims 1-49, wherein R x Each occurrence of is independently H, alkyl, or heterocycle optionally substituted with alkyl, halogen, or OH.

51. The compound according to claim 50, wherein R x Each occurrence of is independently H or alkyl.

52. The compound according to claim 51, wherein R x Each occurrence of is independently H or Me.

53. The compound of claim 1, wherein the compound is selected from the group consisting of Examples 2-5 and Tables 1-5.

54. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

55. A method of treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from pain, skin disorders, respiratory diseases, fibrotic diseases, inner ear disorders, fever or other temperature regulation disorders, urinary tract or bladder disorders, autoimmune diseases, ischemia, central nervous system (CNS) disorders, inflammatory disorders, gastrointestinal disorders, and cardiovascular disorders.

56. The method of claim 55, wherein 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, hyperesthesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve damage, post-stroke pain, or pain associated with teeth and dental damage.

57. The method of claim 55, wherein the urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, bladder instability, or bladder outlet obstruction.

58. The method of claim 55, wherein the skin disorder is a burn, psoriasis, eczema, or pruritus.

59. The method of claim 55, wherein the skin disorder is pruritus caused by atopic dermatitis or psoriasis.

60. The method of claim 55, wherein the respiratory disease is inflammatory airway disease, airway hyperresponsiveness, idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough or chronic cough.

61. The method of claim 55, wherein the ischemia is CNS hypoxia or a condition associated with reduced blood flow to the CNS.

62. The method of claim 55, wherein the autoimmune disease is rheumatoid arthritis or multiple sclerosis.

63. The method of claim 55, wherein the central nervous system disorder is associated with neurodegeneration.

64. The method of claim 55, wherein the gastrointestinal disorder is inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, vomiting, or gastroduodenal ulcer.

65. The method of claim 55, wherein the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

66. The method of claim 55, wherein the mammalian species is human.

67. A method of inhibiting transient receptor potential ankyrin 1 (TRPA1) in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof.

68. The method of claim 67, wherein the mammalian species is human.

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