WO2020102575A1 - Heterocyclic aminothiazoles and uses thereof - Google Patents

Heterocyclic aminothiazoles and uses thereof Download PDF

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Publication number
WO2020102575A1
WO2020102575A1 PCT/US2019/061532 US2019061532W WO2020102575A1 WO 2020102575 A1 WO2020102575 A1 WO 2020102575A1 US 2019061532 W US2019061532 W US 2019061532W WO 2020102575 A1 WO2020102575 A1 WO 2020102575A1
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alkyl
thiazol
methanone
phenyl
membered
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PCT/US2019/061532
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French (fr)
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Jason David BURCH
Stephane Dorich
Lee David FADER
Miguel St-Onge
Bin Chen
Daniel Guay
Serge Leger
Eric Levesque
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Inception Ibd, Inc.
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Publication of WO2020102575A1 publication Critical patent/WO2020102575A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • heterocyclic aminothiazole compounds are modulators of the vanin family of pantetheinase. In other embodiments, the compounds are modulators of vanin-1. In certain embodiments, the compounds are inhibitors of vanin-1. Also provided are compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention or amelioration of diseases or disorders related to vanin-1 activity or one or one or more symptoms associated with such dieases or disorder.
  • Vanin-1 is a pantetheinase that hydrolyses pantetheine to form pantothenic acid
  • vitamin B5 vitamin B5
  • vanin-1 expression is up-regulated in multiple cells types exposed to various stimuli including inflammatory and oxidative stress conditions.
  • vanin-1 the vanin family includes secreted and membrane-associated enzymes. Specifically, three family members have been described in humans (vanin-1, vanin-2 and vanin-3) and two in mice (vanin-1 and vanin-3) all of which have pantetheinase activity. The only known substrate of the vanin enzymes is pantetheine and vanin-1 is believed to be the major pantetheinase in vivo (Pitari et al, FEBS Lett 483, 149-154 (2000)).
  • Pantothenic acid is an essential factor in the synthesis of coenzyme A (CoA) which is involved in multiple cellular processes, for example, the metabolism of short- and long-chain fatty acids (Leonardi et al., Prog. Lipid. Res., 44, 125-153 (2005)).
  • Cysteamine is thought to be a key regulator of essential metabolic pathways, putatively inhibiting enzymes such as transglutaminases (Jeitner et ah, Biochem. Pharmacol. 69, 961-970 (2005) and Elli et ah, Lab. Invest.
  • caspase 3 (Lesort et ah, J. Biol. Chem., 278, 3825-3830 (2003)), GST A3 (Di Leandro et ah, Free Radic. Biol. Med., 44, 1088-1096 (2008)), protein kinase Cs (Chu et ah, Cancer Res., 65, 10478-10485 (2005)), and g- glutamylcysteine synthase (g-GCS) which catalyzes a key step in the synthesis of glutathione (GSH), the major cellular antioxidant molecule (Martin et ah, J. Clin. Invest., 113, 591-597 (2004)).
  • GSH glutathione
  • vanin-1 In addition to this role associated with oxidative stress through cysteamine-dependent modulation of GSH levels, vanin-1 expression and activity have been shown to be inversely correlated with levels of PPARy, a nuclear receptor involved in the dampening of pro- inflammatory signaling. Thus, vanin-1 may upregulate oxidative stress and inflammation and contribute to disease pathogenesis (F. Martin et al, supra, and C. Berruyer et al., J. Exp. Med., 203, 2817-2827 (2006), particularly in tissues where vanin-1 is highly expressed, such as the mucosa of subjects with inflammatory bowel diseases (IBD) (Gensollen et al, Inflamm. Bowel. Dis., 19, 2315-2325 (2013)).
  • IBD inflammatory bowel diseases
  • vanin-1 -deficient mice are more resistant to paraquat poisoning and to exposure to lethal doses of g-irradiation. These mice have reduced levels of pro-inflammatory cytokines as well as a reduced apoptotic response in the small intestine following exposure to oxidative stress (Berruyer et al, Mol. Cell. Biol. 24, 7214-7224 (2004)). In addition to the reported reduced inflammation, vanin-1 KO mice have increased GSH levels and absence of cysteamine in tissues where vanin-1 expression is predominant (liver and kidney) (Pitari et al, supra).
  • cystamine Intraperitoneal administration of cystamine abrogates the resistant phenotype of the mutant mice demonstrating that cysteamine/cystamine participate in the tissue response following exposure to stress (Berruyer et al, 2004, supra). Vanin-1 deficiency also reduces inflammation and injury in the gut in animals exposed acutely to indomethacin or infected chronically with Schistosoma mansoni (Martin et al, supra).
  • vanin-1 -deficient mice are protected in DSS- and TNBS-induced mouse models of colitis, by showing reduced levels of multiple pro-inflammatory cytokines, attenuated recruitment of myeloid cells to the mucosa, and reduced colonic tissue damage (Berruyer et al, 2006, supra and Pouyet et ah, Inflamm. Bowel Dis., 16, 96-104 (2010)).
  • Vanin-1 may also be implicated in other diseases beyond IBD.
  • vanin-N vanin-N
  • vanin- 1 has been associated with the regulation of multiple key metabolic pathways. Expression of vanin- 1 is high in liver and strongly induced by fasting via PPARa induction, and leads to an increase the expression of gluconeogenic genes and hepatic glucose output, resulting in hyperglycemia (van Diepen et al, Sci. Rep., 6, 21906 (2016) and Chen et al, Diabetes, 63, 2073-2085 (2014)). Recently, increased vanin-1 activity was observed in plasma and liver of high fat diet (HFD)- induced obese mice, as well as ZDF-diabetic rats. VNN1 KO mice have mildly improved glucose tolerance and insulin sensitivity in HFD-fed animals (van Diepen etal, supra).
  • HFD high fat diet
  • Vanin- 1 expression is high in human psoriatic skin leading to the proposal that vanin- 1 plays a role in Thl 7/Thl -driven inflammatory skin conditions (Jansen et al, J. Invest. Dermatol., 129, 2167-2174 (2009)).
  • expression of vanin-1 in whole blood is higher in subjects suffering from chronic pediatric immune thrombocytopenia (ITP) (Zhang et al., Blood, 117, 4569-4579 (2011)).
  • Vanin-1 mRNA expression levels have been shown to correlate with HDL-C levels supporting a potential role of vanin-1 in cardiovascular disease (Kaskow e/a/., Eur. J. Hum. Genet., 22, 688-695 (2014)).
  • VNN1 cardiovascular diseases
  • Vanin-1 may also be a potential therapeutic target for neointimal hyperplasia following revascularization as it plays a role in driving smooth muscle cell activation in post- arterial injury (Dammanahalli et al, PLoS One, 7, e39106 (2012)).
  • SSc systemic sclerosis
  • X 1 is N or CR al ;
  • X 2 is N or CR a2 ;
  • X 3 is N or CR a3 ;
  • X 4 is N or CR a4 ;
  • R° is hydrogen, halo or C1-C6 alkyl
  • R al , R a2 , R a3 and R a4 are each independently hydrogen or halo;
  • R 1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR 10 , -SR 10 , - C(0)OR 10 , -C(0)N(R n )(R 12 ), -S(0)tR 9 , -S(0)tN(R n )(R 12 ), -P(0)(R 9 ) 2 , and -SFs, wherein the optional substituents are one to five groups selected from Ci-Ce alkyl, halo and Ci-Ce haloalkyl;
  • Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 10, 0 to 8, 0 to 5 or 1 to 5 Q substituents selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5- to 10- membered heteroaryl, and optionally substituted 5-
  • each R 9 and R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 10 , R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 11 and R 12 , and R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl
  • compositions comprising compounds of Formula (I), or pharmaceutically acceptable salts thereof, and methods of making and using compounds of Formula (I), or pharmaceutically acceptable salts thereof.
  • compounds of Formula (I), or pharmaceutically acceptable salts thereof are inhibitors of vanin proteins, such as vanin-1, and may be used for treating certain diseases, disorders, and conditions, either as mono therapies or as components of combination therapies.
  • X 1 is N or CR al ;
  • X 2 is N or CR a2 ;
  • X 3 is N or CR a3 ;
  • X 4 is N or CR a4 ;
  • R° is hydrogen, halo or C1-C6 alkyl
  • R al , R a2 , R a3 and R a4 are each independently hydrogen or halo
  • R 1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR 10 , -SR 10 , - C(0)OR 10 , -C(0)N(R n )(R 12 ), -S(0)tR 9 , -S(0)tN(R n )(R 12 ), -P(0)(R 9 ) 2 , and -SFs, wherein the optional substituents are one to five groups selected from C1-C6 alkyl, halo and C1-C6 haloalkyl;
  • Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 10, 0 to 8, 0 to 5 or 1 to 5 Q substituents selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5- to 10- membered heteroaryl, and optionally substituted
  • each R 9 and R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 10 , R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 11 and R 12 , and R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1 or 2; n is 0, 1 or 2; and each t is independently 1 or 2.
  • Ring A is an N-linked pyrrolidine, azetidine, piperidine, piperazine, morpholine, thiomorpholine, perhydro-l,4-diazepine, perhydro-l,4-thiazepine, 1,2,3,4-tetrahydroisoquinoline, 3-azabicyclo[3.1.0]hexane, 2-azabicyclo[2. 1.
  • Ring A is an N-linked azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, perhydro-l,4-diazepine or perhydro-1,4- thiazepine.
  • R° is hydrogen, halo or C1-C6 alkyl; and R 1 and Ring A are as described for Formula (I) or Formula (la).
  • R 1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10- membered heteroaryl, -OR 10 , -SR 10 , - C(0)OR 10 , -C(0)N(R n )(R 12 ), -S(0)tR 9 , -S(0)tN(R n )(R 12 ), -P(0)(R 9 ) 2 , or -SFs where the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to five groups selected from C1-C6 alkyl, halo and Ci- Ce haloalkyl
  • Y is -C(R 3a )(R 3b )-, -NR 2 -, -0-, -S- or -S(0)t-; provided that when Y is -NR 2 -, -0-, -S- or -S(0)t-, neither m nor n is 0;
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each, when present, independently selected from (i), (ii), (iii), (iv) and (v):
  • R 3a and R 3b , R 4a and R 4b , R 5a and R 5b , R 6a and R 6b , and R 7a and R 71 ’ together with the carbon atom to which they are attached, form an oxo group; and the remainder of R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each, when present, selected from (i);
  • one of the following pairs R 3a and R 6a , R 3a and R 7a , R 4a and R 5a , R 5a and R 6a , R 4a and R 7a , andR 6a and R 7a form a bridged alkylene group selected from -CH2-, - C )i- and -(CH2)3- , wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR 24 - or -S- or - S(0)t- and wherein the bridged alkylene may further optionally be substituted with C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl(Ci-C6 alkyl) or -R u OR x and the remainder of R 2 , R 3a , R 3b , R 4a , R 4b , R
  • R 9 and R 13 are each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 10 , R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
  • R 11 and R 12 , and R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R v is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);; or
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);;
  • each R y and R z is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);, together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; m is 0, 1 or 2; n is 0, 1 or 2; and each t is independently 1 or 2.
  • R° is hydrogen, halo or Ci-Ce alkyl
  • R al , R a2 , R a3 and R a4 are each independently hydrogen or halo
  • Y, R 1 , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , R 71 ’, and m and n are as described for Formula (II).
  • R al , R a2 , R a3 and R a4 are each independently hydrogen or halo; Y, R 1 , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , m and n are as described for Formula (II) or (Ila).
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are selected from (i)(a) and (i)(b) as follows:
  • R 2 when present, is Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl (Ci-Cealkyl), -C(0)R 13 , -C(0)OR 14 , -C(0)N(R 16 )(R 17 ) or -S(0)tR 13 ; and R 3a , R 3b ,
  • R 2 when present, is hydrogen; up to three of R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each, when present, independently halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 3- to 8- membered heteroaryl, 3- to 8- membered heteroaryl(Ci-C6
  • each R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • R 2 when present, is C1-C6 alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci- Cealkyl), Ci-C6haloalkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci- C6alkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl (Ci-Cealkyl), -C(0)R 13 , -C(0)OR 14 , -C(0)N(R 16 )(R 17 ) or -S(0)tR 13 ; and R 3a , R 3b , R 4
  • each R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3 to 8- membered cycloalkyl, 3 to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3 to 8- membere
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3 to 8- membered cycloalkyl, 3 to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3 to 8- membered heterocyclyl, 3 to 8- membered heterocyclyl(Ci-C6 alkyl), , 5 to 10 membered heteroaryl or 5 to 10 membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3 to 8- membered heterocyclyl;
  • R 2 when present, is hydrogen; up to three of R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each, when present, independently halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3 to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3 to 8- membered heterocyclyl, 3 to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 3 to 8- membered heteroaryl, 3 to 8- membered heteroaryl(
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • R 2 when present, is C1-C6 alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci- Cealkyl), Ci-C6haloalkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci- C6alkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl (Ci-Cealkyl), -C(0)R 13 , -C(0)OR 14 , -C(0)N(R 16 )(R 17 ) or -S(0)tR 13 ; and R 3a , R 3b , R 4
  • each R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, aralkyl, or heteroaralkyl;
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R v is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R y and R z is independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • each R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl, each R u is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • each R 13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl,
  • 3- to 8- membered cycloalkyl 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl,
  • 3- to 8- membered cycloalkyl 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R v is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
  • each R y and R z is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • R 3a and R 6a , R 3a and R 7a , R 4a and R 5a , R 5a and R 6a , R 4a and R 7a , and R 6a and R 7a form a bridged alkylene group -CH2-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR 24 - or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-Cio aryl, Ce- Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6alkyl), and the remainder of R 3a , R 3b , R 4a , R 4b , R 5a , R 51 ’, R 6a ,
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; R 20 is each independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and the remaining variables are as described for Formula (II), (Ila) or (lib).
  • R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each, when present, independently selected from hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-C6alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6alkyl), -OR 15 , -SR 15
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • R 20 is each independently hydrogen, Ci-Ce alkyl or Ci-Ce haloalkyl
  • R 24 is hydrogen, C i-Ce alkyl, Ci-Ce hydroxyalkyl, aralkyl, or heteroaralkyl;
  • each R u is independently a direct bond, Ci -Ce alkylene or Ci-Ce alkenylene;
  • each R v is independently C i-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R y and R z is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 are selected from (i), (ii), (iii), (iv), (v) and (vi) as follows:
  • R 2 when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; and R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C
  • R 2 when present, is hydrogen; one, two or three of R 3a , R 4a , R 5a R 6a and R 7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 , N(R 16 )(R 17 ), -C(0)R 13 , -C(0)0R 14 or -C(0)N(R 16 )(R 17 ), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8-
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), C6-C10 Ci-C6haloalkoxy(Ci-C6 alkyl), aryl(Ci-C6 alkyl), heteroaralkyl, heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 3b and R 4a and R 4b , together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroary
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 4a , R 3a and R 5a , and R 4a and R 6a , together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyano
  • R 2 when present, is hydrogen, C i-Ce alkyl, C i-Ce haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) , 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 6a , R 3a and R 7a , R 4a and R 5a , R 5a and R 6a , R 4a and R 7a , and R 6a and R 7a , form a bridged alkylene group -CH2-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may
  • R 2 and R 4a and R 2 and R 5a together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ce- C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -R u OR x and -R u C(0)OR x] ; and the remainder of R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’, are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C 6 alky
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl),
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 are selected from (i), (ii), (iii) and (iv) as follows:
  • R 2 when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; and R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C
  • R 2 when present, is hydrogen; one, two or three of R 3a , R 4a , R 5a R 6a and R 7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 ,
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 4a , R 3a and R 5a , and R 4a and R 6a , together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyan
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) , 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 6a , R 3a and R 7a , R 4a and R 5a , R 5a and R 6a , R 4a and R 7a , and R 6a and R 7a , form a bridged alkylene group -CH2-, - C h)i- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl) 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R v is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are selected from (i), (ii) and (111):
  • R 2 when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; and R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b ,
  • R 2 when present, is hydrogen; one, two or three of R 3a , R 4a , R 5a R 6a and R 7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 , N(R 16 )(R 17 ), -C(0)R 13 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 ), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- member
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 4a , R 3a and R 5a , and R 4a and R 6a , together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyan
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl) 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are selected from (i), (ii), (iii) , (iv), (v) and (vi) as follows:
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl,
  • R 3a and R 4a is halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 , - N(R 16 )(
  • R 2 when present, is hydrogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of R 5a and R 5b , and when present, R 6a , R 6b , R 7a and R 7b , is halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 5- to 10- membered heteroaryl, -OR 15 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 )wherein the C6-C10 aryl or 5- to 10- membered heteroaryl,
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 3b and R 4a and R 4b , together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 ary
  • R 2 when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), heteroaryl, -C(0)R 13 or -C(0)OR 14 ; one of the following pairs R 3a and R 6a , R 3a and R 7a , R 4a and R 5a , R 5a and R 6a , R 4a and R 7a , and R 6a and R 7a , form a bridged alkylene group -CH2-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -
  • R 2 and R 4a and R 2 and R 5a together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 C1-C6, haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -R u OR x and -R u C(0)OR x ; and the remainder of R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’, are each, when present, independently hydrogen, halogen cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl or Ci
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
  • each R v is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R y and R z is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each t is independently 1 or 2; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
  • Y is -C(R 3a )(R 3b )-;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 are selected as follows:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 , - N(R 16 )(R 17 ), -C(0)R 13 , -C(0)0R 14 or -C(0)N(R 16 )(R 17 ), wherein the 3- to 8- membered
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each independently, when present, hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl, -OR 15 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 ) wherein the 3- to 8- membered cycloalkyl, Ce- Cio aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl is optionally
  • R 13 is each independently Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and each t is independently 1 or 2; and the remaining variables are as described for Formula (I), (II), (Ila) or (lib).
  • Y is -C(R 3a )(R 3b )-;
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are selected as follows:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 , - N(R 16 )(R 17 ), -C(0)R 13 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 ), wherein the 3- to 8- membered
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently, when present, hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl, -OR 15 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 ) wherein the 3- to 8- membered cycloalkyl, Ce- C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl is optionally substitute
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 16 and R 17 are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and the remaining variables are as described for Formulae (I), (II), (Ila) or (lib).
  • R 3a , R 3b R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are selected from (i), (ii) and (iii) as follows:
  • R 3a , R 3b R 4a and R 4b are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl -OR 15 , -SR 15 , -S(0)tR 13 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 ), wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-
  • R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 5- to 10- membered heteroaryl -OR 15 , -SR 15 , -S(0)tR 13 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 ) wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R 3a , R 3b , R 4a
  • R 3a and R 4a together with adjacent atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ce-Cio aryl(Ci-C 6 alkyl), -ROR X or -C(0)0R x ; R 3b , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each, independently, when present, hydrogen or halogen;
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and
  • each t is independently 1 or 2.
  • n 0 or 1 ;
  • R° is hydrogen, halo or Ci-Ce alkyl
  • R al , R a2 , R a3 and R a4 are each independently hydrogen or halo;
  • R 1 is halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR 10 , -SR 10 , - C(0)OR 10 , -C(0)N(R n )(R 12 ), -S(0)tR 9 , -S(0)tN(R n )(R 12 ), -P(0)(R 9 ) 2 , and -SFs, wherein the optional substituents are one to five groups each independently selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; and
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are as described for Formula (I), (II) or
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are selected from (i), (ii), (iii) and (iv) as follows:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each, when present, independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, heteroaryl, -OR 15 , -SR 15 , -S(0)tR 13 , -N(R 16 )(R 17 ), -N(R 20 )C(0)R 13 , -C(0)R 13 , -C(0)0R 14 , -C(0)N(R 16 )(R 17 ) wherein the 3- to 8- membere
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R 20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
  • each t is independently 1 or 2.
  • R° is hydrogen, halo or C1-C6 alkyl
  • R al , R a2 , R a3 and R a4 are each independently hydrogen or halo;
  • R 1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR 10 , -SR 10 , - C(0)OR 10 , -C(0)N(R n )(R 12 ), -S(0)tR 9 , -S(0)tN(R n )(R 12 ), -P(0)(R 9 ) 2 , and -SFs, wherein the optional substituents are one to five groups each independently selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; and
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are as described for Formula (I), (II), (Ila), (III) or (IV).
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are selected from (i), (ii), (iii), (iv) and (v) as follows:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each, when present, independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR 15 , -C(0)R 13 , -C(0)OR 14 or -C(0)N(R 16 )(R 17 );
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each, when present, independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR 15 , -C(0)OR 14 , -C(0)NR 16 R 17 , wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
  • R 4a and R 6a together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with halogen, C1-C6 alkyl or -R u OR x ; and R 3a , R 3b , R 4b , R 5a , R 5b and R 6b , are each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ROR X or -C(0)0R x ; and
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • R 24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
  • each t is independently 1 or 2; and the other variables are as described for Formulae (I),
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are selected from (i), (ii), and (iii) as follows:
  • R 3a and R 5a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), C1-C6 haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 5- to 10- membered heteroaryl, -OR 15 , -C(0)OR 14 , -C(0)N(R 16 )(R 17 ); the other of R 3a and R 5a , and R 3b , R 5b , R 4a , R 4b , R 6a and R 6b , are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 15 , -C(0)OR 14 , -C(0)NR 16 R 17 , 3- to 8- membered cycloalkyl, 3- to 8- member
  • R 3a and R 4a together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R u OR x or - C(0)OR x ;
  • R 3b , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen or halogen;
  • R 5a and R 6a together, form a bridged alkylene group -(CH2)-, -(CH2)2- or -(CIl2)3- wherein one carbon atom of -(CH2)2- or -( ⁇ 2)3- may be replaced with -0-, -NR 24 - or -S(0)t- and the remainder of R 3a , R 3b R 4a , R 4b , R 5a , R 5b , R 6a and R >b are each independently hydrogen or halogen;
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
  • each R u is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
  • each t is independently 1 or 2; and the other variables are as described for Formulae
  • R 3a is halogen, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -OR 15 or -C(0)0R 14 ; and R 3b , R 4a , R 4b , R 5a , R 5b , R 6a andR 6b are each independently hydrogen or halogen; andR 14 andR 15 , are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl
  • R 1 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are as described for Formulae (I), (II), (Ha), (lib), (HI), (IV) or (IVa).
  • R 1 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are as described for Formulae (I), (II), (Ha), (lib) or (III).
  • Y is -C(R 3a )(R 3b )-, -NR 2 -, -0-, -S- or S(0)t-;
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are selected from (i), (ii), (iii), (iv) and(v) as follow:
  • R 2 when present, is hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci -Ce hydroxyalkyl, Ci-Ce alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl; and one, two or three of R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10-
  • R 3a and R 4a together with the carbon atom to which they are attached, form C6-C10 aryl, 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 haloalkyl and -R u OR x or substituted with two adjacent groups that form a 3 - to 8- membered heterocyclyl ring; and the R 3b , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b , are each, when present, independently halogen, C1-C6 alkyl, Ci- Ce haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR 15 ;
  • R 4a and R 6a together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl optionally substituted with halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) or heteroaralkyl; and R 2 , R 3a , R 3b , R 5a , R 5b , R 7a and R 71 ’, and R 4b and R 6b , when present, are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, 5- to 10- membered heteroaryl or -OR 15 ;
  • R 2 and R 4a together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl; and the remainder of R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’, are each, when present, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR 15 ;
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
  • t is 1 or 2; and the other variables are as described for Formula (I), (II), (Ha), (lib) or (III).
  • Y is -C(R 3a )(R 3b )-, -NR 2 -, -0-, -S- or -S(0)t-;
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are selected from (1), (11), (111) and (iv) as follow:
  • R 2 when present, is hydrogen, and and one, two or three of R 3a , R 3b , R 4a ,
  • R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or -OR 15 and the remainder of R 3a , R 3b , R 4 , R 4b 3 R 5a 3 R 5b R 6a 3 R 6b 3 R 7a and R 71 ’ are each independently hydrogen or halo; or R 2 is C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, heteroaralkyl, -C(0)R 13 or -C(0)OR 14 and R
  • R 3a and R 4a together with the carbon atom to which they are attached, form C6-C10 aryl, 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 haloalkyl and -R u OR x ; and R 3b , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’, are each, selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; or
  • R 2 and R 4a together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl; and the remainder of R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’, are each, when present, independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each R u is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
  • each R x is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • each t is independently 1 or 2; and the other variables are as described for Formula (I),
  • R 3a , and R 3b is each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, Ci- Ce alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl),
  • R 4a , R 4b , R 5a and R 5b is each independently hydrogen, C6-C10 aryl or 5- to 10- membered heteroaryl, or
  • R 3a and R 3b together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), and C6-C10 aryl(Ci-C6 alkyl); and the remainder of R 4a , R 4b , R 5a are R 5b are each independently hydrogen or halogen
  • R 13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 14 and R 15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
  • R 16 and R 17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
  • each t is independently 1 or 2; wherein the variables are as described for
  • Y is -NR 2 -, -0-, -S- or -S(0)t-;
  • R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’ are selected from (i), (ii) and (iii) as follow:
  • R 2 is hydrogen, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and R 4a ,R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 71 ’, are each independently hydrogen or halogen;
  • R 4a and R 6a together with the carbon atom to which they are attached, form C6-C10 aryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and -R u OR x ; and R 2 , R 3a , R 3b , R 5a , R 5b , R 7a and R 71 ’, are each independently hydrogen or halogen; and
  • R 2 and R 4a or R 2 and R 5a together with the carbon atom to which they are attached, form C6-C10 aryl or 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and -R u OR x ; and the and the remainder of R 4a , R 4b , R 5a , R 5b , R 6 a, j ⁇ 6 b ⁇ j ⁇ 7 a anc j j ⁇ b are eac ] 1 independently hydrogen or halogen;
  • each t is independently 1 or 2; wherein the variables are as described for Formulae (I), (II) or (IIa).
  • R 1 is halogen, cyano, C1-C6 haloalkyl, 5- to 10- membered heteroaryl, -OR 10 , SR 10 , -S(0)tR 9 , -S(0)tN(R n )(R 12 ), or -SFs where the 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and Ci- C6 haloalkyl; R 9 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci- Ce alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membere
  • R 10 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
  • R 11 and R 12 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and each t is independently 1 or 2.
  • R 1 is halogen, cyano, C1-C6 haloalkyl, 5- to 10- membered heteroaryl, -OR 10 , -SR 10 , or - SF5 where the 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; R 10 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), C6-C10 aryl,
  • R 1 is -SC Me.
  • the compound of Formula (I) or (II) is selected from:
  • R bb R wherein the variables are as described for Formula (I) or (II).
  • the compound of Formula (I) or (II) is selected from:
  • the compound of Formula (I) is selected from:
  • Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Other embodiments provide a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising a compound of Formula (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (Vllb), or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.
  • Some embodiments provide a method for the treatment of a disease or condition selected from: an inflammatory bowel disease, a colorectal cancer, and a gastritis, comprising administering a therapeutically effective amount of a compound of any of claims 1 to 28, or a solvate, hydrate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, to a subject in need thereof.
  • Some embodiments provide a method for the treatment of inflammatory bowel disease comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, a compound of a compound of Formula (I), (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (Vllb), or a pharmaceutically accepteable salt of any of the foregoing), to a subject in need thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, a compound of a compound of Formula (I), (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (
  • inventions provide a method for the treatment of inflammatory bowel disease comprising administering to a subjectsubject in need thereof a compound of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
  • the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.
  • Some embodiments provide a method of inhibiting vanin activity, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof.
  • Other embodiments provide a method of inhibiting vanin activity, comprising contacting a cell with a compound of Formula (la), or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof.
  • the cell is an epithelial cell.
  • the cell is in a subject in need of vanin inhibition.
  • the vanin activity is selected from vanin-1 activity, vanin-2 activity, vanin-3 activity, or a combination of any of the foregoing.
  • the vanin activity is vanin-1 activity.
  • the vanin activity is vanin-1 activity, vanin-2 activity, and vanin-3 activity.
  • any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment.
  • the terms are to be interpreted synonymously with the phrases“having at least” or“including at least.”
  • the term“comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term“comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.
  • the term“subject” includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans. In some embodiments, the subject is a human.
  • a group is described as being“substituted” or“optionally substituted” that group may be unsubstituted or substituted with the indicated number of the indicated substituents.
  • an aryl group optionally substituted with 1 or 2 halogens.
  • the indicated group is optionally substituted with one or more of the indicated substituents.
  • an aryl group optionally substituted with halogen.
  • the indicated“optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, hydroxy, alkoxy, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino.
  • a group is unsubstituted; for example, a “C1-C6 alkyl group” is unsubstited, whereas an “optionally substituted C1-C6 alkyl group” may be substituted or unsubstituted, and a“substituted C1-C6 alkyl group” is substituted.
  • “C a -Cb” in which“a” and“b” are integers refer to the number of carbon atoms in a group.
  • the indicated group can contain from“a” to“b”, inclusive, carbon atoms.
  • a“C1-C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3) 2 CH-, CH3CH2CH2CH2-, CH3CH 2 CH(CH3)- and (CH3)3C-. If no“a” and“b” are designated, the broadest range described in these definitions is to be assumed.
  • R a and R b of an NR a R b group are indicated to be“joined together,” or when“R a and R b together with the nitrogen atom to which they are attached, form heterocyclyl”, it means that they are covalently bonded to one another to form a ring:
  • R which represents any nitrogen containing heterocycle including but not limited to monocyclic and bi-cyclic heterocyclyl groups, as defined herein, for example, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
  • halo or“halogen” refers to any radical of fluorine, chlorine, bromine or iodine.
  • alkyl refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-Ce alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it.
  • an alkyl is a Ci-Ce alkyl which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples of alkyl include without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. .
  • alkylene refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having one to eight or one to six carbon atoms, and includes but is not limited to methylene, ethylene, propylene and n- butylene.
  • the alkylene chain may be attached to the rest of the molecule through any two carbons of the chain.
  • alkenylene refers to a straight or branched unsaturated divalent hydrocarbon chain consisting solely of carbon and hydrogen atoms having two to eight carbon atoms, wherein the unsaturation is present only as double bonds which can exist between any two carbon atoms in the chain.
  • Alkenylene includes but is not limited to ethenylene, prop-l-enylene and but-2-enylene.
  • the alkenylene chain may be attached to the rest of the molecule through any two carbons of the chain
  • cycloalkyl refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having the indicated number of ring carbon atoms between 3 and 12 carbon atoms, or between 3 and 8 carbon atoms.
  • Multi cyclic cycloalkyls may be fused, bridged or spiro ring systems.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and norbornyl.
  • cycloalkenyl refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups having the indicated number of ring carbon atoms between 5 and 12 carbon atoms.
  • a ring carbon e.g., saturated or unsaturated
  • Any atom can be optionally substituted e.g., by one or more substituents.
  • Cycloalkenyl moieties can include without limitation, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.
  • cycloalkylalkyl or“cycloalkyl(alkyl)” refers to cycloalkyl group connected, as a substituent, via an alkylene group.
  • haloalkyl refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5 or 6) are replaced by halo.
  • the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro).
  • “Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). .
  • alkoxy refers to a group of formula -O-(alkyl).
  • Alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy.
  • thioalkoxy refers to a group of formula -S-(alkyl).
  • haloalkoxy and thiohaloalkoxy refer to -O-(haloalkyl) and -S-(haloalkyl), respectively.
  • one or more hydrogen atoms in the alkyl portion of the group may be replaced with deuterium, for example, a deutero methoxy group (-OCD3). .
  • aralkyl and“aryl(alkyl)” refer to an aryl group connected, as a substituent, via an alkylene group.
  • Non-limiting examples of “aralkyl” include benzyl, 2- phenylethyl, and 3-phenylpropyl groups. .
  • alkenyl refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds.
  • Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl.
  • alkynyl refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds.
  • Alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-butynyl, and 2-hexynyl.
  • heterocycle represents a stable 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a stable 6-, 7-, 8- , 9-, 10-, 11-, or 12-membered bicyclic heterocyclic ring system wherein carbon atoms together with from 1 to 5, 1 to 4 or 1 to 3 heteroatoms selected from N, O and S, constitute said ring or ring system and which ring or ring system comprises at least one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings, and further wherein the nitrogen and sulfur atoms may optionally be oxidized as N-oxide, sulfoxide or sulfone, and wherein the nitrogen atom may optionally be quaternized.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems including lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
  • a heterocycle can be bonded via a ring carbon atom or, if available, via a ring nitrogen atom.
  • Bicyclic heterocyclic ring systems may be fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of which 1 or 2 are heteroatoms independently selected from N, O and S.
  • a heterocyclyl group is bicyclic, and in which case, the second ring may be an aromatic or a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms independently selected from N, O and S, or the second ring may be a benzene ring, or a“cycloalkyl”, or a“cycloalkenyl”, as defined herein.
  • heterocyclic groups include, but are not limited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thiet,
  • heterocyclylalkyf refers to a heterocyclic group connected, as a substituent, via an alkylene group. Examples include but are not limited to tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H- thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).
  • aryl as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 6 members in each ring (i.e., 6 to 10 total ring atoms) wherein at least one ring is aromatic.
  • Aryl groups include, but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, or lH-indenyl.
  • heteroaryl represents a stable 5-, 6- or 7-membered monocyclic- or stable 9- or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the second ring need not be aromatic and need not comprise a heteroatom.
  • bicyclic“heteroaryl” includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three, heteroatoms, as defined immediately above, fused to a benzene ring, or a second monocyclic“heteroaryl”, or a“heterocyclyl”, a“cycloalkyl”, or a “cycloalkenyl”, as defined above.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzo
  • heteroaryl and“heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2- thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused analogs.
  • treating refers generally to controlling, alleviating, ameliorating, slowing the progress of or eliminating a named condition once the condition has been established.
  • the term“preventing”, “prevent”, or“prevention” also refers to delaying the onset of, or reducing the risk of developing a named condition or of a process that can lead to the condition, or the recurrence of symptoms of a condition.
  • the term“therapeutically effective amount” or“effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • the compounds of this disclosure may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures.
  • the compounds of the present disclosure may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (e.g., enantiomers, diastereomers).
  • isomers e.g., enantiomers, diastereomers.
  • the compounds of the present disclosure include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds of the present disclosure may also be represented in multiple tautomeric forms, in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented.
  • a term used in the present disclosure encompasses a group that may tautomerize, all tautomeric forms are expressly included thereunder.
  • hydroxy substituted heteroaryl groups include, but are not limited to, 2- hydroxypyridine as well as 2-pyridone, 1 -hydroxyisoquinoline as well as l-oxo-1,2- dihyroisoquinoline, 2-hydroxypyrimidine as well as 2-pyrimidone, 2-hydroxy quinoline as well as 2-quinolinone, 5-hydroxy-l,2,4-oxadiazole as well as l,2,4-oxadiazole-5(4H)one, and the like. All such isomeric forms of such compounds are expressly included in the present disclosure.
  • the compounds of the present disclosure include the compounds themselves, as well as their salts, solvate, and solvate of the salt, if applicable.
  • Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included.
  • a salt for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • “pharmaceutically acceptable salts” refer to derivatives wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, camphorsulfonic, gluconic, mandelic, mucic, pantothenic, oxalic, isethionic, and the like.
  • inorganic acids such as
  • salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases.
  • Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, A'-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.
  • Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present disclosure. The formation of solvates is described in greater detail in “Solvents and Solvent Effects in Organic Chemistry”; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein by reference in its entirety. A person of ordinary skill in the art would recognize the solvates of the present disclosure.
  • the present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not.
  • An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 S, 33 S, 34 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I.
  • Particular isotopic variants of a compound according to the present disclosure may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body, especially compounds labeled with 3 H, 14 C and/or 18 F isotopes are suitable for this purpose.
  • the incorporation of isotopes for example of deuterium, can lead to particular therapeutic benefits for the compounds described herein.
  • deuteration may impart greater metabolic stability of the compound and for example, extend the half-life in the body or reduce the active dose required.
  • Such modifications of the compounds described herein may therefore in some cases also constitute a preferred embodiment of the present disclosure.
  • hydrogen atoms of the compounds described herein may be replaced with deuterium atoms.
  • Isotopic variants of the compounds described herein can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
  • compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a carrier or an adjuvant that may be administered to a subject, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or salt of the solvate thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • the quantity of a compound of the present disclosure in a unit dose of preparation is at 1 mg to 1,000 mg, 2 mg to 900 mg, 3 mg to 800 mg, 4 mg to 700 mg, 5 mg to 600 mg, 10 mg to 500 mg, 50 mg to 400 mg, 100 mg to 300 mg, 150 mg to 250 mg, or any value in between.
  • the total daily dosage may be divided and administered in portions during the day, for example, once per day, twice per day, three times per day or four times per day. In some embodiments, the total dosage may be administered once per week, twice per week, three times per week, four times per week, five times per week or six times per week.
  • the pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • the pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • solid dosage forms of the instant pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary
  • the dosage form may also comprise buffering agents.
  • Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of the instant pharmaceutical compositions of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding pharmaceutical compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • liquid dosage forms of the instant pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate (EtOAc), benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing
  • the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions of the instant compounds may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at RT but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at RT but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Some embodiments provide methods of treating diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or viral infections comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.
  • Other embodiments provide the use of an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or viral infections.
  • Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or viral infections.
  • Some embodiments provide methods of treating an inflammatory disease or disorder, autoimmune disease, metabolic disease or cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.
  • inventions provide the use of an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of an inflammatory disease or disorder, autoimmune disease, metabolic disease or cancer. Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating an inflammatory disease or disorder, metabolic disease, autoimmune disease or cancer.
  • the disease may be, but not limited to, one of the following classes: autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection- based diseases, trauma or tissue-injury based diseases, fibrotic diseases, genetic diseases, cardiovascular diseases, neurological diseases, neurodegenerative diseases, respiratory diseases, pulmonary diseases, airways diseases, renal diseases, skin and/ or dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases, pain and sensory diseases, hematopoietic diseases, joint diseases, muscle diseases, and bone diseases.
  • autoimmune diseases inflammatory diseases, allergic diseases, metabolic diseases, infection- based diseases, trauma or tissue-injury based diseases, fibrotic diseases, genetic diseases, cardiovascular diseases, neurological diseases, neurodegenerative diseases, respiratory diseases, pulmonary diseases, airways diseases, renal diseases, skin and/ or dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases, pain and sensory diseases, hematopoietic diseases, joint diseases, muscle diseases, and bone diseases.
  • autoimmune diseases include, but are not limited to: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, systemic lupus erythematosus (and resulting complications), Sjogren's syndrome, multiple sclerosis, asthma, glomerular nephritis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis, Behcet's disease, lupus nephritis, scleroderma, systemic scleroderma, type 1 or juvenile on-set diabetes, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, antiphospholipid antibody syndrome, atrophic gastritis of pernicious anemia, autoimmune alopecia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune encephalomyelitis, autoimmune thrombocytopenia, Bullous pe
  • Inflammatory diseases include, but are not limited to: chronic obstructive pulmonary diseases, airway hyper-responsiveness, cystic fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, gingivitis, atherosclerosis, chronic prostatitis, glomerular nephritis, ulcerative colitis, uveitis, periodontal disease, or an indication listed in a separate category herein.
  • Pain conditions include, but are not limited to: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post- traumatic injury, pain associated with irritable bowel syndrome, gout, pain associated with any of the other indications listed within this specification, or an indication listed in a separate category herein.
  • Respiratory, airway and pulmonary conditions include, but are not limited to: asthma (which may encompass chronic, late, bronchial, allergic, intrinsic, extrinsic or dust), chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis, interstitial lung disease, acute lung injury, sarcoidosis, allergic rhinitis, chronic cough, bronchitis, recurrent airway obstruction, emphysema, or bronchospasm, or an indication listed in a separate disease category herein.
  • asthma which may encompass chronic, late, bronchial, allergic, intrinsic, extrinsic or dust
  • chronic obstructive pulmonary disease idiopathic pulmonary fibrosis
  • pulmonary arterial hypertension cystic fibrosis
  • cystic fibrosis interstitial lung disease
  • acute lung injury sarcoidosis
  • allergic rhinitis allergic rhinitis
  • chronic cough bron
  • Gastrointestinal (GI) disorders include, but are not limited to: irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with Gl distension, ulcerative colitis, Crohn's disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, or an indication listed in a separate disease category herein.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • biliary colic and other biliary disorders include, but are not limited to: irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with Gl distension, ulcerative colitis, Crohn's disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocyto
  • Allergic diseases include, but are not limited to: anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, allergic reactions to: food, drugs, insect bites, pollen; or an indication listed in a separate disease category herein.
  • Infection-based diseases include, but are not limited to: sepsis, septic shock, viral diseases, malaria, Lyme disease, ocular infections, conjunctivitis, Whipple Disease, or an indication listed in a separate disease category herein.
  • Trauma and tissue injury-based conditions include, but are not limited to: renal glomerular damage, reperfusion injury (for example to heart, kidney, lung), spinal cord injury, tissue scarring, tissue adhesion, tissue repair, transplant rejection (for examples to heart, lung, bone marrow, cartilage, cornea, kidney, limb, liver, muscle, myoblast, pancreas, pancreatic islet, skin, nerve, small intestine, trachea), hypersensitivities, or an indication listed in a separate disease category herein.
  • Fibrotic diseases include, but are not limited to: idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, or an indication listed in a separate disease category herein.
  • Joint, muscle and bone disorders include, but are not limited to: osteoarthritis, osteoporosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, erosive osteoarthritis of the hand, arthrofibrosis/traumatic knee injury, anterior cruciate knee ligament tear, relapsing polychondritis, recurrent multifocal osteomyelitis, Majeed syndrome, ankylosing spondylitis, gout of the lumbar spine, antisynthetase syndrome, idiopathic inflammatory myopathies, articular chondrocalcinosis, systemic-onset juvenile idiopathic arthritis (SJIA), gout and pyrophosphate crystal arthritis, or an indication listed in a separate disease category herein.
  • osteoarthritis osteoporosis
  • rheumatoid arthritis juvenile arthritis
  • psoriatic arthritis erosive osteoarthritis of the hand
  • arthrofibrosis/traumatic knee injury anterior cruci
  • Skin/ dermatological diseases include, but are not limited to: psoriasis, atopic dermatitis, cutaneous lupus, acne, dermatomyositis, eczema, pruritus, scleroderma, Sweet Syndrome/neutrophilic dermatosis, neutrophilic panniculitis, acrodermatitis (form of pustular psoriasis), or an indication listed in a separate disease category herein.
  • Renal diseases include, but are not limited to: acute kidney injury (AKI) (sepsis- AKI, coronary artery bypass graft- AKI, cardiac surgery-AKI, non-cardiac surgery- AKI, transplant surgery-AKI cisplatin-AKI, contrast/imaging agent induced-AKI), glomerulonephritis, IgA nephropathy, crescentic GN, lupus nephritis, HIV associated nephropathy, membraneous nephropathy, C3 glomerulopathy, Dense deposit disease, ANCA vasculitis, diabetic nephropathy, hemolytic-uremic syndrome, atypical Hemolytic-uremic syndrome, nephrotic syndrome, nephritic syndrome, hypertensive nephrosclerosis, ApoLl nephropathy, focal segmental glomerulosclerosis, Alport syndrome, Fanconi syndrome, crystal nephropathy, nephrolithia
  • Hematopoietic diseases include, but are not limited to: hemolytic anemia, or an indication listed in a separate disease category herein.
  • Liver diseases include, but are not limited to: liver fibrosis, liver cirrhosis, nonalcoholic steatohepatitis (NASH), or an indication listed in a separate disease category herein.
  • liver fibrosis liver cirrhosis
  • NASH nonalcoholic steatohepatitis
  • Oral diseases include, but are not limited to: gingivitis, periodontal disease or an indication listed in a separate disease category herein.
  • Metabolic diseases include, but are not limited to: Type 2 diabetes (and resulting complications), gout and hyperuricemia, metabolic syndrome, insulin resistance, obesity, obesity- related hyperglycemia or an indication listed in a separate disease category herein.
  • Compounds of the present disclosure are also useful in the treatment of a proliferative disease selected from a benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non
  • Cardiovascular diseases include, but are not limited to coronary heart disease, acute coronary syndrome, ischaemic heart disease, first or recurrent myocardial infarction, secondary myocardial infarction, non-ST segment elevation myocardial infarction, or ST segment elevation myocardial infarction, ischemic sudden death, transient ischemic attack, peripheral occlusive arterial disease, angina, atherosclerosis, hypertension, heart failure (such as congestive heart failure), diastolic dysfunction (such as left ventricular diastolic dysfunction, diastolic heart failure, and impaired diastolic filling), systolic dysfunction (such as systolic heart failure with reduced ejection fraction), vasculitis, ANCA vasculitis, post- myocardial infarction cardiac remodeling atrial fibrillation, arrhythmia (ventricular), ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial
  • venous thrombosis deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • thrombosis includes occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty).
  • Cardiovascular complications of type 2 diabetes are associated with inflammation, and include conditions such as macrovascular disease, hyperglycemia, metabolic syndrome, impaired glucose tolerance, hyperuricemia, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and insulin resistance syndrome, or an indication listed in a separate disease category herein.
  • Neuroinflammatory and neurodegenerative conditions include diseases or diorders such as multiple sclerosis, migraine; epilepsy; Alzheimer's disease; Parkinson's disease; brain injury; stroke; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, and brain hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV associated dementia, Alzheimer's associated dementia, Huntington's associated dementia, Lewy body dementia, vascular dementia, drug related dementia, delirium, and mild cognitive impairment); mental deficiency (including Down syndrome and fragile X syndrome); sleep disorders (including hypersomnia, circadian rhythm sleep disorder, insomnia, parasomnia, and sleep deprivation) and psychiatric disorders (such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive
  • the acute or chronic autoimmune and/or inflammatory condition is a disorder of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • the acute or chronic autoimmune and/or inflammatory condition are respiratory disorders such as asthma, chronic obstructive pulmonary disease, pulmonary arterial hypertension or idiopathic pulmonary fibrosis.
  • the acute or chronic autoimmune and/or inflammatory condition is a systemic inflammatory disorder such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, scleroderma or inflammatory bowel disease (Crohn's disease and ulcerative colitis).
  • a systemic inflammatory disorder such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, scleroderma or inflammatory bowel disease (Crohn's disease and ulcerative colitis).
  • the acute or chronic autoimmune and/or inflammatory condition is multiple sclerosis.
  • Some embodiments provide methods of treating a metabolic disease by administering a therapeutically effective amount of the compound of Formula (I) wherein the metabolic disease is diabetes or hyperglycemia.
  • Other embodiments provide the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of a metabolic disease wherein the metabolic disease is diabetes or hyperglycemia.
  • Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating diabetes or hyperglycemia.
  • Some embodiments provide methods of treating an inflammatory disease or disorder, by administering a therapeutically effective amount of the compound of Formula (I) wherein the inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension.
  • inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension.
  • inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension.
  • Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating an inflammatory disease or disorder, wherein the inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension.
  • inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension.
  • the present disclosure relates to methods for the treatment of disease or disorder selected from inflammatory bowel disease (including ulcerative colitis and Crohn's disease), colorectal cancer, and gastritis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or salt of a solvate thereof.
  • Some embodiments provide the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of disease or disorder selected from inflammatory bowel disease (including ulcerative colitis and Crohn's disease), colorectal cancer, and gastritis.
  • a disease or disorder selected from inflammatory bowel disease (including ulcerative colitis and Crohn's disease), colorectal cancer, and gastritis.
  • said disease or disorder is inflammatory bowel disease.
  • said disease or disorder is ulcerative colitis.
  • said disease or disorder is Crohn’s disease.
  • the compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, or any value in between (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg, or any value in between) every 4 to 120 hours, or any value in between.
  • parenterally e.g., subcutaneously, intracutaneously
  • compositions are administered by oral administration or by injection.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • dosage forms include from 0.001 milligrams to 2,000 milligrams, or any value in between (including, from 0.001 milligrams to 1,000 milligrams, from 0.001 milligrams to 500 milligrams, from 0.01 milligrams to 250 milligrams, from 0.01 milligrams to 100 milligrams, from 0.05 milligrams to 50 milligrams, and from 0.1 milligrams to 25 milligrams, or any value in between) of a compound of Formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • the dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.
  • Appropriate dosage levels may be determined by any suitable method known to one skilled in the art of treating inflammatory diseases.
  • the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used.
  • actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition and mode of administration, without being toxic to the subject.
  • Non-steroidal anti-inflammatory drugs including but not limited to, nonselective COXl/2 inhibitors such as piroxicam, naproxen, flubiprofen, fenoprofen, ketoprofen, ibuprofen, etodolac (Lodine), mefanamic acid, sulindac, apazone, pyrazolones (such as phenylbutazone), salicylates (such as aspirin); selective COX2 inhibitors such as: celecoxib, rofecoxib, etoricoxib, valdecoxib, meloxicam; Immunomodulatory and/ or anti-inflammatory agents, including but not limited to, methotrexate, leflunomide, ciclesonide, chloroquine, hydroxychloroquine, d-penicillamine, auranofin, sulfa
  • NSAIDs Non-steroidal anti-inflammatory drugs
  • Leukotriene pathway modulators including but not limited to, 5-LO inhibitors (such as zileuton), FLAP antagonists (such as veliflapon, fiboflapon), LTD4 antagonists (such as montelukast, zafirlukast or pranlukast); HI receptor antagonists, including but not limited to, cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; PDE4 inhibitors, including but not limited to, apremilast, roflumilast or AN2728; Vitamin D receptor modulators, including but not limited to, pari cal citol; Nrf2 pathway activators, including but not limited to, fumarates, sulfurophane and bardoxolone methyl; Modulators of the RAR-related orphan receptor (ROR
  • Additional therapeutic agents include antithrombotic agents (anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents), anti-arrhythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type), cardiac glycosides, diuretics, mineralocorticoid receptor antagonists, NO donating agents such as organonitrates, NO promoting agents such as phosphodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal), anti osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti anxiety agents, anti-proliferative agents, anti-tumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid hormone receptor antagonist), anti-infective agents,
  • antithrombotic agents include fondaparinux, edoxaban, betrixaban, apixaban and rivaroxaban, warfarin, heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin), hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, ticagrelor, prasugrel, tirofiban, ifetroban, eptifibatide, abciximab, dabigatran, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokina
  • Suitable anti-arrythmic agents include: Class I agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K + channel openers such as lAch inhibitors, and iKur inhibitors (e.g., compounds such as those disclosed in W001/40231).
  • Class I agents such as propafenone
  • Class II agents such as metoprolol, atenolol, carvadiol and propranolol
  • Class III agents such as sotalol, dofetilide, amiodarone, azimilide and ibutilide
  • Class IV agents such as ditiazem and verapamil
  • K + channel openers such as lAch inhibitor
  • Suitable anti-hypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g.,
  • Dual ET/AII antagonist e.g., compounds disclosed in WO 00/01389
  • neutral endopeptidase (NEP) inhibitors neutral endopeptidase (NEP) inhibitors
  • vasopepsidase inhibitors dual NEP-ACE inhibitors
  • gemopatrilat and nitrates an exemplary antianginal agent is ivabradine.
  • Examples of suitable calcium channel blockers include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.
  • Examples of suitable cardiac glycosides include digitalis and ouabain.
  • Examples of suitable combination mineralocorticoid receptor antagonists include spironolactone and eplerenone.
  • suitable combination phosphodiesterase inhibitors include: PDE3 inhibitors (such as cilostazol); and PDE5 inhibitors (such as sildenafil).
  • suitable cholesterol/lipid lowering agents and lipid profile therapies include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.
  • Atherosclerotic agents include agents that modulate the action of PCSK9, for example, bococizumab.
  • Anti-inflammatory agents also include sPLA2 and lpPLA2 inhibitors (such as darapladib), 5 LO inhibitors (such as atreleuton) and IL-1 and IL-1 r antagonists (such as canakinumab).
  • sPLA2 and lpPLA2 inhibitors such as darapladib
  • 5 LO inhibitors such as atreleuton
  • IL-1 and IL-1 r antagonists such as canakinumab
  • anti-diabetic agents particularly type 2 anti-diabetic agents.
  • suitable anti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors, GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors).
  • Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in W02009144554, W02003072197, WO2009144555 and W02008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or W02010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O- acyltransferase inhibitors, a PDE10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tola
  • SIRT-1 inhibitor e.g., resveratrol, GSK2245840 or GSK184072
  • DPP-IV dipeptidyl peptidease IV
  • an insulin secreatagogue e.g., those in W02005116014, sitagbptin, vildagbptin, alogliptin, dutogbptin, bnagliptin and saxagbptin
  • an insulin secreatagogue e.g., those described in W02020116014, sitagbptin, vildagbptin, alogliptin, dutogbptin, bnagliptin and saxagbptin
  • an insulin secreatagogue e.g., those in W02005116014, sitagbptin, vildagbptin, alogliptin, dutogbptin, bnagliptin and saxagbp
  • GSK1362885 a VPAC2 receptor agonist
  • SGLT2 inhibitors such as those described in Chao et ah, Nat. Rev. Drug Disc. 9, 551-559 (2010) including dapagliflozin, canagliflozin, empagliflozin, tofogbflozin (CSG452), ASP-1941 , THR1474, TS-071 , ISIS388626 and LX421 1 as well as those in W02010023594, a glucagon receptor modulator such as those described in Demong, et ah, Ann. Rep. Med. Chem.
  • GPR119 modulators particularly agonists, such as those described in W02010140092, WO2010128425, W02010128414, WO2010106457, Jones, et ah, Med. Chem. 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov et ah, Curr. Op. Investig.
  • TGR5 also termed GPBAR1 receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235.
  • HM74A high affinity nicotinic acid receptor
  • anti-diabetic agents that can be combined with the compounds of the present disclosure can be found, for example, at page 28, line 35 through page 30, line 19 of WO201 1005611.
  • Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyi transferase enzymes, inhibitors of fructose 1 ,6-diphosphatase, inhibitors of aldose reductase, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g.
  • PKCa, RKOb, PKCy inhibitors of fatty acid synthetase, inhibitors of serine palmitoyi transferase, modulators of GPR81 , GPR39, GPR43, GPR41 , GPR105, Kvl .3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1 , SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILI beta, modulators of RXRalpha.
  • suitable anti-diabetic agents include mechanisms listed by Carpino, P. A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.
  • the compounds of the present disclosure may be used in combination with neuroinflammatory and neurodegenerative agents in mammals.
  • additional neuroinflammatory and neurodegenerative agents include antidepressants, antipsychotics, anti pain agents, anti-Alzheimer's agents, and anti-anxiety agents.
  • Examples of particular classes of antidepressants that can be used in combination with the compounds of the present disclosure include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, and atypical antidepressants.
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.
  • suitable SSRIs include fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine.
  • suitable reversible inhibitors of monoamine oxidase include moclobemide.
  • SNRIs of use in the present disclosure include venlafaxine.
  • suitable atypical anti-depressants include bupropion, lithium, trazodone and viloxazine.
  • anti-Alzheimer's agents include NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine.
  • suitable classes of anti-anxiety agents that can be used in combination with the compounds of the present disclosure include benzodiazepines and serotonin 1A receptor (5-HT1A) agonists, and CRF antagonists.
  • Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam, and prazepam.
  • Suitable 5-HT1 A receptor agonists include buspirone and ipsapirone.
  • Suitable CRF antagonists include verucerfont.
  • Suitable atypical antipsychotics include pabperidone, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine.
  • Suitable nicotine acetylcholine agonists include CP-601927 and varenicbne.
  • Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and zi conotide.
  • co-administration refers to a combination of a compound of the present disclosure and one or more other pharmaceutically active ingredient, or a pharmaceutically acceptable salt thereof, includes the following:
  • Step 1 A solution of 2-chlorothiazole (4.17 g, 34.87 mmol) in THF (40 mL) was cooled to -78 °C and then nBuLi (2.5 M, 14.66 mL) was added dropwise. The solution was stirred for 50 min. In a second flask, 3-methylsulfonylbenzaldehyde (5.00 g, 27.14 mmol) was dissolved in THF (40 mL) and cooled to -78 °C. The solution of the thiazolyl anion was then added dropwise to the second flask via a cold cannula over 5 minutes.
  • Step 2 This product was dissolved in DCM (15 mL) and Dess-Martin periodinane (6.75 g, 15.9 mmol) was added. After stirring for 15 minutes, the reaction was quenched by addition of 100 mL 1 : 1 sat. Na2S203(aq): sat. NaHC03(aq), and the mixture was stirred vigorously for 60 minutes. The layers were separated, then the aqueous fraction was further extracted with 2 x 100 mL EtOAc.

Abstract

The present disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts, solvates and salts of the solvates thereof, pharmaceutical compositions containing compounds of formula (I), as well as the use of compounds of Formula (I) for the treatment of inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis.

Description

HETEROCYCLIC AMINOTHIAZOLES AND USES THEREOF
FIELD
[0001] Provided herein are heterocyclic aminothiazole compounds. In certain embodiments, the compounds are modulators of the vanin family of pantetheinase. In other embodiments, the compounds are modulators of vanin-1. In certain embodiments, the compounds are inhibitors of vanin-1. Also provided are compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention or amelioration of diseases or disorders related to vanin-1 activity or one or one or more symptoms associated with such dieases or disorder.
BACKGROUND
[0002] Vanin-1 is a pantetheinase that hydrolyses pantetheine to form pantothenic acid
(vitamin B5) and the low-molecular-weight thiol cysteamine. Vanin-1 expression is up-regulated in multiple cells types exposed to various stimuli including inflammatory and oxidative stress conditions. In addition to vanin-1, the vanin family includes secreted and membrane-associated enzymes. Specifically, three family members have been described in humans (vanin-1, vanin-2 and vanin-3) and two in mice (vanin-1 and vanin-3) all of which have pantetheinase activity. The only known substrate of the vanin enzymes is pantetheine and vanin-1 is believed to be the major pantetheinase in vivo (Pitari et al, FEBS Lett 483, 149-154 (2000)).
[0003] Both products of vanin (pantothenic acid (vitamin B5) and cysteamine) have been shown to play roles in diverse biological processes. Pantothenic acid is an essential factor in the synthesis of coenzyme A (CoA) which is involved in multiple cellular processes, for example, the metabolism of short- and long-chain fatty acids (Leonardi et al., Prog. Lipid. Res., 44, 125-153 (2005)). Cysteamine is thought to be a key regulator of essential metabolic pathways, putatively inhibiting enzymes such as transglutaminases (Jeitner et ah, Biochem. Pharmacol. 69, 961-970 (2005) and Elli et ah, Lab. Invest. 91, 452-461 (2011)), caspase 3 (Lesort et ah, J. Biol. Chem., 278, 3825-3830 (2003)), GST A3 (Di Leandro et ah, Free Radic. Biol. Med., 44, 1088-1096 (2008)), protein kinase Cs (Chu et ah, Cancer Res., 65, 10478-10485 (2005)), and g- glutamylcysteine synthase (g-GCS) which catalyzes a key step in the synthesis of glutathione (GSH), the major cellular antioxidant molecule (Martin et ah, J. Clin. Invest., 113, 591-597 (2004)). In addition to this role associated with oxidative stress through cysteamine-dependent modulation of GSH levels, vanin-1 expression and activity have been shown to be inversely correlated with levels of PPARy, a nuclear receptor involved in the dampening of pro- inflammatory signaling. Thus, vanin-1 may upregulate oxidative stress and inflammation and contribute to disease pathogenesis (F. Martin et al, supra, and C. Berruyer et al., J. Exp. Med., 203, 2817-2827 (2006), particularly in tissues where vanin-1 is highly expressed, such as the mucosa of subjects with inflammatory bowel diseases (IBD) (Gensollen et al, Inflamm. Bowel. Dis., 19, 2315-2325 (2013)).
[0004] Indeed, vanin-1 -deficient mice are more resistant to paraquat poisoning and to exposure to lethal doses of g-irradiation. These mice have reduced levels of pro-inflammatory cytokines as well as a reduced apoptotic response in the small intestine following exposure to oxidative stress (Berruyer et al, Mol. Cell. Biol. 24, 7214-7224 (2004)). In addition to the reported reduced inflammation, vanin-1 KO mice have increased GSH levels and absence of cysteamine in tissues where vanin-1 expression is predominant (liver and kidney) (Pitari et al, supra). Intraperitoneal administration of cystamine abrogates the resistant phenotype of the mutant mice demonstrating that cysteamine/cystamine participate in the tissue response following exposure to stress (Berruyer et al, 2004, supra). Vanin-1 deficiency also reduces inflammation and injury in the gut in animals exposed acutely to indomethacin or infected chronically with Schistosoma mansoni (Martin et al, supra). Furthermore, vanin-1 -deficient mice are protected in DSS- and TNBS-induced mouse models of colitis, by showing reduced levels of multiple pro-inflammatory cytokines, attenuated recruitment of myeloid cells to the mucosa, and reduced colonic tissue damage (Berruyer et al, 2006, supra and Pouyet et ah, Inflamm. Bowel Dis., 16, 96-104 (2010)).
[0005] In addition: (i) there is a significant increase in vanin plasma activity in both ulcerative colitis (UC) and Crohn’s disease (CD) subjects, (ii) there is an increase in vanin-1 mRNA and protein levels in the colonic mucosa of IBD subjects, and (iii) single nucleotide polymorphisms (SNPs) in the vanin-1 gene (VNN1) in IBD subjects that lead to increased vanin- 1 activity, and potentially to lower levels of PPARy and some pro-inflammatory cytokines (Gensollen et al, supra).
[0006] Vanin-1 may also be implicated in other diseases beyond IBD. For example, vanin-
1 has been associated with the regulation of multiple key metabolic pathways. Expression of vanin- 1 is high in liver and strongly induced by fasting via PPARa induction, and leads to an increase the expression of gluconeogenic genes and hepatic glucose output, resulting in hyperglycemia (van Diepen et al, Sci. Rep., 6, 21906 (2016) and Chen et al, Diabetes, 63, 2073-2085 (2014)). Recently, increased vanin-1 activity was observed in plasma and liver of high fat diet (HFD)- induced obese mice, as well as ZDF-diabetic rats. VNN1 KO mice have mildly improved glucose tolerance and insulin sensitivity in HFD-fed animals (van Diepen etal, supra). Vanin- 1 expression is high in human psoriatic skin leading to the proposal that vanin- 1 plays a role in Thl 7/Thl -driven inflammatory skin conditions (Jansen et al, J. Invest. Dermatol., 129, 2167-2174 (2009)). In addition, expression of vanin-1 in whole blood is higher in subjects suffering from chronic pediatric immune thrombocytopenia (ITP) (Zhang et al., Blood, 117, 4569-4579 (2011)). Vanin-1 mRNA expression levels have been shown to correlate with HDL-C levels supporting a potential role of vanin-1 in cardiovascular disease (Kaskow e/a/., Eur. J. Hum. Genet., 22, 688-695 (2014)). In addition, polymorphisms in VNN1 gene are associated with blood pressure and HDL levels further supporting a role for vanin in cardiovascular diseases (Wang et al, PLoS Genet., 10, el 004641 (2014)). Vanin-1 may also be a potential therapeutic target for neointimal hyperplasia following revascularization as it plays a role in driving smooth muscle cell activation in post- arterial injury (Dammanahalli et al, PLoS One, 7, e39106 (2012)). Recently, control of fibrosis, vasculopathy, autoimmunity and oxidative stress in systemic sclerosis (SSc) have been attributed to vanin-1. Levels of vanin-1 and pantothenic acid appear to determine SSc severity and open new therapeutic approaches in SSc (Kavian et al, J. Immunol. 197, 3326-3335 (2016)).
[0007] Overall these data highlight a potential role of vanin-1 in the pathogenesis of inflammatory diseases including IBD. Thus, there is a need to identify novel small molecule inhibitors of vanin-1 as potential therapies.
SUMMARY
[0008] Provided herein are compounds of Formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt, solvate, clathrate, or hydrate thereof, wherein:
X1 is N or CRal; X2 is N or CRa2; X3 is N or CRa3; X4 is N or CRa4;
provided that no more than two of X1, X2, X3, and X4 are N;
R° is hydrogen, halo or C1-C6 alkyl;
Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo;
R1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, - C(0)OR10, -C(0)N(Rn)(R12), -S(0)tR9, -S(0)tN(Rn)(R12), -P(0)(R9)2, and -SFs, wherein the optional substituents are one to five groups selected from Ci-Ce alkyl, halo and Ci-Ce haloalkyl;
Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 10, 0 to 8, 0 to 5 or 1 to 5 Q substituents selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5- to 10- membered heteroaryl, and optionally substituted 5- to 10- membered heteroaryl(Ci-C6 alkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), - N(R20)C(O)R13, -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17), wherein the optional substituents are selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, hydroxyl and Ci-C6hydroxyalkyl;
each R9 and R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R10, R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R11 and R12, and R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;
m is 0, 1 or 2; n is 0, 1 or 2; and each t is independently 1 or 2.
[0009] Also provided herein are compositions comprising compounds of Formula (I), or pharmaceutically acceptable salts thereof, and methods of making and using compounds of Formula (I), or pharmaceutically acceptable salts thereof. In certain embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are inhibitors of vanin proteins, such as vanin-1, and may be used for treating certain diseases, disorders, and conditions, either as mono therapies or as components of combination therapies.
DETAILED DESCRIPTION
[0010] Provided herein are compounds of Formula (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt, solvate, clathrate, or hydrate thereof, wherein: X1 is N or CRal; X2 is N or CRa2; X3 is N or CRa3; X4 is N or CRa4;
provided that no more than two of X1, X2, X3, and X4 are N;
R° is hydrogen, halo or C1-C6 alkyl; Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo;
R1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, - C(0)OR10, -C(0)N(Rn)(R12), -S(0)tR9, -S(0)tN(Rn)(R12), -P(0)(R9)2, and -SFs, wherein the optional substituents are one to five groups selected from C1-C6 alkyl, halo and C1-C6 haloalkyl;
Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 10, 0 to 8, 0 to 5 or 1 to 5 Q substituents selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5- to 10- membered heteroaryl, and optionally substituted 5- to 10- membered heteroaryl(Ci-C6 alkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), - N(R20)C(O)R13, -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17), wherein the optional substituents are selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, hydroxyl and Ci-C6hydroxyalkyl;
each R9 and R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R10, R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R11 and R12, and R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1 or 2; n is 0, 1 or 2; and each t is independently 1 or 2.
[0011] In certain embodiments, Ring A is an N-linked pyrrolidine, azetidine, piperidine, piperazine, morpholine, thiomorpholine, perhydro-l,4-diazepine, perhydro-l,4-thiazepine, 1,2,3,4-tetrahydroisoquinoline, 3-azabicyclo[3.1.0]hexane, 2-azabicyclo[2. 1. 1 ]hexane, 6-oxa-3- azabicyclo[3.1.0]hexane, 2-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[2.2.1]heptane, 3- azabicyclo[3.2.0]heptane, diazabicyclo [3.3.0] octane, 5-azaspiro[2.4]heptane, 8- azabicyclo[3.2.1]octane, 3-azabicyclo[3.3.0]octane, 6-oxa-3-azabicyclo [3.3.0] octane, 7-oxa-3- azabicyclo[3.3.0]octane, 3-oxa-7-azabicyclo[3.3.0]octane-2one, 3-oxa-8-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[2.2.1]octane, 3-azabicyclo[3.2.1]octane, 8- azabicyclo[3.2.1]octane, pyrazolo[4,5-c]pyridine, 4,5,6,7-tetrahydropyrazolo[4,5-c]pyridine, 3,8- diazabicyclo[4.3.0]nonane, 7-oxa-2-azaspiro[4.4]nonane, 7-oxa-2-azabicyclo[4.3.0]nonane or 9- azabicyclo[3.3.1]nonane. In certain embodiments, Ring A is an N-linked azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, perhydro-l,4-diazepine or perhydro-1,4- thiazepine.
[0012] In certain embodiments, provided herein are compounds of Formula (I) having the
Formula (la):
Figure imgf000008_0001
hydrogen or halo; and R1 and Ring A are as described for Formula (I).
[0013] In certain embodiments, provided herein are compounds of Formula (I) or (la) having the Formula (lb):
Figure imgf000008_0002
wherein R° is hydrogen, halo or C1-C6 alkyl; and R1 and Ring A are as described for Formula (I) or Formula (la).
[0014] In certain embodiments, provided herein are compounds of Formula (I) having the
Formula (II):
Figure imgf000009_0001
wherein: R1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, - C(0)OR10, -C(0)N(Rn)(R12), -S(0)tR9, -S(0)tN(Rn)(R12), -P(0)(R9)2, or -SFs where the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to five groups selected from C1-C6 alkyl, halo and Ci- Ce haloalkyl;
Y is -C(R3a)(R3b)-, -NR2-, -0-, -S- or -S(0)t-; provided that when Y is -NR2-, -0-, -S- or -S(0)t-, neither m nor n is 0;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently selected from (i), (ii), (iii), (iv) and (v):
(i) hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heteroaryl(Ci- Ce alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17), wherein R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each further independently selected from halogen, cyano, -OR15, -SR15, - S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13 and wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substitutents each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl and C1-C6 hydroxyalkyl;
(ii) one of the following pairs, R3a and R3b, R3a and R4a, R3a and R5a, R4a and R4b, R4a and R6a, R5a and R5b, R6a and R6b, and R7a and R71’, together with the carbon atom to which they are attached, form an optionally substituted 3- to 8- membered cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3- to 8- membered heterocyclyl or optionally substituted 5- to 10- membered heteroaryl, where the 3 to 8 membered cycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or 3- to 8- membered heterocyclyl groups are optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl) and 5 to 10 membered heteroaryl(Ci-C6 alkyl), -RuORx, -RuC(0)Rv, -RuC(0)ORx and -RuC(0)NRyRz or wherein two adjacent Q groups on the aryl ring form a heterocycl ring and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, is selected from (i);
(iii) one of R3a and R3b, R4a and R4b, R5a and R5b, R6a and R6b, and R7a and R71’, together with the carbon atom to which they are attached, form an oxo group; and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, selected from (i);
(iv) one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, andR6a and R7a, form a bridged alkylene group selected from -CH2-, - C )i- and -(CH2)3- , wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S- or - S(0)t- and wherein the bridged alkylene may further optionally be substituted with C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl(Ci-C6 alkyl) or -RuORx and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, selected from (i); and
(v) one of the following pairs R2 and R4a and R2 and R5a, together with the carbon atom to which they are attached, form an optionally substituted 3 to 8 membered heterocyclyl or an optionally substituted 5 to 10 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl or 5 to 10 membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5 to 10 membered heteroaryl(Ci-C6 alkyl), -RuORx, -RuC(0)Rv and -RuC(0)ORx; and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, selected from (i);
R9 and R13 are each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R10, R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R11 and R12, and R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl,
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rv is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);; or
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);;
each Ry and Rz is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);, together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; m is 0, 1 or 2; n is 0, 1 or 2; and each t is independently 1 or 2.
[0015] In certain embodiments, provided herein are compounds of Formula (I) or (II) having the Formula (Ha):
Figure imgf000012_0001
wherein R° is hydrogen, halo or Ci-Ce alkyl; Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo; Y, R1, R4a, R4b, R5a, R5b, R6a, R6b, R7a, R71’, and m and n are as described for Formula (II).
[0016] In certain embodiments, provided herein are compounds of Formula (I), (II) or (Ila) having the Formula (lib):
Figure imgf000012_0002
wherein Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo; Y, R1, R4a, R4b, R5a, R5b, R6a, R6b, R7a, R7b, m and n are as described for Formula (II) or (Ila).
[0017] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are selected from (i)(a) and (i)(b) as follows:
(i)(a) R2, when present, is Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl (Ci-Cealkyl), -C(0)R13, -C(0)OR14, -C(0)N(R16)(R17) or -S(0)tR13; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci- Cealkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-C10 aryl, Ce- Cioaryl(Ci-Cealkyl), 3- to 8- membered heteroaryl, 3- to 8- membered heteroaryl(Ci-Cealkyl), - OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)0R14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl); and
(b) R2, when present, is hydrogen; up to three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each, when present, independently halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 3- to 8- membered heteroaryl, 3- to 8- membered heteroaryl(Ci-C6alkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(O)R13, - C(0)R13, -C(0)0R14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-Cioaryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-C6alkyl) and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci- Cealkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, heterocyclyl(Ci-C6alkyl), Ce- Cio aryl, C6-Cioaryl(Ci-C6alkyl), 3- to 8- membered heteroaryl, 3- to 8- membered heteroaryl(Ci- Cealkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(O)R13, -C(0)R13, -C(0)OR14 or - C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- Cio aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl) ;
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0018] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) where R2, when present, is C1-C6 alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci- Cealkyl), Ci-C6haloalkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci- C6alkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl (Ci-Cealkyl), -C(0)R13, -C(0)OR14, -C(0)N(R16)(R17) or -S(0)tR13; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each, when present, independently hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci- Ce alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-Cealkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 3- to 8- membered heteroaryl, 3- to 8- membered heteroaryl(Ci-Cealkyl), -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3 to 8- membered cycloalkyl, 3 to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3 to 8- membered heterocyclyl or 3 to 8- membered heterocyclyl(Ci-C6 alkyl), 5 to 10 membered heteroaryl or 5 to 10 membered heteroaryl(Ci-C6 alkyl);
R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3 to 8- membered cycloalkyl, 3 to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3 to 8- membered heterocyclyl, 3 to 8- membered heterocyclyl(Ci-C6 alkyl), , 5 to 10 membered heteroaryl or 5 to 10 membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3 to 8- membered heterocyclyl;
and the remaining variables are as described for Formulae (II), (Ila) or (lib).
0019 In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) where R2, when present, is hydrogen; up to three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each, when present, independently halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3 to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3 to 8- membered heterocyclyl, 3 to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 3 to 8- membered heteroaryl, 3 to 8- membered heteroaryl(Ci-C6alkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(O)R13, - C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3 to 8- membered cycloalkyl, 3 to 8- membered heterocyclyl, C6-Cio aryl or 5 to 10 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl) and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci- Cealkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), 3 to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3 to 8- membered heterocyclyl, heterocyclyl(Ci-Cealkyl), Ce- Cio aryl, C6-Cioaryl(Ci-C6alkyl), 3 to 8- membered heteroaryl, 3 to 8- membered heteroaryl(Ci- Cealkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(O)R13, -C(0)R13, -C(0)OR14 or - C(0)N(R16)(R17) wherein the 3 to 8- membered cycloalkyl, 3 to 8- membered heterocyclyl, Ce- Cio aryl or 5 to 10 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl) ; each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0020] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) where R2, when present, is C1-C6 alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci- Cealkyl), Ci-C6haloalkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci- C6alkyl), C6-C10 aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl (Ci-Cealkyl), -C(0)R13, -C(0)OR14, -C(0)N(R16)(R17) or -S(0)tR13; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are independently selected from (i), (ii) and (iii):
(i) one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b, R6a and R6b, and R7a and R7b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl where the 3- to 8- membered cycloalkyl or 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, C6-Cioaryl(Ci-C6alkyl) and heteroaryl(Ci-C6alkyl) and -RuORx; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci- C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-Cealkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), - N(R20)C(O)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci- Cealkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
(ii) one of the following pairs R3a and R4a, R3a and R5a and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-Cio aryl or 3- to 8- membered heteroaryl, each optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-C6alkyl, Ci- Cehaloalkyl, C6-Cioaryl(Ci-C6alkyl), 3- to 8- membered heteroaryl, RuORx, -RuC(0)Rv, -RuC(0)ORx and -RuC(0)NRyRz or wherein two adjacent Q groups on the Cearyl ring may optionally form a 3- to 8- membered heterocyclyl ring; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci- Cealkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-Cealkyl), C6-C10 aryl, Ce- Cioaryl(Ci-Cealkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-Cealkyl), - OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl); and
(iii) one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group -CH2-, -{CYh)i- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-Cio aryl, Ce- Cioaryl(Ci-Cealkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-Cealkyl), and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-C10 aryl, Ce- Cioaryl(Ci-Cealkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-Cealkyl), - OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl,
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, aralkyl, or heteroaralkyl;
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rv is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
[0021] each Ry and Rz is independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0022] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b, R6a and R6b, and R7a and R7b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl where the 3- to 8- membered cycloalkyl or 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, C6-Cioaryl(Ci-C6alkyl) and heteroaryl(Ci-C6alkyl) and -RuORx; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci- Cealkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-Cealkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-Cealkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), - N(R20)C(0)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci- Cealkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17, are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl, each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0023] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein one of the following pairs R3a and R4a, R3a and R5a and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 3- to 8- membered heteroaryl, each optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ce- Cioaryl(Ci-Cealkyl), 3- to 8- membered heteroaryl, -RuORx, -RuC(0)Rv, -RuC(0)ORx and -RuC(0)NRyRz or wherein two adjacent Q groups on the Cearyl ring may optionally form a 3- to 8- membered heterocyclyl ring; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b, are each, when present, independently selected from hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-Cealkyl), C6-Cio aryl, C6-Cioaryl(Ci- Cealkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-Cealkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
[0024] R14 and R15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl,
3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
[0025] R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl,
3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
[0026] each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl,
[0027] each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
[0028] each Rv is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
[0029] each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
[0030] each Ry and Rz is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0031] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group -CH2-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-Cio aryl, Ce- Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6alkyl), and the remainder of R3a, R3b, R4a, R4b, R5a, R51’, R6a, R6b, R7a and R71’, is each, when present, independently selected from hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-Cealkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-Cealkyl), C6-C10 aryl, Ce- Cioaryl(Ci-Cealkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-Cealkyl), - OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; R20 is each independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and the remaining variables are as described for Formula (II), (Ila) or (lib).
[0032] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein one of the following pairs R2 and R4a and R2 and R5a, together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), heteroaryl(Ci-C6 alkyl), -RuORx, -RuC(0)Rv, -RuC(0)ORx];
the remainder of R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-C6alkoxy(Ci-C6alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, cycloalkyl(Ci-C6alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6alkyl), C6-Cio aryl, C6-Cioaryl(Ci-C6alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6alkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(O)R13, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-Cioaryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, Ci-C6alkyl, halo(Ci-Cealkyl), hydroxyl and hydroxy(Ci-Cealkyl);
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R20 is each independently hydrogen, Ci-Ce alkyl or Ci-Ce haloalkyl,
R24 is hydrogen, C i-Ce alkyl, Ci-Ce hydroxyalkyl, aralkyl, or heteroaralkyl;
each Ru is independently a direct bond, Ci -Ce alkylene or Ci-Ce alkenylene;
each Rv is independently C i-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ry and Rz is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
and the remaining variables are as described for Formula (II), (Ila) or (lib).
[0033] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii), (iii), (iv), (v) and (vi) as follows:
(i) R2, when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl , -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R2, when present, is hydrogen; one, two or three of R3a, R4a, R5a R6a and R7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR15, -SR15, -S(0)tR13, N(R16)(R17), -C(0)R13, -C(0)0R14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R51’, R6a, R6b, R7a and R7b , is each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl),, -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
(iii) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), C6-C10 Ci-C6haloalkoxy(Ci-C6 alkyl), aryl(Ci-C6 alkyl), heteroaralkyl, heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R3b and R4a and R4b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx, and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ , is each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
(iv) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R4a, R3a and R5a, and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)0Rx, and the remainder of R3a, R3b, R4a,R4b, R5a, R5b, R6a, R6b, R7a and R71’, is each, when present, independently selected from hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)0R14 and -C(0)N(R16)(R17);
(v) R2, when present, is hydrogen, C i-Ce alkyl, C i-Ce haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) , 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group -CH2-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be substituted with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, is each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
(vi) one of the following pairs R2 and R4a and R2 and R5a, together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ce- C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx]; and the remainder of R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl) 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0034] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii), (iii) and (iv) as follows:
(i) R2, when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl , -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R2, when present, is hydrogen; one, two or three of R3a, R4a, R5a R6a and R7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR15, -SR15, -S(0)tR13,
N(R16)(R17), -C(0)R13, -C(0)0R14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R51’, R6a, R6b, R7a and R7b , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
(iii) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R4a, R3a and R5a, and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx, and the remainder of R3a, R3b, R4a,R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17); and
(iv) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) , 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group -CH2-, - C h)i- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be substituted with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)0R14 and -C(0)N(R16)(R17);
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl) 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rv is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0035] In certain embodiments, provided herein are compounds of Formula (II), (Ila) or
(lib) wherein R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii) and (111): (i) R2, when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl , -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R2, when present, is hydrogen; one, two or three of R3a, R4a, R5a R6a and R7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR15, -SR15, -S(0)tR13, N(R16)(R17), -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R51’, R6a, R6b, R7a and R7b , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl),, -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17); and
(iii) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R4a, R3a and R5a, and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx, and the remainder of R3a, R3b, R4a,R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)0R14 and -C(0)N(R16)(R17); and
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl) 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
and the remaining variables are as described for Formula (II), (Ila) or (lib).
[0036] Provided herein are compounds of Formula (II), (Ila) or (lib) wherein R3a, R3b R4a,
R4b, R5a, R5b, R6a, R6b, R7a and R7b are selected from (i), (ii), (iii) , (iv), (v) and (vi) as follows:
(i) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl,
C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of R3a and R4a is halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)0R14 or -C(0)N(R16)(R17), wherein the cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the other of R3a and R4a, is selected from hydrogen, halogen, cyano, C1-C6 alkyl, Ci- Ce haloalkyl, -RORX, -RuC(0)Rv, -RuC(0)ORx and -RuC(0)NRyRz; and R3b, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently hydrogen, halogen, cyano, C1-C6 alkyl, Ci- Ce haloalkyl Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl) or Ci-C6haloalkoxy(Ci-C6 alkyl);
(ii) R2, when present, is hydrogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of R5a and R5b , and when present, R6a, R6b, R7a and R7b, is halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14 or -C(0)N(R16)(R17)wherein the C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; R3a and R3b, and the remainder of R5a, R5b, R6a, R6b, R7aand R71’, is each, when present, independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl) or Ci-C6haloalkoxy(Ci-C6 alkyl);
(iii) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R3b and R4a and R4b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), - RuORx and -RuC(0)ORx, and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ is each, when present, independently hydrogen, halogen cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl or Ci-C6haloalkoxy(Ci-C6 alkyl);
(iv) one of the following pairs R3a and R4a, and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl wherein the 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)0Rx, and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each when present, independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalky, hydroxyl, Ci-C6hydroxyalkyl and C1-C6 alkoxy(Ci- Ce alkyl or Ci-C6haloalkoxy(Ci-C6 alkyl);
(v) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group -CH2-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl or Ci-C6haloalkoxy(Ci-C6 alkyl); and
(vi) one of the following pairs R2 and R4a and R2 and R5a, together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 C1-C6, haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx; and the remainder of R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently hydrogen, halogen cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl or Ci-C6haloalkoxy(Ci-C6 alkyl);
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
each Rv is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ry and Rz is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each t is independently 1 or 2; and the remaining variables are as described for Formulae (II), (Ila) or (lib).
[0037] In certain embodiments, provided herein are compounds of Formula (I), (II), (Ila) or (lib) wherein:
Y is -C(R3a)(R3b)-;
R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71» are selected as follows:
(i) one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)0R14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; or
(ii) one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b and R6a and R6b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl or oxo where the 3- to 8- membered cycloalkyl and 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxyl; or
(iii) one of the following pairs R3a and R4a, and R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, alkyl, haloalkyl or C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)ORx; or
(iv) R4a and R5a together or R5a and R6a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -O- , -NR24- or -S(0)t- and wherein the bridged alkylene may optionally be substituted with hydroxy, C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each independently, when present, hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, Ce- Cio aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from Ci-Ce alkyl, halogen and Ci-Ce haloalkyl;
R13 is each independently Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and each t is independently 1 or 2; and the remaining variables are as described for Formula (I), (II), (Ila) or (lib).
[0038] In certain embodiments, provided herein are compounds of Formulae (I), (II), (Ila) or (lib) wherein:
Y is -C(R3a)(R3b)-;
R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected as follows:
(i) one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; or
(ii) one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b and R6a and R6b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl or oxo where the 3- to 8- membered cycloalkyl and 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxyl; or
(iii) one of the following pairs R3a and R4a, and R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, alkyl, haloalkyl or C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)ORx;
and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b, are each independently, when present, hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci- Cehydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14 or -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, Ce- C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17 are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and the remaining variables are as described for Formulae (I), (II), (Ila) or (lib).
[0039] In certain embodiments, provided herein are compounds of Formulae (I), (II), (Ila) or (lib) wherein Y is -C(R3a)(R3b)-;
R3a, R3bR4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii) and (iii) as follows:
(i) one, two or three of R3a, R3bR4a and R4b, are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl -OR15, -SR15, -S(0)tR13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each independently, when present, hydrogen or halogen;
(ii) one, two or three of R5a, R5b, R6a, R6b, R7a and R71’ are each independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 5- to 10- membered heteroaryl -OR15, -SR15, -S(0)tR13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b R5a, R5b, R6a, R6b, R7a and R7b, are each independently, when present, hydrogen or halogen; and
(iii) R3a and R4a, together with adjacent atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ce-Cio aryl(Ci-C6 alkyl), -RORX or -C(0)0Rx; R3b, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, independently, when present, hydrogen or halogen;
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and
each t is independently 1 or 2.
[0040] In certain embodiments, provided herein are compounds of Formula (II), (Ha), or
(lib) wherein m is 0, 1 or 2 and n is 0 or 1 and the other variables are as described for Formula (II), (Ila), or (lib).
[0041] In certain embodiments, provided herein are compounds of Formula (II), (Ila), or
(lib) wherein m is 0 or 1 and n is 0 or 1 and the other variables are as described for Formula (II), (Ila), or (lib).
[0042] In certain embodiments, provided herein are compounds of Formula (II), (Ila), or
(lib) wherein m is 1 and n is 0 or 1 and the other variables are as described for Formula (II), (Ila), or (lib).
[0043] In certain embodiments, provided herein are compounds of Formula (I), (II) or (Ila) having the Formula (III):
Figure imgf000040_0001
wherein n is 0 or 1 ;
R° is hydrogen, halo or Ci-Ce alkyl;
Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo;
R1 is halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, - C(0)OR10, -C(0)N(Rn)(R12), -S(0)tR9, -S(0)tN(Rn)(R12), -P(0)(R9)2, and -SFs, wherein the optional substituents are one to five groups each independently selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; and
R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are as described for Formula (I), (II) or
(Ha)
[0044] In certain embodiments, provided herein are compounds of Formulae (I), (II), (Ila) or (III) having the Formula (IV):
Figure imgf000040_0002
wherein R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are selected from (i), (ii), (iii) and (iv) as follows:
(i) one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are each, when present, independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, heteroaryl, -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)0R14, -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from Ci- Ce alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14 or -C(0)NR16R17, wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b and R6a and R6b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl or oxo where the 3- to 8- membered cycloalkyl and 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxy; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b, are each, when present, independently selected as in (i); and
(iii) one of the following pairs R3a and R4a, and R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, alkyl, haloalkyl or C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)ORx; and the remaining pair R3a and R4a or R4a and R6a, and R3b, R4b, R5a, R5b, R6b, R7a and R71’, are each, when present, independently selected as in (i);
(iv) R4a and R5a together or R5a and R6a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -O- , -NR24- or -S(0)t- and wherein the bridged alkylene may optionally be substituted with hydroxy, C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b, are eachindependently selected as in (i);
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl,
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
each t is independently 1 or 2.
[0045] Provided herein are compounds of Formulae (I), (II), (Ha), (III) or (IV) having the
Formula (IVa):
Figure imgf000042_0001
wherein R° is hydrogen, halo or C1-C6 alkyl;
Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo; R1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, - C(0)OR10, -C(0)N(Rn)(R12), -S(0)tR9, -S(0)tN(Rn)(R12), -P(0)(R9)2, and -SFs, wherein the optional substituents are one to five groups each independently selected from C1-C6 alkyl, halo and C1-C6 haloalkyl; and
R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are as described for Formula (I), (II), (Ila), (III) or (IV).
[0046] In certain embodiments, provided herein are compounds of Formulae (I), (II), (Ila),
(III) or (IV) having the Formula (IVa) wherein: R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are selected from (i), (ii), (iii), (iv) and (v) as follows:
(i) one or two of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are each, when present, independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)R13, -C(0)OR14 or -C(0)N(R16)(R17);
and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b, are each, when present, independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14, -C(0)NR16R17, wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R3a and R3b together, or R4a and R4b together, with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen , C1-C6 alkyl, Ci- Ce haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxy; the remaining pair R3a and R3b or R4a and R4b, is each independently hydrogen or hydroxy and R5a, R5b, R6a and R6b are hydrogen; (iii) R3a and R4a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four groups each independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)0Rx; R3b, R4b, R5a, R5b, R6a and R6b, are each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -RORX or -C(0)0Rx;
(iv) R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with halogen, C1-C6 alkyl or -RuORx; and R3a, R3b, R4b, R5a, R5b and R6b, are each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -RORX or -C(0)0Rx; and
(v) R4a and R5a together or R5a and R6a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -O- , -NR24- or -S(0)t- and wherein the bridged alkylene may optionally be substituted with hydroxy, C6-C10 aryl, 5- to 10- membered, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); the remainder of R3a and R3b R4a, R4b, R5a, R5b, R6a and R6b, are each, when present, independently hydrogen or halogen;
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
each t is independently 1 or 2; and the other variables are as described for Formulae (I),
(II), (Ila), (III) or (IV).
[0047] In certain embodiments, provided herein is a compound of Formulae (I), (II), (Ila),
(III), or (IV) having the Formula (IVa) wherein R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are selected from (i), (ii), and (iii) as follows:
(i) one of R3a and R5a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), C1-C6 haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14, -C(0)N(R16)(R17); the other of R3a and R5a , and R3b, R5b, R4a, R4b, R6a and R6b, are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR15, -C(0)OR14, -C(0)NR16R17, 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R3a and R4a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -RuORx or - C(0)ORx; R3b, R4b, R5a, R5b, R6a and R6b are each independently hydrogen or halogen; and
(iii) R5a and R6a together, form a bridged alkylene group -(CH2)-, -(CH2)2- or -(CIl2)3- wherein one carbon atom of -(CH2)2- or -(ϋΪ2)3- may be replaced with -0-, -NR24- or -S(0)t- and the remainder of R3a, R3b R4a, R4b, R5a, R5b, R6a and R >b are each independently hydrogen or halogen;
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
each t is independently 1 or 2; and the other variables are as described for Formulae
(I), (II), (Ila), (III) or (IV).
[0048] In certain embodiments, provided herein is a compound of Formulae (I), (II), (Ila),
(III), or (IV) having the Formula (IVa) wherein R3a is halogen, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -OR15 or -C(0)0R14; and R3b, R4a, R4b, R5a, R5b, R6a andR6bare each independently hydrogen or halogen; andR14 andR15, are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and the other variables are as described for Formulae (I), (II), (Ha), (III) or (IV).
[0049] In certain embodiments, provided herein is a compound of Formulae (I), (II), (III),
(IV) or (IVa) having the Formula (IVb) :
Figure imgf000046_0001
wherein R1 , R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are as described for Formulae (I), (II), (Ha), (lib), (HI), (IV) or (IVa).
[0050] In some embodiments, provided herein are compounds of Formulae (I), (II), (Ha),
(lib) or (III) having the Formula (V):
Figure imgf000047_0001
wherein R1 , R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are as described for Formulae (I), (II), (Ha), (lib) or (III).
[0051] In some embodiments, provided herein are compounds of Formula (I), (II), (Ha),
(lib) (III) or (V) wherein:
wherein Y is -C(R3a)(R3b)-, -NR2-, -0-, -S- or S(0)t-;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii), (iii), (iv) and(v) as follow:
(i) R2, when present, is hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci -Ce hydroxyalkyl, Ci-Ce alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl; and one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or -OR15 and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15;
(ii) R3a and R4a, together with the carbon atom to which they are attached, form C6-C10 aryl, 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 haloalkyl and -RuORx or substituted with two adjacent groups that form a 3 - to 8- membered heterocyclyl ring; and the R3b, R4b, R5a, R5b, R6a, R6b, R7a and R7b, are each, when present, independently halogen, C1-C6 alkyl, Ci- Ce haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15;
(iii) R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl optionally substituted with halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) or heteroaralkyl; and R2, R3a, R3b, R5a, R5b, R7a and R71’, and R4b and R6b, when present, are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, 5- to 10- membered heteroaryl or -OR15;
(iv) R5a and R6a together, or R6a and R7a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3-and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R51’, R6b, R7a and R71’, are each halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15; and
(v) R2 and R4a, together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl; and the remainder of R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15;
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
t is 1 or 2; and the other variables are as described for Formula (I), (II), (Ha), (lib) or (III).
[0052] In some embodiments, provided herein are compounds of Formula (I), (II), (Ha),
(lib) (III) or (V) wherein:
Y is -C(R3a)(R3b)-, -NR2-, -0-, -S- or -S(0)t-;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are selected from (1), (11), (111) and (iv) as follow:
(i) R2, when present, is hydrogen, and and one, two or three of R3a, R3b, R4a,
R4b, R5a, R5b, R6a, R6b, R7a and R7b are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or -OR15 and the remainder of R3a, R3b, R4 , R4b 3 R5a 3 R5b R6a 3 R6b 3 R7a and R71’ are each independently hydrogen or halo; or R2 is C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, heteroaralkyl, -C(0)R13 or -C(0)OR14 and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15 ; or
(ii) R3a and R4a, together with the carbon atom to which they are attached, form C6-C10 aryl, 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 haloalkyl and -RuORx; and R3b, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; or
(iii) R5a and R6a together, or R6a and R7a together, form a bridged alkylene group -CH2-, -{CYh)i - or -(CH2)3- and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6b, R7a and R7b, are each, independently hydrogen, halogen, alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl; and
(iv) R2 and R4a, together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl; and the remainder of R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci- Ce alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each t is independently 1 or 2; and the other variables are as described for Formula (I),
(II), (Ila), (lib), (III) or (V).
[0053] In some embodiments, provided herein are compounds of Formulae (I), (II), (Ila),
(III) or (V) having the Formula (Va):
Figure imgf000050_0001
wherein the variables are as described for Formulae (I), (II), (Ha), (III) or (V).
[0054] In some embodiments, provided herein are compounds of Formulae (I), (II), (Ha),
(III), (V) or (Va) having the Formula (Vb):
Figure imgf000050_0002
wherein the variables are as described for Formulae (I), (II), (Ha), (III) or (V).
[0055] In some embodiments, provided herein are compounds of Formulae (I), (II), (Ha),
(III), (V) or (Va) having the Formula (Vc):
Figure imgf000050_0003
wherein the variables are as described for Formulae (I), (II), (Ha), (III), (V) or (Va).
[0056] In some embodiments, provided herein are compounds of Formula (I), (II), (Ha),
(lib), (III), (V), (Va) or (Vc) having the Formula (Vd):
Figure imgf000051_0001
wherein the variables are as described for Formulae (I), (II), (Ha), (lib), (III), (V), (Va) or (Vc).
[0057] In some embodiments, provided herein are compounds Formula (I), (II) or (Ila) having the Formula (VI):
Figure imgf000051_0002
R3a, and R3b is each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, Ci- Ce alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl),
-OR15, -SR15, -S(0)tR13, -N(R16)(R17), -C(0)OR14, Ce-Cio aryl or 5- to 10- membered heteroaryl; and
R4a, R4b, R5a and R5b is each independently hydrogen, C6-C10 aryl or 5- to 10- membered heteroaryl, or
(ii) R3a and R3b together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), and C6-C10 aryl(Ci-C6 alkyl); and the remainder of R4a, R4b, R5a are R5b are each independently hydrogen or halogen
R13 is each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
each t is independently 1 or 2; wherein the variables are as described for
Formulae (I), (II) or (Ha).
[0058]
[0059] In some embodiments, provided herein are compounds of Formula (VI) having the
Formula (Via):
Figure imgf000052_0001
wherein the variables are as described for Formula (VI).
[0060] In some embodiments, provided herein are compounds of Formula (VI) having the
Formula (VIb):
Figure imgf000052_0002
wherein the variables are as described for Formula (VI).
[0061] In some embodiments, provided herein are compounds of Formula (VI) having the
Formula (Vic):
Figure imgf000053_0001
wherein the variables are as described for Formula (VI).
[0062] In some embodiments, provided herein are compounds of Formula (I), (II) or (Ila) having the Formula (VII):
Figure imgf000053_0002
wherein:
Y is -NR2-, -0-, -S- or -S(0)t-;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii) and (iii) as follow:
(i) R2 is hydrogen, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and R4a,R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each independently hydrogen or halogen;
(ii) R4a and R6a, together with the carbon atom to which they are attached, form C6-C10 aryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and -RuORx ; and R2, R3a, R3b, R5a, R5b, R7a and R71’, are each independently hydrogen or halogen; and
(iii) R2 and R4a or R2 and R5a together with the carbon atom to which they are attached, form C6-C10 aryl or 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and -RuORx; and the and the remainder of R4a, R4b, R5a, R5b, R6a, j^6b^ j^7a ancj j^b are eac]1 independently hydrogen or halogen;
each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene; each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each t is independently 1 or 2; wherein the variables are as described for Formulae (I), (II) or (IIa).
[0063] In some embodiments, provided herein are compounds of Formula (VII) having the
Formula (Vila):
Figure imgf000054_0001
wherein the variables are as described for Formula (VII).
[0064] In some embodiments, provided herein are compounds of Formula (VII) having the
Formula (Vllb):
Figure imgf000054_0002
wherein the variables are as described for Formula (VII).
[0065] In certain embodiments, in compounds of Formula (I), (II), (Ha), (lib), (III), (IV),
(IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or
(Vllb): R1 is halogen, cyano, C1-C6 haloalkyl, 5- to 10- membered heteroaryl, -OR10, SR10, -S(0)tR9, -S(0)tN(Rn)(R12), or -SFs where the 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and Ci- C6 haloalkyl; R9 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci- Ce alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R10 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
R11 and R12, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and each t is independently 1 or 2.
[0066] In certain embodiments, in compounds of Formula (I), (II), (Ha), (lib), (III), (IV),
(IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (VHb): R1 is halogen, cyano, C1-C6 haloalkyl, 5- to 10- membered heteroaryl, -OR10, -SR10, or - SF5 where the 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; R10 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and each t is independently 1 or 2. In some embodiments, in compounds of of Formula (I), (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (Vllb): R1 is -SC Me.
[0067] In certain embodiments, the compound of Formula (I) or (II) is selected from:
Figure imgf000056_0001
R5a Tri R7b
Rbb R wherein the variables are as described for Formula (I) or (II).
[0068] In some embodiments, the compound of Formula (I) or (II) is selected from:
Figure imgf000057_0001
Figure imgf000058_0001
wherein the variables are as described for Formula (I) or (II).
[0069] In some embodiments, the compound of Formula (I) is selected from:
(3-(methylsulfonyl)phenyl)(2-(piperidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(pyrrobdin-l-yl)thiazol-5-yl)methanone;
l-(4-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)piperazin-l-yl)ethan-l-one;
(2-(4-methylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
tert-butyl 4-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)piperazine-l-carboxylate;
tert-butyl 2-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)octahydro-5H-pyrrolo[3,4- c]pyridine-5-carboxylate;
tert-butyl 5-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole- 2(lH)-carboxylate;
(3-(methylsulfonyl)phenyl)(2-(l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)thiazol-
5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)thiazol-5- yl)methanone;
(2-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(piperazin-l-yl)thiazol-5-yl)methanone; (2-(2-(pyridin-3-yl)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(5-benzyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-phenylpiperidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-phenylpyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-phenylpiperidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-phenylpyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(pyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone
(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(R)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(S)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(4-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(pyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethoxy)phenyl)methanone;
N,N-dimethyl-3-(2-(pyrrolidin-l-yl)thiazole-5-carbonyl)benzenesulfonamide;
(2-(3-(pyridin-2-yl)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(3-(pyridin-3-yl)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (3-bromophenyl)(2-(pyrrobdin-l-yl)thiazol-5-yl)methanone;
(2-(3 ,3 -dimethy l-2-(pyridin-3 -y l)azetidin- 1 -yl)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
3-(2-(3-fluoropyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(S)-3-(2-(3-fluoropyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(R)-3-(2-(3-fluoropyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-hydroxypyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(S)-3 -(2-(3 -hy droxypyrrolidin- 1 -y l)thiazole- 5-carbonyl)benzonitrile;
(R)-3-(2-(3-hydroxypyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(isoindobn-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(4-hy droxy-3 -(1 H-pyrazol- 1 -yl)piperidin- 1 -y l)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
(2-(3 -hy droxy-4-( 1 H-pyrazol- 1 -yl)piperidin- 1 -y l)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone; (2-(3 -hy droxy-4-( 1 H-pyrazol- 1 -yl)pyrrolidin- 1 -y l)thiazol- 5-y 1)(3 - (trifluoromethyl)phenyl)methanone;
3-(2-(l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-azabicyclo[3.1.0]hexan-3-yl)thiazole-5-carbonyl)benzonitrile;
(2-(pyrrolidin-l-yl)thiazol-5-yl)(3-(pyrrobdin-l-ylsulfonyl)phenyl)methanone;
(3-(morpholinosulfonyl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
3-(2-(2-phenylpyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(2-phenylpiperidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(2-(2-phenylazetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
3-(2-(3-(hydroxymethyl)pyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(S)-3-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(R)-3-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(2-(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3,3-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3,4-dimethoxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-((3S,4R)-3,4-dimethoxypyrrobdin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3-methoxypyrrobdin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3 -( 1 H-pyrazol- 1 -yl)pyrrobdin- 1 -yl)thiazol-5-y 1)(3 - (methylsulfonyl)phenyl)methanone;
(2-(3,3-dimethylpyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-chlorophenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(2-oxa-7-azaspiro[4.4]nonan-7-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-fluoropiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(4-fluoropiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(4,4-difluoropiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(2-azabicyclo[2.2.1]heptan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
l-(5-(3-(trifluoromethyl)benzoyl)thiazol-2-yl)pyrrolidin-3-one;
(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-2-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(3-(trifluoromethyl)phenyl)(2-(3-(trifluoromethyl)piperidin-l-yl)thiazol-5-yl)methanone;
(3-(trifluoromethyl)phenyl)(2-(4-(trifluoromethyl)piperidin-l-yl)thiazol-5-yl)methanone;
(2-(3-(difluoromethoxy)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(2-azabicyclo[3.1.0]hexan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-((lR,5S)-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-morpholinothiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-(hydroxymethyl)-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
rac-(2-((3S*,4S*)-3-(hydroxymethyl)-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(2-azabicyclo[2.1.1 ]hexan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-((3S,4R)-3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-methoxyazetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((R)-3 -fluoropyrrolidin- 1 -yl)thiazol-5 -yl)(3 - ((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((S)-3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((R)-3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((S)-3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(3 -fluoropyrrolidin- 1 -yl)thiazol-5 -yl)(3 - ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-(benzylthio)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone; (3-(benzylsulfonyl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(pyrrolidin-l-yl)thiazol-5-yl)(3-((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(2-azaspiro[3.3]heptan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(8-azabicyclo[3.2.1]octan-8-yl)thiazole-5-carbonyl)benzonitrile;
(2-(3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; rac-(2-((3S*,4S*)-3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-azabicyclo[2.2.2]octan-2-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(2-azabicyclo[2.2.2]octan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone; (2-((l S,4S)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-fluoro-3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3,4-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-((3S,4R)-3,4-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
3-(2-(2-(pyridin-2-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-(pyridin-2-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-(pyridin-3-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-(lH-pyrazol-l-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(2-(2H-tetrazol-5-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(3-(methylsulfonyl)phenyl)(2-morpholinothiazol-5-yl)methanone;
3-(2-morpholinothiazole-5-carbonyl)benzonitrile;
(2-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-fluoro-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; rac-(2-((3R*,4R*)-3-fluoro-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((3S*,4S*)-3,4-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)thiazol-5- yl)methanone;
(3-(methylsulfonyl)phenyl)(2-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl)thiazol-5-yl)methanone;
(2-(6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone; (2-((lR,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2,6-dimethylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-((2S,6R)-2,6-dimethylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
3-(2-(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazole-5- carbonyl)benzonitrile;
(2-(2-(4-fluorophenyl)pyrrobdin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-bromophenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-bromophenyl)(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)methanone;
(S)-(3-bromophenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(l -methyl- lH-pyrazol-5-yl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)(3-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone;
(2-(2,6-dimethylmorphobno)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(l-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxy-3-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3 -hydroxypyrrolidin- 1 -y l)-4-methy lthiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrobdin-l-yl)-4-methylthiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone; (S)-(2-(3-hydroxypyrrolidin-l-yl)-4-methylthiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(2-(hydroxymethyl)piperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carbonitrile;
(R)-l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carbonitrile;
(S)-l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carbonitrile;
(2-(3-hydroxyazetidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)azetidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; methyl l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carboxylate;
(2-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(R)-(2-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carboxybc acid;
l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carboxamide;
N-methyl-l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carboxamide; (2-(2-methylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(2-methylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(2-methylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (R)-(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone; (S)-(2-(2-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; methyl l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)azetidine-3-carboxylate;
(2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((3aR*,6aR*)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-hydroxy-2,2-dimethylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3 -hy droxy-2-methylpyrrobdin- 1 -y l)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
rac-(2-((2R*,3R*)-3-hydroxy-2-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((2S,3R)-3-hydroxy-2-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3 -hy droxy-4-methylpyrrobdin- 1 -y l)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
rac-(2-((3R*,4S*)-3-hydroxy-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone; (2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(isopropylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(isopropylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(isopropylsulfonyl)phenyl)methanone;
5-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)hexahydro-lH-furo[3,4-c]pyrrol-l-one;
(2-(hexahydrofuro[3,2-b]pyridin-4(2H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((l S*,5R*,6R*)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((l S*,5R*,6S*)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((l S*,5R*,6R*)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-(3-hydroxy-4-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((3R*,4R*)-3-hydroxy-4-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2- (7 -hydroxy- 5 -azaspiro [2.4] heptan- 5 -y l)thiazol- 5 -y 1) (3 - (methylsulfonyl)phenyl)methanone;
(2-(4-hydroxy-3,3-dimethylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(hexahydrofuro[2,3-c]pyridin-6(2H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(phenylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(phenylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)(3-(phenylsulfonyl)phenyl)methanone;
(3-(ethylsulfonyl)phenyl)(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(ethylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(S)-(3-(ethylsulfonyl)phenyl)(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)methanone; (3-(cyclopropylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(cyclopropylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5- yl)methanone;
(S)-(3-(cyclopropylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5- yl)methanone;
(3-(cyclobutylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(cyclobutylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(S)-(3-(cyclobutylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(3-hydroxypyrrolidin-l -yl)thiazol-5-yl)(3-((l -methyl- lH-pyrazol-4- yl)sulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-((l-methyl-lH-pyrazol-4- yl)sulfonyl)phenyl)methanone;
(S)-(2-(3 -hydroxypyrrolidin- 1 -y l)thiazol- 5-y 1)(3 -((1 -methyl- 1 H-pyrazol-4- yl)sulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5- yl)methanone;
(S)-(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone
(3-(pentafluoro- 6-sulfanyl)phenyl)(2-(pyrrolidin- l -yl)thiazol-5-yl)methanone;
2-(3 -hydroxypyrrolidin- 1 -yl)thiazol-5-yl)(3-(pentafluoro- 6-sulfanyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro-/J5- sulfanyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro- 6- sulfanyl)phenyl)methanone;
2-(3 -(hy droxymethy l)pyrrolidin- 1 -yl)thiazol-5 -yl)(3 -(pentafluoro-lό- sulfanyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro- 6- sulfanyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro-/J5- sulfanyl)phenyl)methanone; 2-(2-(methoxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(2-(methoxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(2-(methoxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
4-hydroxy-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-2- carboxylic acid;
(2R,4S)-4-hydroxy-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-2- carboxylic acid;
(25.45)-4-hydroxy-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-2- carboxylic acid;
4-fluoro-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-2-carboxybc acid;
(25.45)-4-fluoro-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-2- carboxamide;
(2-(2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(4-hydroxy-2-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-((2R,4S)-4-hydroxy-2-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; (Example 155)b (2-((3aS,6aS)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; (Example 155)b
(2-(6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lS,5R,6S)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; (Example 164)c
(2-((lR,5S,6R)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; (Example 164)c
(2-((lS,5R,6R)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; (Example 165)b
(2-((lR,5S,6S)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; (Example 165)b
(2-(4-benzyl- 1 ,4-diazepan- 1 -yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzoylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(6-chloro-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
N-(l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)piperidin-4-yl)benzamide;
(2-(3,4-dihydro-2,7-naphthyridin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-(benzo[d]isoxazol-3-yl)piperazin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(6-benzyloctahydro- 1 H-pyrrolo [3 ,4-b]pyridin- 1 -y l)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
rac-(2-((4aS* ,7aR* )-6-benzy loctahydro- 1 H-pyrrolo[3 ,4-b]pyridin- 1 -yl)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone; rac-(2-((2S * , 5R* )-4-benzyl-2, 5-dimethylpiperazin- 1 -yl)thiazol-5-y 1)(3 - (methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(4-(l-phenylethyl)piperazin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl)thiazol-5-yl)methanone;
(2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((lS*,4S*)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(l -benzyl- l,7-diazaspiro[4.4]nonan-7-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3 -benzyl-3 , 8-diazabicyclo [3.2.1] octan-8-yl)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,3s,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzyl-3-(hydroxymethyl)piperazin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(7, 8-dihydro- [1,3] dioxolo [4,5 -g] isoquinolin-6(5H)-y l)thiazol-5-y 1)(3 - (methylsulfonyl)phenyl)methanone;
(2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
ethyl 5-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylate;
(2-(2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone; (2-(2-benzyl-2,7-diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(5-chloro-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(7,8-dihydro-l,6-naphthyridin-6(5H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3 -(methy lsulfony l)phenyl)(2-( 1 ,2,3,5 -tetrahy dro-4H-benzo[e] [ 1 ,4] diazepin-4-y l)thiazol- 5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-phenylmorpholino)thiazol-5-yl)methanone;
(S)-(3-(methylsulfonyl)phenyl)(2-(3-phenylmorpholino)thiazol-5-yl)methanone;
(2-(4-methyl-2-phenylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(4-(pyridin-3-ylmethyl)piperazin-l-yl)thiazol-5- yl)methanone;
(2-(6-(hydroxymethyl)-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(l -methyl-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
4-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)-3-phenylpiperazin-2-one;
(3 -(hydroxymethy l)-3 ,4-dihy droisoquinolin-2( 1 H)-yl)thiazol-5 -yl)(3 - (methylsulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
2-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)isoindoline-5-carbonitrile;
2-(3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; and
(2-((lR,3s,5S)-3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone.
[0070] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Other embodiments provide a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Other embodments provide a pharmaceutical composition comprising a compound of Formula (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (Vllb), or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.
[0071] Some embodiments provide a method for the treatment of a disease or condition selected from: an inflammatory bowel disease, a colorectal cancer, and a gastritis, comprising administering a therapeutically effective amount of a compound of any of claims 1 to 28, or a solvate, hydrate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, to a subject in need thereof.
[0072] Some embodiments provide a method for the treatment of inflammatory bowel disease comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, a compound of a compound of Formula (I), (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (Vllb), or a pharmaceutically accepteable salt of any of the foregoing), to a subject in need thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, a compound of a compound of Formula (I), (II), (Ila), (lib), (III), (IV), (IVa) (IVb), (IVc), (IVd), (V), (Va), (Vb), (Vc), (Vd), (VI), (Via), (VIb), (Vic), (VII), (Vila), or (Vllb), or a pharmaceutically accepteable salt of any of the foregoing). Other embodiments provide a method for the treatment of inflammatory bowel disease comprising administering to a subjectsubject in need thereof a compound of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
[0073] In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.
[0074] Some embodiments provide a method of inhibiting vanin activity, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof. Other embodiments provide a method of inhibiting vanin activity, comprising contacting a cell with a compound of Formula (la), or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof. In some embodiments, the cell is an epithelial cell. In some embodiments, the cell is in a subject in need of vanin inhibition. In some embodiments, the vanin activity is selected from vanin-1 activity, vanin-2 activity, vanin-3 activity, or a combination of any of the foregoing. In some embodiments, the vanin activity is vanin-1 activity. In some embodiments, the vanin activity is vanin-1 activity, vanin-2 activity, and vanin-3 activity.
[0075] Any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment.
A. DEFINITIONS
[0076] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0077] As used in the specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. The use of“or” or “and” means“and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as“include”,“includes,” and“included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms“comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases“having at least” or“including at least.” When used in the context of a process, the term“comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term“comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.
[0078] The term“subject” includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans. In some embodiments, the subject is a human.
[0079] Whenever a group is described as being“substituted” or“optionally substituted” that group may be unsubstituted or substituted with the indicated number of the indicated substituents. For example, an aryl group optionally substituted with 1 or 2 halogens. When a specific number of optional substituents is not listed, the indicated group is optionally substituted with one or more of the indicated substituents. For example, an aryl group optionally substituted with halogen. If no substituents are indicated, it is meant that the indicated“optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, hydroxy, alkoxy, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino. Unless otherwise indicated as“substituted” or“optionally substituted,” a group is unsubstituted; for example, a “C1-C6 alkyl group” is unsubstited, whereas an “optionally substituted C1-C6 alkyl group” may be substituted or unsubstituted, and a“substituted C1-C6 alkyl group” is substituted.
[0080] As used herein,“Ca-Cb” in which“a” and“b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from“a” to“b”, inclusive, carbon atoms. Thus, for example, a“C1-C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no“a” and“b” are designated, the broadest range described in these definitions is to be assumed.
[0081] If two“R” groups are described as being“joined together” the R groups and the atom(s) they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl ring. For example, without limitation, if Ra and Rb of an NRaRb group are indicated to be“joined together,” or when“Ra and Rb together with the nitrogen atom to which they are attached, form heterocyclyl”, it means that they are covalently bonded to one another to form a ring:
Figure imgf000078_0001
[0082] R which represents any nitrogen containing heterocycle including but not limited to monocyclic and bi-cyclic heterocyclyl groups, as defined herein, for example, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
[0083] The term“halo” or“halogen” refers to any radical of fluorine, chlorine, bromine or iodine.
[0084] The term“alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-Ce alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. In some embodiments, an alkyl is a Ci-Ce alkyl which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples of alkyl include without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. .
[0085] The term“alkylene” refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having one to eight or one to six carbon atoms, and includes but is not limited to methylene, ethylene, propylene and n- butylene. The alkylene chain may be attached to the rest of the molecule through any two carbons of the chain.
[0086] The term “alkenylene” refers to a straight or branched unsaturated divalent hydrocarbon chain consisting solely of carbon and hydrogen atoms having two to eight carbon atoms, wherein the unsaturation is present only as double bonds which can exist between any two carbon atoms in the chain. Alkenylene includes but is not limited to ethenylene, prop-l-enylene and but-2-enylene. The alkenylene chain may be attached to the rest of the molecule through any two carbons of the chain
[0087] The term“cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having the indicated number of ring carbon atoms between 3 and 12 carbon atoms, or between 3 and 8 carbon atoms. Multi cyclic cycloalkyls (such as bicyclic) may be fused, bridged or spiro ring systems. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and norbornyl.
[0088] The term“cycloalkenyl” refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups having the indicated number of ring carbon atoms between 5 and 12 carbon atoms. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom can be optionally substituted e.g., by one or more substituents. Cycloalkenyl moieties can include without limitation, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.
[0089] The term“cycloalkylalkyl” or“cycloalkyl(alkyl)” refers to cycloalkyl group connected, as a substituent, via an alkylene group.
[0090] The term“haloalkyl” refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5 or 6) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro).“Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). .
[0091] As referred to herein, the term“alkoxy” refers to a group of formula -O-(alkyl).
Alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term“thioalkoxy” refers to a group of formula -S-(alkyl). The terms “haloalkoxy” and “thiohaloalkoxy” refer to -O-(haloalkyl) and -S-(haloalkyl), respectively. In any of the aforementioned groups, one or more hydrogen atoms in the alkyl portion of the group may be replaced with deuterium, for example, a deutero methoxy group (-OCD3). .
[0092] As used herein,“aralkyl” and“aryl(alkyl)” refer to an aryl group connected, as a substituent, via an alkylene group. Non-limiting examples of “aralkyl” include benzyl, 2- phenylethyl, and 3-phenylpropyl groups. .
[0093] The term“alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl.
[0094] The term“alkynyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. Alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-butynyl, and 2-hexynyl. [0095] The term“heterocycle”,“heterocyclyl” or“heterocyclic” as used herein except where noted, represents a stable 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a stable 6-, 7-, 8- , 9-, 10-, 11-, or 12-membered bicyclic heterocyclic ring system wherein carbon atoms together with from 1 to 5, 1 to 4 or 1 to 3 heteroatoms selected from N, O and S, constitute said ring or ring system and which ring or ring system comprises at least one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings, and further wherein the nitrogen and sulfur atoms may optionally be oxidized as N-oxide, sulfoxide or sulfone, and wherein the nitrogen atom may optionally be quaternized. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems including lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. A heterocycle can be bonded via a ring carbon atom or, if available, via a ring nitrogen atom. Bicyclic heterocyclic ring systems may be fused, bridged, or spiro bicyclic heterocyclic ring system(s). In some embodiments, heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of which 1 or 2 are heteroatoms independently selected from N, O and S. In some embodiments, a heterocyclyl group is bicyclic, and in which case, the second ring may be an aromatic or a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms independently selected from N, O and S, or the second ring may be a benzene ring, or a“cycloalkyl”, or a“cycloalkenyl”, as defined herein. Examples of such heterocyclic groups include, but are not limited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3 -dioxolane, 1,3-oxazolidine, 1,3-thiazolidine, tetrahydrothiopyran, tetrahydrotriazine, 1,3 -dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro- oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-l,4-diazepine, perhydro-1,4- oxazepine, perhydro-l,4-thiazepine, 3-azabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane, 6- oxa-3-azabicyclo[3.1.0]hexane, 2-azabicyclo[2.2.1] heptane, 3-oxa-8-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, diazabicyclo [3.3.0] octane, 7- azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 5- azaspiro[2.4]heptane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.3.0]octane, 6-oxa-3- azabicyclo[3.3.0]octane, 7-oxa-3-azabicyclo [3.3.0] octane, 3-oxa-7-azabicyclo[3.3.0]octane-2one, 3-oxa-8-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[2.2.1]octane, 3- azabicyclo[3.2.1]octane, 8-azabicyclo [3.2.1] octane, pyrazolo[4,5-c]pyridine, 4, 5,6,7- tetrahydropyrazolo[4,5-c]pyridine, 3,8-diazabicyclo[4.3.0]nonane, 7-oxa-2-azaspiro[4.4]nonane, 7-oxa-2-azabicyclo[4.3.0]nonane, 9-azabicyclo[3.3.1]nonane, tropane, 2-oxa-6- azaspiro[3.3]heptane, dihydrobenzofuran, diydrobenzimidazolyl, dihydrobenzoxazole, and dihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides thereof.
[0096] A “heterocyclylalkyf’or “heterocyclyl(alkyl)” refers to a heterocyclic group connected, as a substituent, via an alkylene group. Examples include but are not limited to tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H- thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).
[0097] The term“aryl” as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 6 members in each ring (i.e., 6 to 10 total ring atoms) wherein at least one ring is aromatic. Aryl groups include, but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, or lH-indenyl.
[0098] The term“heteroaryl”, as used herein except where noted, represents a stable 5-, 6- or 7-membered monocyclic- or stable 9- or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In the case of a“heteroaryl” which is a bicyclic group, the second ring need not be aromatic and need not comprise a heteroatom. Accordingly, bicyclic“heteroaryl” includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three, heteroatoms, as defined immediately above, fused to a benzene ring, or a second monocyclic“heteroaryl”, or a“heterocyclyl”, a“cycloalkyl”, or a “cycloalkenyl”, as defined above. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzothiadiazole, isoindole, pyrrolopyridines, imidazopyridines such as imidazo[l,2-a]pyridine, pyrazolopyridine, pyrrolopyrimidine and N-oxides thereof.
[0099] As used herein,“heteroaralkyl” and“heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2- thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused analogs.
[00100] The term “treating”, “treat”, or “treatment” refers generally to controlling, alleviating, ameliorating, slowing the progress of or eliminating a named condition once the condition has been established. In addition to its customary meaning, the term“preventing”, “prevent”, or“prevention” also refers to delaying the onset of, or reducing the risk of developing a named condition or of a process that can lead to the condition, or the recurrence of symptoms of a condition.
[00101] The term“therapeutically effective amount” or“effective amount” is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
[00102] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature {See, Biochem. 11 :942-944 (1972)).
Compound Forms and Salts
[00103] The compounds of this disclosure may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. The compounds of the present disclosure may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (e.g., enantiomers, diastereomers). [00104] It will also be appreciated that when two or more asymmetric centers are present in the compounds of the disclosure, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the disclosure.
[00105] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this disclosure are encompassed within the scope of this disclosure. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diaster eomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
[00106] The compounds of the present disclosure include all cis, trans, syn, anti, entgegen ( E ), and zusammen (Z) isomers as well as mixtures thereof. The compounds of the present disclosure may also be represented in multiple tautomeric forms, in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. In addition, where a term used in the present disclosure encompasses a group that may tautomerize, all tautomeric forms are expressly included thereunder. For example, hydroxy substituted heteroaryl groups include, but are not limited to, 2- hydroxypyridine as well as 2-pyridone, 1 -hydroxyisoquinoline as well as l-oxo-1,2- dihyroisoquinoline, 2-hydroxypyrimidine as well as 2-pyrimidone, 2-hydroxy quinoline as well as 2-quinolinone, 5-hydroxy-l,2,4-oxadiazole as well as l,2,4-oxadiazole-5(4H)one, and the like. All such isomeric forms of such compounds are expressly included in the present disclosure.
[00107] The compounds of the present disclosure include the compounds themselves, as well as their salts, solvate, and solvate of the salt, if applicable. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
[00108] As used herein,“pharmaceutically acceptable salts” refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. When the compound of the present disclosure is basic, pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, camphorsulfonic, gluconic, mandelic, mucic, pantothenic, oxalic, isethionic, and the like.
[00109] When the compound of the present disclosure is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, A'-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.
[00110] Lists of suitable salts may be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; Berge et al,“Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1-19; and“Pharmaceutical Salts: Properties, Selection, and Use. A Handbook”; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety.
[00111] Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present disclosure. The formation of solvates is described in greater detail in “Solvents and Solvent Effects in Organic Chemistry”; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein by reference in its entirety. A person of ordinary skill in the art would recognize the solvates of the present disclosure.
[00112] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 32S, 33S, 34S, 36S,18F, 36C1, 82Br, 123I, 124I, 125I, 129I and 131I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body, especially compounds labeled with 3H, 14C and/or 18F isotopes are suitable for this purpose. In addition, in some embodiments, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits for the compounds described herein. For example, deuteration may impart greater metabolic stability of the compound and for example, extend the half-life in the body or reduce the active dose required. Such modifications of the compounds described herein may therefore in some cases also constitute a preferred embodiment of the present disclosure. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. Isotopic variants of the compounds described herein can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein. B. FORMULATION
[00113] The term“pharmaceutical composition” as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier.
[00114] The term“pharmaceutically acceptable carrier” refers to a carrier or an adjuvant that may be administered to a subject, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or salt of the solvate thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
[00115] In some embodiments, the quantity of a compound of the present disclosure in a unit dose of preparation is at 1 mg to 1,000 mg, 2 mg to 900 mg, 3 mg to 800 mg, 4 mg to 700 mg, 5 mg to 600 mg, 10 mg to 500 mg, 50 mg to 400 mg, 100 mg to 300 mg, 150 mg to 250 mg, or any value in between. In some embodiments, the total daily dosage may be divided and administered in portions during the day, for example, once per day, twice per day, three times per day or four times per day. In some embodiments, the total dosage may be administered once per week, twice per week, three times per week, four times per week, five times per week or six times per week.
[00116] In some embodiments, the pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[00117] In some embodiments, the pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
[00118] In some embodiments, the pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
[00119] In some embodiments, solid dosage forms of the instant pharmaceutical compositions for oral administration. In some embodiments, the oral dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00120] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
[00121] The solid dosage forms of the instant pharmaceutical compositions of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions which can be used include polymeric substances and waxes.
[00122] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[00123] Some embodiments provide liquid dosage forms of the instant pharmaceutical compositions for oral administration. In some embodiments, the liquid dosages include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate (EtOAc), benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
[00124] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00125] Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
[00126] Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at RT but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[00127] Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
C. METHODS OF USE
[00128] Some embodiments provide methods of treating diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or viral infections comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof. Other embodiments provide the use of an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or viral infections. Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or viral infections. Some embodiments provide methods of treating an inflammatory disease or disorder, autoimmune disease, metabolic disease or cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof. Other embodiments provide the use of an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of an inflammatory disease or disorder, autoimmune disease, metabolic disease or cancer. Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating an inflammatory disease or disorder, metabolic disease, autoimmune disease or cancer.
[00129] In some embodiments the disease may be, but not limited to, one of the following classes: autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection- based diseases, trauma or tissue-injury based diseases, fibrotic diseases, genetic diseases, cardiovascular diseases, neurological diseases, neurodegenerative diseases, respiratory diseases, pulmonary diseases, airways diseases, renal diseases, skin and/ or dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases, pain and sensory diseases, hematopoietic diseases, joint diseases, muscle diseases, and bone diseases.
[00130] Specific autoimmune diseases include, but are not limited to: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, systemic lupus erythematosus (and resulting complications), Sjogren's syndrome, multiple sclerosis, asthma, glomerular nephritis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis, Behcet's disease, lupus nephritis, scleroderma, systemic scleroderma, type 1 or juvenile on-set diabetes, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, antiphospholipid antibody syndrome, atrophic gastritis of pernicious anemia, autoimmune alopecia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune encephalomyelitis, autoimmune thrombocytopenia, Bullous pemphigoid, Chagas disease, celiac disease, chronic hepatitis, Cogan's syndrome, dermatomyositis, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain- Barre syndrome, Hashimoto's disease (or Hashimoto's thyroiditis), hemolytic anemia, hidradentitis suppurativa, idiopathic thrombocytopenia purpura, interstitial cystitis, membranous glomerulopathy, morphea, mystenia gravis, narcolepsy, pemphigus, pernicous anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, Reiter's syndrome, schizophrenia, symphathetic opthalmia, systemic sclerosis, temporal arteritis, thyroiditis, vasculitis, vitiglio, vulvodynia, Wegner's granulomatosis, palmoplantar keratoderma, systemic-onset juvenile idiopathic arthritis (SJIA), or an indication listed in a separate category herein.
[00131] Inflammatory diseases include, but are not limited to: chronic obstructive pulmonary diseases, airway hyper-responsiveness, cystic fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, gingivitis, atherosclerosis, chronic prostatitis, glomerular nephritis, ulcerative colitis, uveitis, periodontal disease, or an indication listed in a separate category herein. [00132] Pain conditions include, but are not limited to: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post- traumatic injury, pain associated with irritable bowel syndrome, gout, pain associated with any of the other indications listed within this specification, or an indication listed in a separate category herein.
[00133] Respiratory, airway and pulmonary conditions include, but are not limited to: asthma (which may encompass chronic, late, bronchial, allergic, intrinsic, extrinsic or dust), chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis, interstitial lung disease, acute lung injury, sarcoidosis, allergic rhinitis, chronic cough, bronchitis, recurrent airway obstruction, emphysema, or bronchospasm, or an indication listed in a separate disease category herein.
[00134] Gastrointestinal (GI) disorders include, but are not limited to: irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with Gl distension, ulcerative colitis, Crohn's disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, or an indication listed in a separate disease category herein.
[00135] Allergic diseases include, but are not limited to: anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, allergic reactions to: food, drugs, insect bites, pollen; or an indication listed in a separate disease category herein.
[00136] Infection-based diseases include, but are not limited to: sepsis, septic shock, viral diseases, malaria, Lyme disease, ocular infections, conjunctivitis, Whipple Disease, or an indication listed in a separate disease category herein.
[00137] Trauma and tissue injury-based conditions include, but are not limited to: renal glomerular damage, reperfusion injury (for example to heart, kidney, lung), spinal cord injury, tissue scarring, tissue adhesion, tissue repair, transplant rejection (for examples to heart, lung, bone marrow, cartilage, cornea, kidney, limb, liver, muscle, myoblast, pancreas, pancreatic islet, skin, nerve, small intestine, trachea), hypersensitivities, or an indication listed in a separate disease category herein. [00138] Fibrotic diseases include, but are not limited to: idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, or an indication listed in a separate disease category herein.
[00139] Joint, muscle and bone disorders include, but are not limited to: osteoarthritis, osteoporosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, erosive osteoarthritis of the hand, arthrofibrosis/traumatic knee injury, anterior cruciate knee ligament tear, relapsing polychondritis, recurrent multifocal osteomyelitis, Majeed syndrome, ankylosing spondylitis, gout of the lumbar spine, antisynthetase syndrome, idiopathic inflammatory myopathies, articular chondrocalcinosis, systemic-onset juvenile idiopathic arthritis (SJIA), gout and pyrophosphate crystal arthritis, or an indication listed in a separate disease category herein.
[00140] Skin/ dermatological diseases include, but are not limited to: psoriasis, atopic dermatitis, cutaneous lupus, acne, dermatomyositis, eczema, pruritus, scleroderma, Sweet Syndrome/neutrophilic dermatosis, neutrophilic panniculitis, acrodermatitis (form of pustular psoriasis), or an indication listed in a separate disease category herein.
[00141] Renal diseases include, but are not limited to: acute kidney injury (AKI) (sepsis- AKI, coronary artery bypass graft- AKI, cardiac surgery-AKI, non-cardiac surgery- AKI, transplant surgery-AKI cisplatin-AKI, contrast/imaging agent induced-AKI), glomerulonephritis, IgA nephropathy, crescentic GN, lupus nephritis, HIV associated nephropathy, membraneous nephropathy, C3 glomerulopathy, Dense deposit disease, ANCA vasculitis, diabetic nephropathy, hemolytic-uremic syndrome, atypical Hemolytic-uremic syndrome, nephrotic syndrome, nephritic syndrome, hypertensive nephrosclerosis, ApoLl nephropathy, focal segmental glomerulosclerosis, Alport syndrome, Fanconi syndrome, crystal nephropathy, nephrolithiasis, nephrotic syndrome, renal transplant rejection, amyloidosis, glomerulonephritis in SJIA, or an indication listed in a separate disease category herein.
[00142] Hematopoietic diseases include, but are not limited to: hemolytic anemia, or an indication listed in a separate disease category herein.
[00143] Liver diseases include, but are not limited to: liver fibrosis, liver cirrhosis, nonalcoholic steatohepatitis (NASH), or an indication listed in a separate disease category herein.
[00144] Oral diseases include, but are not limited to: gingivitis, periodontal disease or an indication listed in a separate disease category herein. [00145] Metabolic diseases include, but are not limited to: Type 2 diabetes (and resulting complications), gout and hyperuricemia, metabolic syndrome, insulin resistance, obesity, obesity- related hyperglycemia or an indication listed in a separate disease category herein.
[00146] Compounds of the present disclosure are also useful in the treatment of a proliferative disease selected from a benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, nonsmall-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma), or an indication listed in a separate disease category herein.
[00147] Cardiovascular diseases include, but are not limited to coronary heart disease, acute coronary syndrome, ischaemic heart disease, first or recurrent myocardial infarction, secondary myocardial infarction, non-ST segment elevation myocardial infarction, or ST segment elevation myocardial infarction, ischemic sudden death, transient ischemic attack, peripheral occlusive arterial disease, angina, atherosclerosis, hypertension, heart failure (such as congestive heart failure), diastolic dysfunction (such as left ventricular diastolic dysfunction, diastolic heart failure, and impaired diastolic filling), systolic dysfunction (such as systolic heart failure with reduced ejection fraction), vasculitis, ANCA vasculitis, post- myocardial infarction cardiac remodeling atrial fibrillation, arrhythmia (ventricular), ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular damage, left ventricular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, fibrinoid necrosis of coronary arteries, adverse remodeling, stroke, and the like, or an indication listed in a separate disease category herein. Also, included are venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty). Cardiovascular complications of type 2 diabetes are associated with inflammation, and include conditions such as macrovascular disease, hyperglycemia, metabolic syndrome, impaired glucose tolerance, hyperuricemia, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and insulin resistance syndrome, or an indication listed in a separate disease category herein.
[00148] Linkage of innate immunity, oxidative stress and inflammation to disease has been demonstrated in neuroinflammatory and neurodegenerative conditions. Neuroinflammatory and neurodegenerative conditions include diseases or diorders such as multiple sclerosis, migraine; epilepsy; Alzheimer's disease; Parkinson's disease; brain injury; stroke; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, and brain hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV associated dementia, Alzheimer's associated dementia, Huntington's associated dementia, Lewy body dementia, vascular dementia, drug related dementia, delirium, and mild cognitive impairment); mental deficiency (including Down syndrome and fragile X syndrome); sleep disorders (including hypersomnia, circadian rhythm sleep disorder, insomnia, parasomnia, and sleep deprivation) and psychiatric disorders (such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder); factitious disorder (including acute hallucinatory mania); impulse control disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, and postpartum depression); psychomotor disorder; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder); drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, ***e addiction, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia, bulimia, binge eating disorder, hyperphagia, and pagophagia); and pediatric psychiatric disorders (including attention deficit disorder, attention deficit/hyperactive disorder, conduct disorder, and autism), myotrophic lateral sclerosis, chronic fatigue syndrome, or an indication listed in a separate disease category herein.
[00149] In one embodiment the acute or chronic autoimmune and/or inflammatory condition is a disorder of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
[00150] In another embodiment the acute or chronic autoimmune and/or inflammatory condition are respiratory disorders such as asthma, chronic obstructive pulmonary disease, pulmonary arterial hypertension or idiopathic pulmonary fibrosis.
[00151] In another embodiment the acute or chronic autoimmune and/or inflammatory condition is a systemic inflammatory disorder such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, scleroderma or inflammatory bowel disease (Crohn's disease and ulcerative colitis).
[00152] In another embodiment the acute or chronic autoimmune and/or inflammatory condition is multiple sclerosis.
[00153] Some embodiments provide methods of treating a metabolic disease by administering a therapeutically effective amount of the compound of Formula (I) wherein the metabolic disease is diabetes or hyperglycemia. Other embodiments provide the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of a metabolic disease wherein the metabolic disease is diabetes or hyperglycemia. Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating diabetes or hyperglycemia.
[00154] Some embodiments provide methods of treating an inflammatory disease or disorder, by administering a therapeutically effective amount of the compound of Formula (I) wherein the inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension. Other embodiments provide the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of an inflammatory disease or disorder, wherein the inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension. Still other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating an inflammatory disease or disorder, wherein the inflammatory disease or disorder is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, immune thrombocytopenia (ITP), systemic sclerosis, neointimal hyperplasia, cardiovascular disease or hypertension. In certain embodiments, the present disclosure relates to methods for the treatment of disease or disorder selected from inflammatory bowel disease (including ulcerative colitis and Crohn's disease), colorectal cancer, and gastritis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or salt of a solvate thereof Some embodiments provide the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for the manufacture of a medicament for the treatment of disease or disorder selected from inflammatory bowel disease (including ulcerative colitis and Crohn's disease), colorectal cancer, and gastritis. Other embodiments provide an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, for treating a disease or disorder selected from inflammatory bowel disease (including ulcerative colitis and Crohn's disease), colorectal cancer, and gastritis. In certain embodiments said disease or disorder is inflammatory bowel disease. In certain embodiments said disease or disorder is ulcerative colitis. In certain embodiments said disease or disorder is Crohn’s disease.
[00155] Dosage and Administration
[00156] The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, or any value in between (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg, or any value in between) every 4 to 120 hours, or any value in between. In certain embodiments, the compositions are administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
[00157] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject’s disposition to the disease, and the judgment of the treating physician.
[00158] In some embodiments, dosage forms include from 0.001 milligrams to 2,000 milligrams, or any value in between (including, from 0.001 milligrams to 1,000 milligrams, from 0.001 milligrams to 500 milligrams, from 0.01 milligrams to 250 milligrams, from 0.01 milligrams to 100 milligrams, from 0.05 milligrams to 50 milligrams, and from 0.1 milligrams to 25 milligrams, or any value in between) of a compound of Formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.
[00159] Appropriate dosage levels may be determined by any suitable method known to one skilled in the art of treating inflammatory diseases. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used. [00160] Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition and mode of administration, without being toxic to the subject. It may therefore be necessary where appropriate to deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the subject, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day.
[00161] Combination Therapy
[00162] In some embodiments, the compounds of the present disclosure may be co administered with one or more additional therapeutic agents: Non-steroidal anti-inflammatory drugs (NSAIDs), including but not limited to, nonselective COXl/2 inhibitors such as piroxicam, naproxen, flubiprofen, fenoprofen, ketoprofen, ibuprofen, etodolac (Lodine), mefanamic acid, sulindac, apazone, pyrazolones (such as phenylbutazone), salicylates (such as aspirin); selective COX2 inhibitors such as: celecoxib, rofecoxib, etoricoxib, valdecoxib, meloxicam; Immunomodulatory and/ or anti-inflammatory agents, including but not limited to, methotrexate, leflunomide, ciclesonide, chloroquine, hydroxychloroquine, d-penicillamine, auranofin, sulfasalazine, sodium aurothiomalate, cyclosporine, azathioprine, mercaptourine, cromolyn, hydroxy carbamide, retinoids, fumarates (such as monomethyl and dimethyl fumarate), mesalamine, glatiramer acetate, mitoxantrone, teriflunomide, suplatast tosilate, mycophenolate mofetil and cyclophosphamide, laquinimod, voclosporin, PUR-1 18, AMG 357, AMG 811 , BCT197; Antibiotics, including but not limited to, metronidazole or ciprofloxacin; Anti-TNFa agents, including but not limited to, infliximab, adalimumab, certolizumab pegol, golimumab and etanercept; Anti-CD20 agents, including but not limited to, rituximab, ocrelizumab, ofatumumab and PF-05280586; Antidiarrheals, such as diphenoxylate (Lomotil) and loperamide (Imodium); Bile acid binding agents, such as cholestyramine, alosetron (Lotronex) and ubiprostone (Amitiza); Laxatives, such as Milk of Magnesia, polyethylene glycol (MiraLax), Dulcolax, Correctol and Senokot, and anticholinergics or antispasmodics such as dicyclomine (Bentyl); T lymphocyte activation inhibitors, including but not limited to, abatacept; Glucocorticoid receptor modulators that may be dosed orally, by inhalation, by injection, topically, rectally, by ocular delivery, including but not limited to, betamethasone, prednisone, hydrocortisone, prednisolone, flunisolide, triamcinoline acetonide, beclomethasone, dipropionate, budesonide, fluticasone propionate, ciclesonide, mometasone furoate, fluocinonide, desoximetasone, methylprednisolone or PF-04171327; Aminosalicyic acid derivatives, including but not limited to, sulfasalazine and mesalazine; Anti-a4 integrin agents, including but not limited to, natalizumab and vedolizumab; al- or a2-adrenergic agonist agents including but not limited to: propylhexidrine, phenylephrine, phenylpropanolamine, pseudoephedrine or naphazobne hydrochloride, oxymethazoline hydrochloride, tetrahydrozobne hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride; b-adrenergic agonists, including but not limited to, metaproterenol, isoprotenerol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, botolterol mesylate, pirbuterol; Anticholinergic agents, including but not limited to, ipratropium bromide, tiotropium bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate, pirenzipine or telenzepine; Inhaled long acting beta- agonists, long acting muscarinic antagonists and long acting corticosteroids, including but not limited, to those included in the following reference: Y. Mushtaq, Nat. Rev. Drug Disc., 2014, 13(4), 253-254; Leukotriene pathway modulators, including but not limited to, 5-LO inhibitors (such as zileuton), FLAP antagonists (such as veliflapon, fiboflapon), LTD4 antagonists (such as montelukast, zafirlukast or pranlukast); HI receptor antagonists, including but not limited to, cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; PDE4 inhibitors, including but not limited to, apremilast, roflumilast or AN2728; Vitamin D receptor modulators, including but not limited to, pari cal citol; Nrf2 pathway activators, including but not limited to, fumarates, sulfurophane and bardoxolone methyl; Modulators of the RAR-related orphan receptor (ROR) family, in particular RORg; Modulator and/ or antagonists of the chemokine receptors, including but not limited to, CCR2 antagonists (such as CCX140, BMS-741672, PF-4634817, CCX-872, NOX-E36), CCR2/5 antagonists (such as PF- 4634817), CCR9 (such as vercirnon, CCX507), CCR1 modulators, CCR4 modulators, CCR5 modulators, CCR6 modulators, CXCR6 modulators, CXCR7 modulators) and CXCR2 modulators (such as danirixin, AZD5069); Prostaglandins, including but not limited to, prostacyclin; PDE5 inhibitors, including but not limited to, sildenafil, PF-489791, vardenafil and tadalafil; Endothelin receptor antagonists, including but not limited to, bosentan, ambrisentan, sparsentan, atrasentan, zibotentan and macitentan; Soluble guanylate cyclase activators, including but not limited to, riociguat; Interferons, including but not limited to, interferon b ΐ a interferon bΐ b; Sphingosine 1-phosphate receptor modulators, including but not limited to, fingolimod, ponesimod; Inhibitors of the complement pathway, including but not limited to, C5aR antagonists (such as CCX168, PMX-53, NN8210), C5 inhibitors (such as eculizumab), inhibitors of complement factors B and D, inhibitors of MASP2 (such as OMS-721) and ARC-1905; Inhibitors of Janus kinases (one of more of JAK1 , JAK2, JAK3, TYK2), including but not limited to, decernotinib, cerdulatinib, JTE-052, ruxolitinib, tofacitinib, baricitinib, peficitinib, GLPG-0634, INCB-47986, INCB-0391 10, PF-04965842, XL-019, ABT-494, R-348, GSK- 2586184, AC-410, BMS-911543 and PF-06263276; Inhibitors of other anti-inflammatory or immunomodulatory kinases, including but not limited to, spleen tyrosine kinase (SYK) inhibitors, p38 MAP kinase inhibitors (such as PF-3715455, PH-797804, AZD-7624, AKP-001 , UR-13870, FX-005, semapimod, pexmetinib, ARRY-797, RV-568, dilmapimod, rabmetinib), PI3K inhibitors (such as GSK-2126458, pilarahsib, GSK-2269557), PI3Kg and/ or PI3Kd inhibitors (such as CAL-lOl/GS-1 101 , duvelisib), INK inhibitors, ERK1 and/ or 2 inhibitors, I KKb inhibitors, BTK inhibitors, ITK inhibitors, ASK1 inhibitors (such as GS-4997), PKC inhibitors (such as sotrastaurin), TrkA antagonists (such as CT-327), MEKl inhibitors (such as E6201); Antioxidants, including but not limited to, myeloperoxidase inhibitors (such as AZD- 3241), NOX4 and other NOX enzymes (such as GKT-137831) and N-acetyl cysteine; Inhibitors of I L5, including but not limited to, mepolizumab, reslizumab and benralizumab; Inhibitors of IL4, including but not limited to, pascolizumab, altrakincept and pitrakinra; Inhibitors of IL13, including but not limited to, tralokinumab, anrukinzumab and lebrikizumab; Anti-IL6 agents, including but not limited to, tocilizumab, olokizumab, siltuximab, PF-4236921 and sirukumab; Inhibitors/Antagonists of IL17/IL17R, including but not limited to, secukinumab, RG-7624, brodalumab and ixekizumab; Antagonists of IL12 and/or IL23, including but not limited to, tildrakizumab, guselkumab, MEDI2070 and AMG 139; Inhibitors of IL33, including but not limited to, AMG 282; Inhibitors of IL9, including but not limited to, MEDI-528; Inhibitors of GM-CSF, including but not limited to, MT203; Anti CD4 agents, including but not limited to, tregalizumab and rigerimod; CRTH2 antagonists, including but not limited to, AZD-1981 ; Inhibitors of B lymphocyte stimulator (BLYS; also known as BAFF), a protein that is often increased in subjects with SLE, including but not limited to, belimumab, tabalumab, blisibimod, and atacicept; CD22-specific monoclonal antibodies, including but not limited to, epratuzumab; Inhibitors of interferon-oc, including but not limited to, sifalimumab and rontalizumab; Inhibitor of type I interferon receptors, including but not limited to, MEDI-546; FCYRI I B agonists, including but not limited to, SM-101 ; Modified and/or recombinant versions of Heat Shock Protein 10 (HsplO, also known as Chaperonin 10 or EPF), including but not limited to, INV-103; Inhibitors of the TNF superfamily receptor 12A (TWEAK receptor), including but not limited to, BIIB-023, enavatuzumab, and RG-7212; Inhibitors of xanthine oxidase, including but not limited to, allopurinol, benzbromarone, febuxostat, topiroxostat, tisopurine and inositols; Inhibitors of URATl (also known as SLC22A12), including but not limited to, lesinurad, RDEA 3170, UR1102 and levotofispam; Inhibitors of toll-like receptors (TLRs), including but not limited to, one or more of TLR7, TLR8, TLR9 (such as IMO-8400, IMO-3100, DV-1 179), TLR2 and/ or TLR4 (such as VB-201, OPN-305); Agonists of TLRs, including but not limited to, TLR7 (such as GSK2245035, AZD8848), TLR9 (such as AZD1419); Activators SIRTl, including but not limited to, SRT2104; A3 receptor agonists, including but not limited to, CF101 ; other agents of use of the treatment of psoriasis, including but not limited to, IDP-118, LAS41004, LEO 80185, LEO 90100, PH-10, WBI-1001, CNT01959, BT-061, cimzia, ustekmumab, MK-3222/SCH 900222, ACT-128800, AEB071, alitretinoin, ASP015K, Apo805Kl , BMS-582949, FP187, hectorai (doxercalciferol), LEO 22811, Ly3009104 (INCB28050), calcipotriene foam (STF 1 15469), tofacitinib (CP-690,550), M518101 and CycloPsorb™; Antifibrotic agents, including but not limited to: pirfenidone, inhibitors of LOXL2 (such as Simtuzumab), FT-011 , modulators of epiregulin and/ or TGFa (such as LY-3016859), modulators of TGFP (such as LY-2382770, fresolimumab); Prolyl hydroxylase inhibitors, including but not limited to, GSK1278863, FG- 2216, ASP- 1517/FG-4592, AKB-6548, JTZ-951 , BAY-85-3934 and DS-1093; Inhibitors of granulocyte macrophage colony-stimulating factor, including but not limited to, GSK3196165 (MORI 03), PD-0360324 and mavrilimumab; Inhibitors of MAdCAM and/ or a4b7 integrin, including but not limited to, PF-00547659 and MEDI7183 (abrilumab); Inhibitors of connective tissue growth factor (CTGF), including but not limited to, PF-06473871 ; Inhibitors of cathepsin C, including but not limited to, GSK2793660; Inhibitors of soluble epoxide hydrolase, including but not limited to, GSK2269557; Inhibitors of the TNFR1 associated death domain protein, including but not limited to, GSK2862277; Anti-CD19 agents, including but not limited to, MEDI-551 and AMG 729; Anti-B7RP1 agents/ inhibitors of ICOS ligand, including but not limited to, MEDI5872 and AMG-557; Inhibitors of thymic stromal lymphoprotein, including but not limited to, AMG157; Inhibitors of IL2, including but not limited to, daclizumab; Inhibitors of Leucine rich repeat neuronal protein 6A, including but not limited to, Anti-Lingo (Biogen); Inhibitors of integrins, including but not limited to, aV/bό (STX-100) and a.n/b3 (VPI-2690B); Anti-CD40L agents, including but not limited to, CDP- 7657; Modulators of the dopamine D3 receptor, including but not limited to, ABT-614; Inhibitors and/ or modulators of galectin-3, including but not limited to, GCS-100 and GR-MD- 02; agents for treating diabetic nephropathy, including but not limited to, DA-9801 and ASP- 8232; Agents for treating acute kidney injury, including but not limited to, THR-184, TRC- 160334, NX-001 , EA-230, ABT-719, CMX-2043, BB-3 and MTP-131; Modulators of inflammasomes, including but not limited to, inhibitors of NLRP3; Modulators of bromodomains, including but not limited to, BRD4; Modulators of GPR43; and Inhibitors of TRP channels, including but not limited to, TRPAl, TRPC3, TRPC5, TRPC6 and TRPC6.
[00163] Additional therapeutic agents include antithrombotic agents (anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents), anti-arrhythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type), cardiac glycosides, diuretics, mineralocorticoid receptor antagonists, NO donating agents such as organonitrates, NO promoting agents such as phosphodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal), anti osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti anxiety agents, anti-proliferative agents, anti-tumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid hormone receptor antagonist), anti-infective agents, anti-viral agents, anti bacterial agents. [00164] Examples of antithrombotic agents include fondaparinux, edoxaban, betrixaban, apixaban and rivaroxaban, warfarin, heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin), hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, ticagrelor, prasugrel, tirofiban, ifetroban, eptifibatide, abciximab, dabigatran, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, streptokinase, boroarginine derivatives and boropeptides (boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof), tenecteplase, lanoteplase (nPA), factor Vila inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex.
[00165] Examples of suitable anti-arrythmic agents include: Class I agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as lAch inhibitors, and iKur inhibitors (e.g., compounds such as those disclosed in W001/40231).
[00166] Examples of suitable anti-hypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginal agent is ivabradine.
[00167] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil. Examples of suitable cardiac glycosides include digitalis and ouabain.
[00168] Examples of suitable combination mineralocorticoid receptor antagonists include spironolactone and eplerenone. Examples of suitable combination phosphodiesterase inhibitors include: PDE3 inhibitors (such as cilostazol); and PDE5 inhibitors (such as sildenafil). Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; cholesterol absorption inhibitors; and cholesteryl ester transfer protein inhibitors. Other atherosclerotic agents include agents that modulate the action of PCSK9, for example, bococizumab.
[00169] Anti-inflammatory agents also include sPLA2 and lpPLA2 inhibitors (such as darapladib), 5 LO inhibitors (such as atreleuton) and IL-1 and IL-1 r antagonists (such as canakinumab).
[00170] Cardiovascular complications of type 2 diabetes are associated with deleterious levels of myeloperoxidase; accordingly, the compounds of the present disclosure may be used in combination with anti-diabetic agents, particularly type 2 anti-diabetic agents. Examples of suitable anti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors, GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors). Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in W02009144554, W02003072197, WO2009144555 and W02008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or W02010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O- acyltransferase inhibitors, a PDE10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an a- amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), an a-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, vogbbose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balagbtazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), a PPAR a/g agonist (e.g., CLX-0940, GW- 1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB- 219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, bxisenatide, dulaglutide, semaglutide, NN-9924.TTP-054, a protein tyrosine phosphatase- 1 B (PTP-1 B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, et ah, Drug Disc. Today, 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., those in W02005116014, sitagbptin, vildagbptin, alogliptin, dutogbptin, bnagliptin and saxagbptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa) such as those described in W02010103437, W02010103438, W02010013161 , WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001 , insulin, an insulin mimetic, a glycogen phosphorylase inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in Chao et ah, Nat. Rev. Drug Disc. 9, 551-559 (2010) including dapagliflozin, canagliflozin, empagliflozin, tofogbflozin (CSG452), ASP-1941 , THR1474, TS-071 , ISIS388626 and LX421 1 as well as those in W02010023594, a glucagon receptor modulator such as those described in Demong, et ah, Ann. Rep. Med. Chem. 2008, 43, 1 19-137, GPR119 modulators, particularly agonists, such as those described in W02010140092, WO2010128425, W02010128414, WO2010106457, Jones, et ah, Med. Chem. 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov et ah, Curr. Op. Investig. Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present disclosure can be found, for example, at page 28, line 35 through page 30, line 19 of WO201 1005611. Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyi transferase enzymes, inhibitors of fructose 1 ,6-diphosphatase, inhibitors of aldose reductase, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa, RKOb, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyi transferase, modulators of GPR81 , GPR39, GPR43, GPR41 , GPR105, Kvl .3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1 , SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILI beta, modulators of RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P. A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.
[00171] The compounds of the present disclosure may be used in combination with neuroinflammatory and neurodegenerative agents in mammals. Examples of additional neuroinflammatory and neurodegenerative agents include antidepressants, antipsychotics, anti pain agents, anti-Alzheimer's agents, and anti-anxiety agents. Examples of particular classes of antidepressants that can be used in combination with the compounds of the present disclosure include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Examples of suitable SSRIs include fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Examples of suitable reversible inhibitors of monoamine oxidase include moclobemide. Examples of suitable SNRIs of use in the present disclosure include venlafaxine. Examples of suitable atypical anti-depressants include bupropion, lithium, trazodone and viloxazine. Examples of anti-Alzheimer's agents include NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine. Examples of suitable classes of anti-anxiety agents that can be used in combination with the compounds of the present disclosure include benzodiazepines and serotonin 1A receptor (5-HT1A) agonists, and CRF antagonists. Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1 A receptor agonists include buspirone and ipsapirone. Suitable CRF antagonists include verucerfont. Suitable atypical antipsychotics include pabperidone, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine. Suitable nicotine acetylcholine agonists include CP-601927 and varenicbne. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and zi conotide.
[00172] As used herein, the terms "co-administration", "co-administered", "a combination of' or "in combination with", refers to a combination of a compound of the present disclosure and one or more other pharmaceutically active ingredient, or a pharmaceutically acceptable salt thereof, includes the following:
[00173] a. simultaneous administration of such a combination of a compound of the present disclosure and a further pharmaceutically active agent to a subject in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said subject,
[00174] b. substantially simultaneous administration of such a combination of a compound of the present disclosure and a further pharmaceutically active agent to a subject in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said subject, whereupon said components are released at substantially the same time to said subject,
[00175] c. sequential administration of such a combination of a compound of the present disclosure and a further pharmaceutically active agent to a subject in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said subject with a significant time interval between each administration, whereupon said components are released at substantially different times to said subject; and, d. sequential administration of such a combination of a compound of the present disclosure and a further pharmaceutically active agent to a subject in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner.
[00176] Furthermore, although the embodiments herein, including in the examples below, have been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.
D. EXAMPLES
[00177] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. Standard abbreviations and acronyms as defined in Journal of Organic Chemistry’s Guideline for Authors updated April 2018 are used herein. Other abbreviations and acronyms used herein are understood by those skilled in the art.
General Synthetic Schemes
[00178] Compounds of the present disclosure may be prepared by procedures described in the following schemes. As depicted in Scheme A, the lithium anion of 2-chlorothiazole (i), generated in situ with a base such as n-butyl lithium, is added to an appropriate aldehyde ii to generate iii. Oxidation of iii to iv, followed by reaction with an appropriate secondary amine provides a compound of Formula (I). The reactions are facilitated through the use of either excess (> 2 equiv.) of amines or by the addition of an additional trialkyl amine such as diethylisopropylamine. Amines are either commercially available or known in the chemical literature. Scheme A
Figure imgf000109_0001
Example 1 Preparation of (2-(4,4-dimethylpiperidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone
1. nBuLi
2. DMP
3. 3,3-dimethyl
Figure imgf000109_0003
Figure imgf000109_0002
piperidine
[00179] Step 1. A solution of 2-chlorothiazole (4.17 g, 34.87 mmol) in THF (40 mL) was cooled to -78 °C and then nBuLi (2.5 M, 14.66 mL) was added dropwise. The solution was stirred for 50 min. In a second flask, 3-methylsulfonylbenzaldehyde (5.00 g, 27.14 mmol) was dissolved in THF (40 mL) and cooled to -78 °C. The solution of the thiazolyl anion was then added dropwise to the second flask via a cold cannula over 5 minutes. After stirring for 1 hour at -78 °C, the reaction was quenched by the addition of sat. NH4CI (aq) (200 mL) and the mixture was warmed to rt. The product was extracted with EtOAc (3 x 200 mL), then the combined organic layers were dried (Na2S04) and concentrated in vacuo. Purification by CombiFlash (120 g; 0: 100 to 100:0 EtOAc: hexanes) provided (2-chlorothiazol-4-yl)-(3-methylsulfonylphenyl)methanol (4.50 g, 14.8 mmol, 54%).
[00180] Step 2. This product was dissolved in DCM (15 mL) and Dess-Martin periodinane (6.75 g, 15.9 mmol) was added. After stirring for 15 minutes, the reaction was quenched by addition of 100 mL 1 : 1 sat. Na2S203(aq): sat. NaHC03(aq), and the mixture was stirred vigorously for 60 minutes. The layers were separated, then the aqueous fraction was further extracted with 2 x 100 mL EtOAc. The combined organic layers were dried (Na2S044) and concentrated in vacuo to provide (2-chlorothiazol-4-yl)-(3-methylsulfonylphenyl)methanone (4.2 g, 13.9 mmol, 93%) of sufficient purity to be used directly.
[00181] Step 3. 4,4-dimethylpiperidine (28.3 mg, 0.249 mmol) and diisopropylethylamine (DIPEA; 0.100 mL, 0.573 mmol) were combined in DMSO (1 mL) then (2-chlorothiazol-4-yl)- (3-methylsulfonylphenyl)methanone (50 mg, 0.166 mmol) was added. The tube was capped and the reaction was heated to 80 °C for 1 hour. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by CombiFlash (4 g column, 0-10% MeOH/DCM) provided the titled compound (63 mg, 0.165 mmol, 99%). MS (ESI) m/z = 379.8 (M+H).
Examples 2-230
[00182] The following compounds in Table 1 were made using the methods described above. The appropriate thiazolyl aryl ketones were made using the appropriate 3 -substituted benzaldehyde in place of 3-formylbenzonitrile using the method described for the preparation of Intermediate 1. An appropriate cyclic amine was reacted to the thiazolyl aryl ketone intermediate using the method described in Example 1.
Table 1.
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
aSupercriticl fluid chromatography (SFC) purification Conditions: ChiralPak IC column; 60% CO2, 20% acetonitrile, 20% ethanol
bSFC purification Conditions: ChiralPak IC column; 45% CO2, 55% isopropanol
CSFC purification Conditions: ChiralPak IA column; 45% CO2, 55% isopropanol
Example 231
Human Vanin-1 Enzvme Assay
[00183] The fluorescent in vitro assay used to measure vanin-1 enzymatic cleavage of pantothenate-7-amino-4-methylcoumarin (pAMC) has essentially been described in Ruan BH et al, Anal. Biochem., 2010, 399(2):284-92 and was used with minor modifications. Rapidly, 190 pL of recombinant human vanin-1 (Sino Biological Inc., Beijing, China) diluted to 10 ng/ml in assay buffer (100 mM sodium phosphate pH 7.5, 0.5 mMDTT, 10 pg/ml BSA, and 0.0025 % Brij- 23), was first added in each well of a white 96-well assay plate, except for the background wells which received only 190 pL of assay buffer. Two microliters of compound serially diluted in DMSO, or DMSO alone for background and no inhibition controls, were then added and the plate was incubated for 10 mm at RT. To begin the assay, 10 pL of pAMC 20 pM in assay buffer was added to each well and the reaction was monitored at RT by reading the fluorescence signal every 30 sec for 30 min on a Spectramax Gemini EM microplate reader (350 nm excitation wavelength and 460 nm emission wavelength).
Using this assay, data for the compounds of the present disclosure are shown in the following Table 3. hVNN-1 ICso ranges: A <100 nM; 100 nM < B<500 nM; 500 nM < C < 2500 nM; 2500 nM < D < 25 pM. TABLE 3:
Figure imgf000137_0002
Figure imgf000137_0003
Figure imgf000137_0001
Figure imgf000137_0004
Figure imgf000138_0002
Figure imgf000138_0003
Figure imgf000138_0001
Figure imgf000138_0004
Figure imgf000139_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I)
Figure imgf000140_0001
or a pharmaceutically acceptable salt, solvate, clathrate, or hydrate thereof, wherein:
X1 is N or CRal;
X2 is N or CRa2;
X3 is N or CRa3;
X4 is N or CRa4;
provided that no more than two of X1, X2, X3, and X4 are N;
R° is hydrogen, halo or Ci-Ce alkyl;
Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo;
R1 is halogen, cyano, Ci-Ce alkyl, Ci-C6haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, -C(0)OR10, - C(0)N(Rn)(R12), -S(0)tR9, -S(0)tN(Rn)(R12), -P(0)(R9)2, and -SFs, wherein the optional substituents are one to five groups selected from C1-C6 alkyl, halo and C1-C6 haloalkyl;
Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 10 Q substituents selected from halogen, cyano, Ci-C6alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), C1-C6 haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5- to 10- membered heteroaryl, and optionally substituted 5- to 10- membered heteroaryl(Ci-C6 alkyl), -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -N(R20)C(O)R13, -C(0)R13, - C(0)OR14 and -C(0)N(R16)(R17), wherein the optional substituents are selected from halogen, Ci- Cealkyl, Ci-C6haloalkyl, hydroxyl and Ci-C6hydroxyalkyl; each R9 and R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R10, R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R11 and R12, and R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;
m is 0, 1 or 2;
n is 0, 1 or 2; and
each t is independently 1 or 2.
2. The compound of claim 1, wherein Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 8 Q substituents.
3. The compound of claim 1 or 2, wherein Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 0 to 5 Q substituents.
4. The compound of any one of claims 1 to 3, wherein Ring A is an N-linked 4- to 12- membered heterocyclyl group substituted with 1 to 5 Q substituents.
5. The compound of any one of claims 1 to 4, wherein:
X1 is CRal;
X2 is CRa2;
X3 is CRa3;
X4 is CRa4; and
Ral, Ra2, Ra3 and Ra4 are each independently hydrogen or halo.
6 The compound of any one of claims 1 to 5, wherein at least two of Ral, Ra2, Ra3, and Ra4 are hydrogen.
7. The compound of any one of claims 1 to 6, wherein Ral, Ra2, Ra3, and Ra4 are hydrogen.
8. The compound of any one of claims 1 to 7, wherein R1 is halogen, cyano, Ci-Ce haloalkyl, 5- to 10- membered heteroaryl, -OR10, -SR10, or -SFs where the 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from Ci- Ce alkyl, halogen and C1-C6 haloalkyl;
R10 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
each t is independently 1 or 2.
9. The compound of any one of claims 1 to 7, wherein R1 is -S(0)tR9 or -S(0)tN(Rn)(R12);
R9 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R11 and R12, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and
each t is independently 1 or 2.
10. The compound of any one of claims 1 to 7, wherein R1 is cyano, C1-C6 haloalkyl, -S(0)tR9, or -SFs; and
R9 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl).
11. The compound of any one of claims 1 to 7, wherein R1 is -S(0)tR9 and R9 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclylalkyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and t is 1 or 2.
12. The compound of claims 1 to 7, wherein R1 is -S(0)tR9; and R9 is C1-C6 alkyl or Ci- Ce haloalkyl.
13. The compound of any one of claims 1-7 having the Formula (II)
Figure imgf000143_0001
wherein:
R1 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10- membered heteroaryl, -OR10, -SR10, -C(0)OR10, - C(0)N(Rn)(R12), -S(0)tR9,
-S(0)tN(Rn)(R12), -P(0)(R9)2, or -SF5 where the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to five groups selected from C1-C6 alkyl, halo and C1-C6 haloalkyl;
Y is -C(R3a)(R3b)-, -NR2-, -0-, -S- or -S(0)t-; provided that when Y is -NR2-, -0-, -S- or -S(0)t-, neither m nor n is 0;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently selected from (i), (ii), (iii), (iv) and (v) as follows:
(i) hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), optionally substituted 3- to 8- membered cycloalkyl, optionally substituted 3- to 8- membered cycloalkyl(Ci-C6 alkyl), optionally substituted 3- to 8- membered heterocyclyl, optionally substituted 3- to 8- membered heterocyclyl(Ci-C6 alkyl), optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl(Ci-C6 alkyl), optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heteroaryl(Ci- Ce alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17), wherein R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each further independently selected from halogen, cyano, -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -N(R20)C(0)R13 and wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl and C1-C6 hydroxyalkyl;
(ii) one of the following pairs, R3a and R3b, R3a and R4a, R3a and R5a, R4a and R4b, R4a and R6a, R5a and R5b, R6a and R6b, and R7a and R71’, together with the carbon atom to which they are attached, form an optionally substituted 3- to 8- membered cycloalkyl, optionally substituted Ce- C10 aryl, optionally substituted 3- to 8- membered heterocyclyl or optionally substituted 5- to 10- membered heteroaryl, where the 3 to 8 membered cycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or 3- to 8- membered heterocyclyl groups are optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl) and 5 to 10 membered heteroaryl(Ci-C6 alkyl), -RuORx, -RuC(0)Rv, -RuC(0)ORx and -RuC(0)NRyRz or wherein two adjacent Q groups on the aryl ring form a heterocycl ring and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and each R71’ is, when present, independently selected from (i);
(iii) one of R3a and R3b, R4a and R4b, R5a and R5b, R6a and R >b, and R7a and R71’, together with the carbon atom to which they are attached, form an oxo group; and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently selected from
(1);
(iv) one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group selected from -CH2-, - C h)i- and -(CH2)3-, wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl(Ci-C6 alkyl) or - RuORx and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently selected from (i); and
(v) one of the following pairs R2 and R4a and R2 and R5a, together with the carbon atom to which they are attached, form an optionally substituted 3 to 8 membered heterocyclyl or an optionally substituted 5 to 10 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl or 5 to 10 membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5 to 10 membered heteroaryl(Ci-C6 alkyl), -RuORx, -RuC(0)Rv and -RuC(0)ORx; and the remainder of R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each, when present, independently selected from (i);
R9 and R13 are each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R10, R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R11 and R12, and R16 and R17, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), , 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
each Rv is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);; or
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ry and Rz is independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);, together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
m is 0, 1 or 2;
n is 0, 1 or 2; and
each t is independently 1 or 2.
14. The of compound of any one of claims 1-13 wherein
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii), (iii), (iv), (v) and (vi) as follows:
(i) R2, when present, is C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), or Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl , -OR15, -SR15, -S(0)tR13, - N(R16)(R17), -C(0)R13, -C(0)OR14 or
-C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four substituents each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R2, when present, is hydrogen; one, two or three of R3a, R4a, R5a R6a and R7a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl, -OR15, -SR15, -S(0)tR13,
N(R16)(R17), -C(0)R13, -C(0)OR14 or
-C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)0R14 and
-C(0)N(R16)(R17);
(iii) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce alkoxy(Ci-C6 alkyl), C6-C10 Ci-C6haloalkoxy(Ci-C6 alkyl), aryl(Ci-C6 alkyl), heteroaralkyl, heteroaryl, -C(0)R13 or -C(0)0R14; one of the following pairs R3a and R3b and R4a and R4b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)0Rx, and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b , are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl),, -C(0)R13, -C(0)0R14 and -C(0)N(R16)(R17);
(iv) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R4a, R3a and R5a, and R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx, and the remainder of R3a, R3b, R4a,R4b, R5a, R5b, R6a, R6b, R7a and R71’, is each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
(v) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) , 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), -C(0)R13 or -C(0)OR14; one of the following pairs R3a and R6a, R3a and R7a, R4a and R5a, R5a and R6a, R4a and R7a, and R6a and R7a, form a bridged alkylene group -CH2-, - C )i- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be substituted with -0-, -NR24- or -S- or -S(0)t- and wherein the bridged alkylene may further optionally be substituted with hydroxyl, C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17); and
(vi) one of the following pairs R2 and R4a and R2 and R5a, together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ce- C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl), -RuORx and -RuC(0)ORx]; and the remainder of R4a, R4b, R5a, R51’, R6a, R >b, R7a and R71’, are each, when present, independently hydrogen or halogen; the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, is each, when present, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), -C(0)R13, -C(0)OR14 and -C(0)N(R16)(R17);
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl) 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene; and each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl).
15. The compound of any one of claims 1- 14 wherein:
Y is -C(R3a)(R3b)-;
R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R are selected as follows:
(i) one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, -OR15, -SR15, -S(0)tR13, -N(R16)(R17), -C(0)R13, -C(0)OR14 or
-C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; or
(ii) one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b and R6a and R6b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl or oxo where the 3- to 8- membered cycloalkyl and 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxyl;
(iii) one of the following pairs R3a and R4a, and R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, alkyl, haloalkyl or C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)ORx; or
(iv) R4a and R5a together or R5a and R6a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S(0)t- and wherein the bridged alkylene may optionally be substituted with hydroxy, C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each independently, when present, hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14 or - C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
each R13 each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, 5- to 10- membered heteroaryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl; and
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl).
16. The compound of any one of claims 1 to 15 wherein:
Y is -C(R3a)(R3b)-;
R3a, R3b R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii) and (iii) as follows:
(i) one, two or three of R3a, R3b R4a, R4b, is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl -OR15, -SR15, -S(0)tR13, -C(0)OR14 or -C(0)N(R16)(R17), wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each independently, when present, hydrogen or halogen;
(ii) one, two or three of R5a, R5b, R6a, R6b, R7a and R71’ is halogen, cyano, C1-C6 alkyl, Ci- Ce haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), Ce- C10 aryl, 5- to 10- membered heteroaryl -OR15, -SR15, -S(0)tR13, -C(0)OR14 or -C(0)N(R16)(R17) wherein the C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b R5a, R5b, R6a, R6b, R7aand R71’, are each independently, when present, hydrogen or halogen; and
(iii) R3a and R4a, together with adjacent atoms to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), -RuORx or -C(0)ORx; R3b, R4b, R5a, R5b, R6a, R6b, R7aand R7b are each, independently, when present, hydrogen or halogen;
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
each t is independently 1 or 2.
17. The compound of any one of claims 1-16 wherein m is 0, 1 or 2 and n is 0 or 1.
18. The compound of any one of claims 1-17 wherein m is 0 or 1 and n is 0 or 1.
19. The compound of any one of claims 1-18 wherein m is 1 and n is 0 or 1.
20. A compound having the Formula (IV)
Figure imgf000152_0001
or a solvate, clathrate, hydrate or pharmaceutically acceptable salt thereof, wherein:
R3a, R3b, R4a, R4b, R5a, R5b, R6a and R >b are selected from (i), (ii), (iii) and (iv) as follows:
(i) one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are each, when present, independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, heteroaryl, -OR15, -SR15, -S(0)tR13,
-N(R16)(R17), -N(R20)C(0)R13, -C(0)R13, -C(0)0R14, -C(0)N(R16)(R17) wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from Ci- Ce alkyl, halogen and C1-C6 haloalkyl; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce alkoxy(Ci-C6 alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)0R14 or -C(0)NR16R17, wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, Ce- C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) one of the following pairs R3a and R3b, R4a and R4b, R5a and R5b and R6a and R6b, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl or oxo where the 3- to 8- membered cycloalkyl and 3- to 8- membered heterocylyl is optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci- C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxy; and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently selected as in (i); and
(iii) one of the following pairs R3a and R4a, and R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one to four Q groups each independently selected from halogen, cyano, alkyl, haloalkyl or C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)ORx; and the remaining pair R3a and R4a or R4a and R6a, and R3b, R4b, R5a, R5b, R6b, R7a and R71’, are each, when present, independently selected as in (i);
(iv) R4a and R5a together or R5a and R6a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S(0)t- and wherein the bridged alkylene may optionally be substituted with hydroxy, C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b, are eachindependently selected as in (i);
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R° is hydrogen, halo or C1-C6 alkyl;
each R20 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl,
R24 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or Ci-Ce alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
each t is independently 1 or 2.
21. The compound of claim 20, wherein R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are selected from (i), (ii), (iii), (iv) and (v) as follows:
(i) one or two of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b are each, when present, independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci- Ce alkyl), Ci-C6haloalkoxy(Ci-C6 alkyl), 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)R13, -C(0)OR14 or - C(0)N(R16)(R17);
and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a and R6b, are each, when present, independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14, -C(0)NR16R17, wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; (ii) R3a and R3b together, or R4a and R4b together, with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four Q groups each independently selected from halogen , Ci-Ce alkyl, Ci- Ce haloalkyl, C i-Ce hydroxyalkyl, C i-Ce alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and hydroxy; the remaining pair R3a and R3b or R4a and R4b, is each independently hydrogen or hydroxy and R5a, R5b, R6a and R6b are hydrogen;
(iii) R3a and R4a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl(Ci-C6 alkyl), -RuORx and -C(0)0Rx; R3b, R4b, R5a, R51’, R6a and R6b, are each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -RORX or -C(0)0Rx;
(iv) R4a and R6a, together with the carbon atoms to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with halogen, C1-C6 alkyl or -RuORx; and R3a, R3b, R4b, R5a, R5b and R6b, are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -RuORx or -C(0)0Rx; and
(v) R4a and R5a together or R5a and R6a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S(0)t- and wherein the bridged alkylene may optionally be substituted with hydroxy, C6-C10 aryl, 5- to 10- membered, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); the remainder of R3a and R3b R4a, R4b, R5a, R5b, R6a and R6b, are each, when present, independently hydrogen or halogen;
each R13 isindependently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
R24 is hydrogen, Ci-Ce alkyl, Ci-Ce hydroxyalkyl, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
each t is independently 1 or 2.
22. The compound of claim 20 or 21 wherein:
R3a, R3b, R4a, R4b, R5a, R5b, R6a and R >b are selected from (i), (ii), and (iii) as follows:
(i) one of R3a and R5a is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci-C6 haloalkoxy(Ci-C6 alkyl), Ce- C10 aryl, 5- to 10- membered heteroaryl, -OR15, -C(0)OR14, -C(0)N(R16)(R17); the other of R3a and R5a , and R3b, R5b, R4a, R4b, R6a and R6b, is each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OR15, -C(0)OR14, -C(0)NR16R17, 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the 3- to 8- membered cycloalkyl, 3- to 8- membered heterocyclyl, C6-C10 aryl or 5- to 10- membered heteroaryl is optionally substituted with one to four groups each independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;
(ii) R3a and R4a, together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl, optionally substituted with one to four groups each independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -RuORx or - C(0)ORx; R3b, R4b, R5a, R5b, R6a and R6b are each independently hydrogen or halogen; and
(iii) R5a and R6a together, form a bridged alkylene group -(CH2)-, -(CH2)2- or -(CH2)3- wherein one carbon atom of -(CH2)2- or -(CH2)3- may be replaced with -0-, -NR24- or -S(0)t- and the remainder of R3a, R3b R4a, R4b, R5a, R5b, R6a and R6b are each independently hydrogen or halogen;
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); or R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl;
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl); and
each t is independently 1 or 2.
23. The compound of any one of claims 19-21 wherein:
R3a is halogen, C1-C6 hydroxyalkyl, C1-C6 alkoxy(Ci-C6 alkyl), Ci- C6haloalkoxy(Ci-C6 alkyl), 5- to 10- membered heteroaryl, -OR15 or -C(0)0R14; and R3b, R4a, R4b, R5a, R5b, R6a and R6b are each independently hydrogen or halogen; and
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl).
24. A compound having the Formula (V)
Figure imgf000157_0001
or a solvate, clathrate, hydrate or pharmaceutically acceptable salt thereof, wherein: Y is -C(R3a)(R3b)-, -NR2-, -0-, -S- or S(0)t-;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii), (iii), (iv) and(v) as follow: (i) R2, when present, is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, or 5- to 10- membered heteroaryl;, and one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or -OR15 and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15;
(ii) R3a and R4a, together with the carbon atom to which they are attached, form C6-C10 aryl, 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 haloalkyl and -RuORx or substituted with two adjacent groups that form a 3- to 8- membered heterocyclyl ring; and the R3b, R4b, R5a, R5b, R6a, R6b, R7a and R7b, are each, when present, independently halogen, C1-C6 alkyl, Ci- Ce haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15;
(iii) R4a and R6a, together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with halogen, Ci- Ce alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl(Ci-C6 alkyl) or heteroaralkyl; and R3a, R3b, R5a, R5b, R7a and R7b, and R4b and R6b, when present, are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, 5- to 10- membered heteroaryl or -OR15;
(iv) R5a and R6a together, or R6a and R7a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3-and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15; and
(v) R2 and R4a, together with the carbon atom to which they are attached, form 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl; and the remainder of R4b, R5a, R5b, R6a, R6b, R7a and R7b, are each, when present, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15;
each R13 each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl);
R° is hydrogen, halo or C1-C6 alkyl; and
t is 1 or 2.
25. The compound of claim 24 wherein:
Figure imgf000159_0001
as follow:
(i) R2, when present, is hydrogen, and and one, two or three of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R7b are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), C6-C10 aryl, 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or -OR15 and the remainder of R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are each independently hydrogen or halo; or R2 is C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl, heteroaralkyl, -C(0)R13 or -C(0)OR14 and R3a, R3b, R4a, R4b, R5a, R5b, R6a, R >b, R7a and R71’ are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl or -OR15 ; or
(ii) R3a and R4a, together with the carbon atom to which they are attached, form C6-C10 aryl, 3- to 8- membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 haloalkyl and -RuORx; and R3b, R4b, R5a, R5b, R6a, R6b, R7a and R7b, are each, selected from hydrogen, halogen, C1-C6 alkyl, Ci- Ce haloalkyl and C1-C6 hydroxyalkyl; or
(iii) R5a and R6a together, or R6a and R7a together, form a bridged alkylene group -CH2- , -(CH2)2- or -(CH2)3- and the remainder of R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each, independently hydrogen, halogen, alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl; and
(iv) R2 and R4a, together with the carbon atom to which they are attached, form 5- to 10- membered heteroaryl; and the remainder of R5a, R5b, R6a, R6b, R7a and R71’, are each, when present, independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;
each R13 each independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); R14 and R15, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and
each t is independently 1 or 2.
26. A compound having the Formula (VI)
Figure imgf000160_0001
or a solvate, clathrate, hydrate or pharmaceutically acceptable salt thereof, wherein:
R3a and R3b are each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), -OR15, -SR15, - S(0)tR13, -N(R16)(R17),
-C(0)0R14, C6-C10 aryl or 5- to 10- membered heteroaryl; and
Figure imgf000160_0002
independently hydrogen, C6-C10 aryl or 5- to 10- membered heteroaryl, or
(ii) R3a and R3b together with the carbon atom to which they are attached, form 3- to 8- membered cycloalkyl or 3- to 8- membered heterocyclyl; each optionally substituted with one to four Q groups each independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Ci-C6haloalkoxy(Ci-C6 alkyl), and C6-C10 aryl(Ci-C6 alkyl); and the remainder of R4a, R4b, R5a are R5bare each independently hydrogen or halogen;
each R13 is independently C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R14 and R15, are each independently hydrogen, Ci-Ce alkyl, C i-Ce haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R16 and R17 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl or 3- to 8- membered heterocyclyl(Ci-C6 alkyl), or together with the nitrogen atom to which they are attached, form 3- to 8- membered heterocyclyl, 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R° is hydrogen, halo or C1-C6 alkyl; and
each t is independently 1 or 2.
27. A compound having the Formula (VII)
Figure imgf000161_0001
or a solvate, clathrate, hydrate or pharmaceutically acceptable salt thereof, wherein: Y is -NR2-, -0-, -S- or -S(0)t-;
R2, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’ are selected from (i), (ii) and (iii) as follow:
(i) R2 is hydrogen, C6-C10 aryl(Ci-C6 alkyl) or 5- to 10- membered heteroaryl(Ci-C6 alkyl); and R4a,R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each independently hydrogen or halogen;
(ii) R4a and R6a, together with the carbon atom to which they are attached, form C6-C10 aryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and -RuORx ; and R2,R3a, R3b, R5a, R5b, R7a and R7b, are each independently hydrogen or halogen; and (iii) R2 and R4a or R2 and R5a together with the carbon atom to which they are attached, form C6-C10 aryl or 5- to 10- membered heteroaryl optionally substituted with one to four Q groups each independently selected from halogen, C1-C6 alkyl, C6-C10 aryl(Ci-C6 alkyl), 5- to 10- membered heteroaryl(Ci-C6 alkyl) and -RuORx; and the and the remainder of R4a, R4b, R5a, R5b, R6a, R6b, R7a and R71’, are each independently hydrogen or halogen;
each Ru is independently a direct bond, C1-C6 alkylene or C2-C6 alkenylene;
each Rx is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8- membered cycloalkyl, 3- to 8- membered cycloalkyl(Ci-C6 alkyl), C6-C10 aryl, C6-C10 aryl(Ci-C6 alkyl), 3- to 8- membered heterocyclyl, 3- to 8- membered heterocyclyl(Ci-C6 alkyl), 5- to 10- membered heteroaryl or 5- to 10- membered heteroaryl(Ci-C6 alkyl);
R° is hydrogen, halo or C1-C6 alkyl; and
each t is independently 1 or 2.
28. The compound of claim 1 selected from:
(3-(methylsulfonyl)phenyl)(2-(piperidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
l-(4-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)piperazin-l-yl)ethan-l-one;
(2-(4-methylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
tert-butyl 4-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)piperazine-l-carboxylate;
tert-butyl 2-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)octahydro-5H-pyrrolo[3,4- c]pyridine-5-carboxylate;
tert-butyl 5-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole- 2(lH)-carboxylate;
(3-(methylsulfonyl)phenyl)(2-(l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)thiazol-
5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)thiazol-5- yl)methanone;
(2-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(piperazin-l-yl)thiazol-5-yl)methanone;
(2-(2-(pyridin-3-yl)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(5-benzyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-phenylpiperidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-phenylpyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-phenylpiperidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-phenylpyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(pyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone (2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(R)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(S)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(4-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(pyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethoxy)phenyl)methanone;
N,N-dimethyl-3-(2-(pyrrolidin-l-yl)thiazole-5-carbonyl)benzenesulfonamide;
(2-(3-(pyridin-2-yl)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(3-(pyridin-3-yl)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (3-bromophenyl)(2-(pyrrobdin-l-yl)thiazol-5-yl)methanone;
(2-(3 ,3 -dimethy l-2-(pyridin-3 -y l)azetidin- 1 -yl)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
3-(2-(3-fluoropyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(S)-3-(2-(3-fluoropyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(R)-3-(2-(3-fluoropyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-hydroxypyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(S)-3 -(2-(3 -hy droxypyrrolidin- 1 -y l)thiazole- 5-carbonyl)benzonitrile;
(R)-3-(2-(3-hydroxypyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(isoindobn-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(4-hy droxy-3 -(1 H-pyrazol- 1 -yl)piperidin- 1 -y l)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
(2-(3 -hy droxy-4-( 1 H-pyrazol- 1 -yl)piperidin- 1 -y l)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
(2-(3 -hy droxy-4-( 1 H-pyrazol- 1 -y l)pyrrolidin- 1 -y l)thiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
3-(2-(l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-azabicyclo[3.1.0]hexan-3-yl)thiazole-5-carbonyl)benzonitrile;
(2-(pyrrolidin- 1 -yl)thiazol-5-yl)(3 -(pyrrolidin- 1 -ylsulfonyl)phenyl)methanone; (3-(morpholinosulfonyl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
3-(2-(2-phenylpyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(2-phenylpiperidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(2-(2-phenylazetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
3-(2-(3-(hydroxymethyl)pyrrobdin-l-yl)thiazole-5-carbonyl)benzonitrile;
(S)-3-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(R)-3-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(2-(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3,3-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3,4-dimethoxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-((3S,4R)-3,4-dimethoxypyrrobdin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3-methoxypyrrobdin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3 -( 1 H-pyrazol- 1 -y l)pyrrobdin- 1 -y l)thiazol-5-y 1)(3 - (methylsulfonyl)phenyl)methanone;
(2-(3,3-dimethylpyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-chlorophenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone
(2-(2-oxa-7-azaspiro[4.4]nonan-7-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-fluoropiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(4-fluoropiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(4,4-difluoropiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(2-azabicyclo[2.2.1]heptan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
l-(5-(3-(trifluoromethyl)benzoyl)thiazol-2-yl)pyrrobdin-3-one;
(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (3-(methylsulfonyl)phenyl)(2-(3-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-2-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(3-(trifluoromethyl)phenyl)(2-(3-(trifluoromethyl)piperidin-l-yl)thiazol-5-yl)methanone;
(3-(trifluoromethyl)phenyl)(2-(4-(trifluoromethyl)piperidin-l-yl)thiazol-5-yl)methanone;
(2-(3-(difluoromethoxy)azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(2-azabicyclo[3.1.0]hexan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-((lR,5S)-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-morpholinothiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-(hydroxymethyl)-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
rac-(2-((3S*,4S*)-3-(hydroxymethyl)-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(2-azabicyclo[2.1.1 ]hexan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-((3S,4R)-3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(azetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-methoxyazetidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((R)-3 -fluoropyrrolidin- 1 -yl)thiazol-5 -yl)(3 - ((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((S)-3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((R)-3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-((S)-3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfinyl)phenyl)methanone;
(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3-((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(3 -fluoropyrrolidin- 1 -yl)thiazol-5 -yl)(3 - ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(3-fluoropyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-(benzylthio)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(benzylsulfonyl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(pyrrolidin-l-yl)thiazol-5-yl)(3-((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(2-azaspiro[3.3]heptan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(8-azabicyclo[3.2.1]octan-8-yl)thiazole-5-carbonyl)benzonitrile;
(2-(3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; rac-(2-((3S*,4S*)-3,4-dihydroxypyrrolidin-l-yl)thiazol-5-yl)(3-
(trifluoromethyl)phenyl)methanone;
(2-(3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-azabicyclo[2.2.2]octan-2-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(2-azabicyclo[2.2.2]octan-2-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((l S,4S)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-fluoro-3-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3,4-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-((3S,4R)-3,4-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
3-(2-(2-(pyridin-2-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-(pyridin-2-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-(pyridin-3-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-(3-(lH-pyrazol-l-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile; 3-(2-(2-(2H-tetrazol-5-yl)pyrrolidin-l-yl)thiazole-5-carbonyl)benzonitrile;
(3-(methylsulfonyl)phenyl)(2-morpholinothiazol-5-yl)methanone;
3-(2-morpholinothiazole-5-carbonyl)benzonitrile;
(2-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-fluoro-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; rac-(2-((3R*,4R*)-3-fluoro-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((3S*,4S*)-3,4-difluoropyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)thiazol-5- yl)methanone;
(3-(methylsulfonyl)phenyl)(2-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl)thiazol-5-yl)methanone;
(2-(6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2,6-dimethylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-((2S,6R)-2,6-dimethylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
3-(2-(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazole-5-carbonyl)benzonitrile;
3-(2-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl)thiazole-5-carbonyl)benzonitrile;
(2-(2-(4-fluorophenyl)pyrrolidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-bromophenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-bromophenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(S)-(3-bromophenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(l -methyl- lH-pyrazol-5-yl)phenyl)(2-(pyrrolidin-l-yl)thiazol-5-yl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone; (R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(l-methyl-lH-pyrazol-5- yl)phenyl)methanone;
(2-(2,6-dimethylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(3-methoxypiperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; (2-(l-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxy-3-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3 -hydroxypyrrolidin- 1 -y l)-4-methy lthiazol-5 -yl)(3 - (trifluoromethyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)-4-methylthiazol-5-yl)(3- (trifluoromethyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)-4-methylthiazol-5-yl)(3- (trifluoromethyl)phenyl)methanone;
(2-(2-(hydroxymethyl)piperidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carbonitrile;
(R)-l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carbonitrile;
(S)-l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carbonitrile;
(2-(3-hydroxyazetidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-(hydroxymethyl)azetidin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone; methyl l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carboxylate;
(2-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone; (R)-(2-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carboxylic acid;
l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-3-carboxamide;
N-methyl-l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-3-carboxamide;
(2-(2-methylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(2-methylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(S)-(2-(2-methylmorpholino)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(R)-(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(S)-(2-(2-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)(3-(trifluoromethyl)phenyl)methanone; methyl l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)azetidine-3-carboxylate;
(2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((3aR*,6aR*)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(2-(hydroxymethyl)pyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone; (S)-(2-(2-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(3-hydroxy-2,2-dimethylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3 -hy droxy-2-methylpyrrolidin- 1 -y l)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
rac-(2-((2R*,3R*)-3-hydroxy-2-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((2S,3R)-3-hydroxy-2-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3 -hy droxy-4-methylpyrrolidin- 1 -y l)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
rac-(2-((3R*,4S*)-3-hydroxy-4-methylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(isopropylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(isopropylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(isopropylsulfonyl)phenyl)methanone;
5-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)hexahydro-lH-furo[3,4-c]pyrrol-l-one;
(2-(hexahydrofuro[3,2-b]pyridin-4(2H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((l S*,5R*,6R*)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((l S*,5R*,6S*)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((l S*,5R*,6R*)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-(3-hydroxy-4-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((3R*,4R*)-3-hydroxy-4-methylpyrrobdin-l-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2- (7 -hydroxy- 5 -azaspiro [2.4] heptan- 5 -y l)thiazol- 5 -y 1) (3 - (methylsulfonyl)phenyl)methanone;
(2-(4-hydroxy-3,3-dimethylpyrrolidin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(hexahydrofuro[2,3-c]pyridin-6(2H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(phenylsulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(phenylsulfonyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)(3-(phenylsulfonyl)phenyl)methanone;
(3-(ethylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(ethylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(S)-(3-(ethylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(cyclopropylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(cyclopropylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(S)-(3-(cyclopropylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(3-(cyclobutylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(cyclobutylsulfonyl)phenyl)(2-(3-hydroxypyrrolidin-l-yl)thiazol-5-yl)methanone;
(S)-(3-(cyclobutylsulfonyl)phenyl)(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)methanone;
(2-(3-hydroxypyrrobdin-l -yl)thiazol-5-yl)(3-((l -methyl- lH-pyrazol-4- yl)sulfonyl)phenyl)methanone;
(R)-(2-(3-hydroxypyrrobdin-l-yl)thiazol-5-yl)(3-((l-methyl-lH-pyrazol-4- yl)sulfonyl)phenyl)methanone;
(S)-(2-(3 -hydroxypyrrobdin- 1 -y l)thiazol- 5-y 1)(3 -((1 -methyl- 1 H-pyrazol-4- yl)sulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-3-yl)pyrrobdin-l-yl)thiazol-5-yl)methanone;
(R)-(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-3-yl)pyrrobdin-l-yl)thiazol-5- yl)methanone;
(S)-(3-(methylsulfonyl)phenyl)(2-(2-(pyridin-3-yl)pyrrolidin-l-yl)thiazol-5-yl)methanone
(3-(pentafluoro- 6-sulfanyl)phenyl)(2-(pyrrolidin- l -yl)thiazol-5-yl)methanone;
2-(3-hydroxypyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro-/J5-sulfanyl)phenyl)methanone; (R)-(2-(3-hydroxypyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro- 6- sulfanyl)phenyl)methanone;
(S)-(2-(3-hydroxypyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro- 6- sulfanyl)phenyl)methanone;
2-(3 -(hy droxymethy l)pyrrolidin- 1 -yl)thiazol-5 -yl)(3 -(pentafluoro-/J5- sulfanyl)phenyl)methanone;
(R)-(2-(3-(hydroxymethyl)pyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro-/J5- sulfanyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)pyrrolidin- l -yl)thiazol-5-yl)(3-(pentafluoro- 6- sulfanyl)phenyl)methanone;
2-(2-(methoxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(S)-(2-(2-(methoxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(2-(methoxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
4-hydroxy-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-2- carboxylic acid;
(2R,4S)-4-hydroxy-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-2- carboxylic acid;
(25.45)-4-hydroxy-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-2- carboxylic acid;
4-fluoro-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrobdine-2-carboxybc acid;
(25.45)-4-fluoro-l-(5-(3-((trifluoromethyl)sulfonyl)benzoyl)thiazol-2-yl)pyrrolidine-2- carboxamide;
(2-(2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-(4-hydroxy-2-methylpyrrobdin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(2-((2R,4S)-4-hydroxy-2-methylpyrrobdin-l-yl)thiazol-5-yl)(3- ((trifluoromethyl)sulfonyl)phenyl)methanone;
2-(2-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
(R)-(2-(2-(hydroxymethyl)pyrrolidin-l-yl)thiazol-5-yl)(3-
((trifluoromethyl)sulfonyl)phenyl)methanone;
2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((3aS,6aS)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lS,5R,6S)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,5S,6R)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lS,5R,6R)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,5S,6S)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzyl- 1 ,4-diazepan- 1 -yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzoylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(6-chloro-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
N-(l-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)piperidin-4-yl)benzamide;
(2-(3,4-dihydro-2,7-naphthyridin-2(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(4-(benzo[d]isoxazol-3-yl)piperazin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((4aS* ,7aR* )-6-benzy loctahydro- 1 H-pyrrolo[3 ,4-b]pyridin- 1 -yl)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
rac-(2-((2S * , 5R* )-4-benzyl-2, 5-dimethylpiperazin- 1 -yl)thiazol-5-y 1)(3 - (methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(4-(l-phenylethyl)piperazin-l-yl)thiazol-5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl)thiazol-5-yl)methanone;
(2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
rac-(2-((lS*,4S*)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(l -benzyl- l,7-diazaspiro[4.4]nonan-7-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
(2-(3 -benzyl-3 , 8-diazabicyclo [3.2.1] octan-8-yl)thiazol-5 -y 1)(3 - (methylsulfonyl)phenyl)methanone;
(2-((lR,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-((lR,3s,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzyl-3-(hydroxymethyl)piperazin-l-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(4-benzylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(2-(7, 8-dihydro- [1,3] dioxolo [4,5 -g] isoquinolin-6(5H)-y l)thiazol-5-y 1)(3 - (methylsulfonyl)phenyl)methanone; (2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
ethyl 5-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylate;
(2-(2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(2-benzyl-2,7-diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(5-chloro-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(7,8-dihydro-l,6-naphthyridin-6(5H)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(3 -(methy lsulfony l)pheny l)(2-( 1 ,2,3,5 -tetrahy dro-4H-benzo[e] [1,4] diazepin-4-y l)thiazol- 5-yl)methanone;
(3-(methylsulfonyl)phenyl)(2-(3-phenylmorpholino)thiazol-5-yl)methanone;
(S)-(3-(methylsulfonyl)phenyl)(2-(3-phenylmorphobno)thiazol-5-yl)methanone;
(2-(4-methyl-2-phenylpiperazin-l-yl)thiazol-5-yl)(3-(methylsulfonyl)phenyl)methanone;
(3-(methylsulfonyl)phenyl)(2-(4-(pyridin-3-ylmethyl)piperazin-l-yl)thiazol-5- yl)methanone;
(2-(6-(hydroxymethyl)-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
(2-(l -methyl-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone;
4-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)-3-phenylpiperazin-2-one;
(3 -(hydroxymethy l)-3 ,4-dihy droisoquinolin-2( 1 H)-yl)thiazol-5 -yl)(3 - (methylsulfonyl)phenyl)methanone;
(S)-(2-(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(lH)-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone;
2-(5-(3-(methylsulfonyl)benzoyl)thiazol-2-yl)isoindobne-5-carbonitrile;
2-(3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3- (methylsulfonyl)phenyl)methanone; and (2-((lR,3s,5S)-3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)(3-
(methylsulfonyl)phenyl)methanone.
29. A pharmaceutical composition comprising the compound of any of Claims 1 to 28, or a solvate, hydrate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
30. A method for the treatment of a disease or condition selected from: an inflammatory bowel disease, a colorectal cancer, and a gastritis, comprising administering a therapeutically effective amount of a compound of any of claims 1 to 28, or a solvate, hydrate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, to a subject in need thereof.
31. The method of claim 30 wherein the inflammatory bowel disease is ulcerative colitis or Crohn’s disease.
32. A method of inhibiting vanin activity, comprising contacting a cell with a compound of any of claims 1 to 28, or a solvate, hydrate or a pharmaceutically acceptable salt thereof, such that vanin activity in the cell is inhibited.
33. The method of claim 32, wherein the cell is an epithelial cell.
34. The method of claim 32 or 33, wherein the vanin activity is activity from vanin-1, vanin-2, vanin-3, or any combination thereof.
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