WO2020102575A1 - Aminothiazoles hétérocycliques et leurs utilisations - Google Patents

Aminothiazoles hétérocycliques et leurs utilisations Download PDF

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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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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/fr

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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.

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Abstract

La présente invention concerne des composés de formule (I) et des sels, solvates et sels de solvates pharmaceutiquement acceptables, des compositions pharmaceutiques contenant des composés de formule (I), ainsi que l'utilisation de composés de formule (I) pour le traitement de maladies intestinales inflammatoires, telles que la maladie de Crohn et la colite ulcéreuse.
PCT/US2019/061532 2018-11-16 2019-11-14 Aminothiazoles hétérocycliques et leurs utilisations WO2020102575A1 (fr)

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WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène
WO2023039602A1 (fr) * 2021-09-13 2023-03-16 Montelino Therapeutics, Inc. Composés bi-fonctionnels et procédés d'ubiquitination ciblée de récepteur des androgènes
WO2023039601A1 (fr) * 2021-09-13 2023-03-16 Montelino Therapeutics, Inc. Composés bi-fonctionnels et procédés d'ubiquitination ciblée du récepteur des androgènes
WO2023039603A3 (fr) * 2021-09-13 2023-04-13 Montelino Therapeutics, Inc. Composés bi-fonctionnels et procédés d'ubiquitination ciblée du récepteur des androgènes
WO2023132208A1 (fr) * 2022-01-07 2023-07-13 国立大学法人大阪大学 Composition pharmaceutique destinée à prévenir ou à traiter l'insuffisance cardiaque
US11787778B2 (en) 2019-01-30 2023-10-17 Montelino Therapeutics, Inc. Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

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