EA042453B1 - CONNECTIONS AS TLR2 ALARM MODULATORS - Google Patents

Description

Cross-reference to related applications

This application claims priority from U.S. Provisional Application No. 62/648879, filed March 27, 2018, titled COMPOUNDS AS MODULATORS OF TLR2 SIGNALING, the contents of which are incorporated herein by reference in their entirety for all purposes.

Technical field

The present invention relates to compounds, pharmaceutical compositions containing such compounds, and to the use of such compounds in methods of treatment or in drugs for the treatment of inflammatory diseases and certain neurological disorders that are associated with inflammatory signaling, including, without limitation, misfolded proteins.

State of the art

Toll-like receptors (TLRs) are signaling receptors of the immune system. When these receptors are activated on cell surfaces, they initiate the recruitment of a family of adapter proteins containing TIR domains and inducing a signaling cascade that ultimately leads to cell-type-specific inflammatory responses, which causes an increase in the level of pro-inflammatory mediators such as IL1, IL6, IL8 and TNFa. Among the various TLR receptors that are expressed on mammalian cells, TLR2 forms heterodimers with TLR1 or TLR6 to initiate inflammatory responses to various microbial ligands. Among the various bacterial ligands are lipopolysaccharides (LPS), acylated lipopeptides, lipoglycans, peptidoglycans, porins, glycosylphosphatidylinositol anchors, as well as other components of the bacterial cell wall, such as pneumococcal lipoteichoic acid (LTA). In addition to microbial TLR2 activation, it has also been found that abnormal aggregation of neuronal-released oligomeric proteins such as alpha-synuclein (aSyn) may trigger similar inflammatory responses in animal models of neurodegenerative diseases, including Parkinson's disease (PD), dementia with bodies Levi, multiple system atrophy (MSA - multiple systems atrophy) and Alzheimer's disease (AD - Alzheimer's disease). See, for example, Kim et al., Nat. commun. 2013, 4, 1562.

The ability of TLR2 to induce signaling through heterodimers allows discrimination between different recognition patterns, allowing the design of ligands with specific inhibition patterns. Kajava et al., J. Biol. Chem. 2010, 285, 6227. Thus, inhibitors that compete primarily with a specific pathological agonist, such as oligomeric pathogenic alpha-synuclein, but do not affect other ligands involved in pro-inflammatory signaling of bacterial or viral pathogens, will be suitable as potential therapeutic agents. infections, or non-competitive inhibitors of TIR-Myd88, such as compounds that indirectly function as non-competitive inhibitors of TLR2 through intracellular inhibition of TIR-Myd88.

The function of toll-like receptors has been associated with various protein folding, protein dimerization, and inflammatory processes, as well as associated diseases such as Alzheimer's disease (Gambuzza, M. et al., Toll-like receptors in Alzheimer's disease: a therapeutic perspective, CNS Neurol Disord Durg Targets, 2014, 13(9), 1542-58), Beraud, D. et al., Misfolded α-synuclein and Toll-like receptors: therapuetic targets for Parkinson's disease , Parkinsonism Relat. Disord. 2012, 18 (Suppl. 1), S17-20), frontotemporal dementia, Lewy body dementia (Lewy body disease), multiple system atrophy (Vieira, B. et al., Neuroinflammation in multiple system atrophy: Response to and cause of α-synuclein aggregation, Front Cell Neurosci 2015, 9, 437), amyotrophic lateral sclerosis (Casula, M. et al., Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue, Neuroscience, 2011, 179, 233-43), more Huntington's disease (Kalathur, R.K.R. et al., Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database, BMC Neurology, 2012, 12, 47), inflammatory diseases, asthma, and chronic obstructive pulmonary disease (COPD) (Zuo, L et al., Molecular regulation of Toll-like receptors in asthma and COPD, Front Physiol. 2016, 6, 312), chronic peptic ulcers (Smith, S., Roll of Toll-like receptors in Helicobacter pylori infection and immunity, World J. Gastrointest. Pathophysiol. 2014, 5(3), 133-146), tuberculosis (Harding, C.V. et al., Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors, Nat. Rev. Microbiol. 2010, 8(4), 296307), rheumatoid arthritis (Huang, Q.-Q. et al., Roll of Toll like receptors in rheumatoid arthritis, Curr. Rheumatol. Rep. 2009, 11(5), 357-364) , chronic sinusitis (Zhang, Q. et al., Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal p olyps, Acta Otolaryngol. 2013, 133(2), 165-173), hepatitis (including hepatitis B and C) (Zhang, E. et al., Toll-like receptor (TLR)-mediated innate immune responses in control of hepatitis B vims (HBV) infection, Med. Microbiol. Immunol. 2015, 204(1), 11-20; Howell, J. et al., Toll-like receptors in hepatitis C infection: implications for pathogenesis and treatment, J. Gastroenterol. Hepatol. 2013, 28(5), 766-776), gout, lupus, psoriasis, psoriatic arthritis (Santegoets, K.C.M. et al., Toll-like receptors in rheumatic diseases: are we paying a high price for our

- 1 042453 defense against bugs? FEBS Letters 2011, 585(23), 3660-3666), vasculitis, laryngitis, pleurisy (Chen, X. et al., Engagement of Toll-like receptor 2 on CD4(+) T cells facilitates local immune responses in patients with tuberculous pleurisy, J. Infect. Dis. 2009, 200(3), 399-408), eczema (Miller, L.S., Toll-like receptors in skin, Adv. Dermatol. 2008, 24, 71-87), gastritis (Schmausser, B. et al., Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori, Int. J. Med. Microbiol. 2005, 295(3), 179-85), vasculitis ( Song, G. G. et al., Toll-like receptor polymorphisms and vasculitis susceptibility: meta-analysis and systematic review, Mol. Biol. Rep. 2013, 40(2), 1315-23), laryngitis (King, S. N. et al., Characterization of the Leukocyte Response in Acute Vocal Fold Injury, PLoS One, 2015; 10(10):e0139260), Gangloff, S.C. et al., Toll-like receptors and immune response in allergic disease, Clin. Rev. Allergy Immunol 2004, 26(2), 115-25), multiple sclerosis (Miranda-Hernandez, S. et al., Role of toll-like receptors in multiple sclerosis, Am. J.Clin. Exp. Immunol. 2013, 2(1), 75-93), Crohn's disease (Cario, E., Toll-like receptors in inflammatory bowel diseases: A decade later, Inflamm. Bowel Dis. 2010, 16(9), 1583-1597) and traumatic brain injury (Hua, F. et al., Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone, J. Neuroinflammation, 2011, 8, 42).

The TLR2 signal transduction pathway can be activated by an external domain (agonist pocket) or by mechanisms involving the cytoplasmic domain of TIR, which mediates homotypic and heterotypic signaling interactions. The proteins MyD88 and TIRAP (Mal) are involved in this type of signaling.

It is important to note that the conserved proline P681 in TLR2 within the BB loop (Brown V. et al. (2006), European Journal of immunology, 36, 742-753) is involved in the dimerization mechanism. A mutation in this loop from P681H terminates MyD88 recruitment and signaling. Thus, compounds that bind close to this loop and restrict its movement during the dimerization process will be useful as inhibitors of TLR2 activation.

This document describes compounds that serve as TLR2 antagonists with high potency and selectivity.

The essence of the invention

In one aspect, provided herein is a compound of formula (A)

or a tautomer, or a pharmaceutically acceptable salt of any of the foregoing,

C ' where indicates that the ring is saturated, partially unsaturated or completely unsaturated;

t YI _h ,G ₇ .R ⁵ ? indicates that ^Gs is attached to the E or Z configuration;

G ₁ and G2 are each independently CR ^x or N;

R ^x is hydrogen or halogen;

one of R ¹ and R ² is -OH and the other is selected from the group consisting of:

(a) -C(O)R ^a , (b) -CH=NR ^j , (c) -S(O)R ^b , (d) -S(O)2R ^c , (e) -NHC(O) R ^d , (f) -NHS(O)2R ^e , (g) -C1-C6-alkyl-R ^f , (h) -C ₂ -C ₆ -alkenyl-R ^g , (i) C ₃ -C ₈ -cycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of =O, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, halogen, -OH, -C(O)H, -C (O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl, (j) C ₃ -C ₈ -cycloalkenyl, unsubstituted or substituted 1 -5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH,

- 2 042453

-C(O)OC1-C6-alkyl, -OC1-C6-alkyl and _C3 - _C8 -cycloalkyl, and (k) heterocycloalkyl unsubstituted or substituted with 1-5 substituents selected from the group consisting of C1- _C6 -alkyl, C1-C ₆ -haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl;

R ^a , R ^b , R ^c and R ^e are each independently:

(a) H, (b) C1- _C6 -alkyl, (c) _C2 - _C6- alkenyl, (d) _C2 -C6 alkynyl, (e) C1-C6-haloalkyl, (f) 3- 10-membered heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C 1 -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, = 0 and -C (O) O - (C ₁ -C ₆ -alkyl), (g) 5-18 membered heteroaryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C1-C6-alkyl, C ₃ -C ₈ -cycloalkyl and -C(O)O-( C ₁ -C ₆ -alkyl), (h) benzoyl or (i) styryl;

^Rd is:

(a) H, (b) C1- _C6 alkyl, (c) _C2 - _C6 alkenyl, (d) _C2 -C6 alkynyl, (e) C1-C6 haloalkyl, (f) heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(0) 0(C1-C6-alkyl), -0(C1-C6-alkyl) and _C3 - _C8- cycloalkyl, (g) heteroaryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C1- _C6 -alkyl, C1-C ₆ -haloalkyl, halogen, -OH, -C (O) H, -C (O) OH, -C (O) O (C ₁ -C ₆ -alkyl), -O (C ₁ -C ₆ -alkyl) and C ₃ -C ₈ -cycloalkyl, or (h) benzoyl;

R ^f and R ^g are each independently -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl or styryl;

R ^m and R ⁿ are each independently H, C1- _C6 alkyl, _C2 -C6-alkenyl, _C2 -C6-alkynyl, or C3-C8-cycloalkyl, unsubstituted or substituted with 1-5 substituents selected from a group consisting of C1-C6-alkyl, C1-C6-haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(0)0C1-C6-alkyl, -0C1-C6 -alkyl and C ₃ -C ₈ -cycloalkyl;

RJ is:

(a) 5-6 membered heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C1- _C6 alkyl, _C3 - _C8 cycloalkyl, =O and -C(O)O-( C ₁ -C ₆ -alkyl), (b) C ₆ -C ₁₂ -aryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C 1 -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and - C(O)O-(C ₁ -C ₆ -alkyl), (c) -OR ^k , (d) -NHR ^k , (e) -NHC(O)R ^k , (f) -NHS(O)2R ^k or (g) -NHC(NH)NH2;

R ^k is C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, or C 6 -C 18 aryl;

R ³ is H, C1-C ₆ alkyl, C1-C ₆ alkoxy, or halo, where C1-C ₆ alkyl and C1-C ₆ alkoxy of R ³ are each independently unsubstituted or substituted 1-5 halogens;

Where:

when R ¹ or R ² is -(C1-C6 alkyl)-OH or -(C1-C6 alkyl)-NR ^m R ⁿ , where R ^m and R ⁿ are each C1-C6 alkyl, R ³ is selected from the group consisting of C 1 -C ₆ -alkyl, C ₂ -C ₆ -alkoxy and halogen;

when R ¹ or R ² is unsubstituted or substituted C3-C8 cycloalkyl, -NHC(O)CH3 or -S(O)2- R ^c , where R ^c is unsubstituted or substituted heterocyclyl, R ³ is selected from the group, consisting of C1-C6 alkyl, C1-C ₆ alkoxy and halogen;

when R ¹ or R ² is -CHO, R ³ is selected from the group consisting of hydrogen, C2-C6 alkoxy and halogen;

when R ¹ or R ² is —C(O)CH3, R ³ is selected from the group consisting of C2- _C6 alkoxy and halogen;

when R ¹ or R ² is -C(O)CH(Br)CH ₃ or -C(O)CH(Br)CH ₂ CH ₃ , G7 is C or CH;

- 3 042453 when R ³ is hydrogen, not more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CF3, not more than one of R ^6a , R ^6b , R ^6c and R ^6d is - CH3 and not more than one of R ^6a , R ^6b , R ^6c and R ^6d is -OH;

Y is -C(O)- or absent, and R ⁴ and R ⁵ are each H or

Y is absent, and R ⁴ and R ⁵ combine to form -S-;

G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S or O;

G ₄ is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O;

G5 is CH(X3-R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O;

G ₆ is CH(X ₄ -R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent;

G7 is N, C or CH;

where, when G ₅ is N, at least one of (i), (ii) and (iii) applies:

(i) at least one of G ₃ , G ₄ and G ₆ is not CH;

(ii) R ⁴ and R ⁵ combine to form -S-;

(iii) R ³ is -OCH ₃ or halogen;

X1, X ₂ , X ₃ and X ₄ are each independently absent, are ^{m or m} ' m is 1-6;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpRq, C6-C18-aryl, heterocyclyl, heteroaryl, - (C1-C6-alkyl)heterocyclyl, -OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O) 2R ^z2 where C1-C6 alkyl and C1-C6 alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with 1-5 groups selected from the group consisting of C3-C ₁₀ -cycloalkyl and halogen; C ₆ -C ₁₈ aryl and heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with 1-5 groups selected from the group consisting of C1-C6 alkyl, C1-C6- alkoxy, -OH and -(C1-C6 alkyl)-OH; and heterocyclyl, -(C1-C6-alkyl)-heterocyclyl and -OC(O)-heterocyclyl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with 1-5 groups selected from the group, consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -OH, -(C ₁ -C ₆ -alkyl)-OH, =O and =S;

R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl and -NR ^r R ^s ;

R ^p represents H or C ₁ -C ₆ -alkyl;

R ^q is C ₂ -C ₃ -alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ;

R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C ₁ -C ₆ alkyl;

Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from:

(a) H, (b) C ₁ -C ₆ -alkyl, (c) C ₃ -C ₈ -cycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of halogen, hydroxyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl and C ₃ -C ₈ -cycloalkyl, and (d) heterocyclyl unsubstituted or substituted with 1-5 substituents selected from the group consisting of halogen, hydroxyl , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₈ cycloalkyl;

or

G5 is CH(X3-R ^6c ) or C(X3-R ^6c ), G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), and R ^6c and R ^6d are taken together with carbon atoms, to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring; where the 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl rings are each independently unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl and -C(O)O- (C ₁ -C ₆ -alkyl);

where, except where otherwise indicated, each heteroaryl independently has up to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and from 3 to 12 ring atoms;

where, except where indicated otherwise, each heterocyclyl or heterocycloalkyl independently has 1 to 10 heteroatoms selected from nitrogen, oxygen and sulfur, and has 3 to 20 ring atoms;

where no more than one of R ^6a , R ^6b , R ^6c and R ^6d is C ₁ -C ₆ -alkoxy or -OH; and where the connection is not a connection from the table. 1X.

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In another aspect, provided herein is a compound of formula (I)

or a tautomer, or a pharmaceutically acceptable salt of any of the above, wherein it indicates that the ring is saturated, partially unsaturated, or completely unsaturated;

? indicates that the ' ^G s is attached to the E- or Z-configuration;

G1 and G2 are each independently CH or N;

one of R1 and ^R2 is -OH and the other is selected from the group consisting of:

(a) -C(O)R ^a , (b) -S(O)R ^b , (c) -S(O)2R ^c , (d) -NHC(O)R ^d , (e) -NHS( O)2R ^e , (f) -C1-C6-alkyl-R ^f , (g) -C ₂ -C ₆ -alkenyl-R ^g , (h) C ₃ -C ₈ -cycloalkyl, unsubstituted or substituted 1-5 substituents selected from the group consisting of =O, C ₁ -C ₆ -alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O )OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl, (i) C ₃ -C ₈ -cycloalkenyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, halogen, -OH, -C (O) H, -C (O) OH, -C (O) OC ₁ -C _{6 -} alkyl, - OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl, and (j) heterocycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ - haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl ;

R ^a , R ^b , R ^c and R ^e are each independently:

(a) H, (b) C ₁ -C ₆ alkyl, (c) C ₂ -C ₆ alkenyl, (d) C ₂ -C ₆ alkynyl, (e) C ₁ -C ₆ haloalkyl, ( f) 3-10 membered heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, =O and -C(O)O-( C ₁ -C ₆ -alkyl), (g) 5-18 membered heteroaryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and - C(O)O-(C ₁ -C ₆ -alkyl), (h) benzoyl or (i) styryl;

^Rd is:

(a) H, (b) C ₁ -C ₆ alkyl, (c) C ₂ -C ₆ alkenyl, (d) C ₂ -C ₆ alkynyl, (e) C ₁ -C ₆ haloalkyl, ( f) heterocyclyl unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O )OH, -C(O)O(C ₁ -C ₆ -alkyl), -O(C ₁ -C ₆ -alkyl) and C ₃ -C ₈ -cycloalkyl, (g) heteroaryl, unsubstituted or substituted 1-5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)O( C ₁ -C ₆ -alkyl), -O(C ₁ -C ₆ -alkyl) and C ₃ -C ₈ -cycloalkyl, or (h) benzoyl;

R ^f and R ^g are each independently unsubstituted heteroaryl, benzoyl or styryl;

- 5 042453

R ³ represents H, C1-C ₆ alkyl, C1-C ₆ alkoxy or halogen;

R ⁴ and R ⁵ are each H or

R ⁴ and R ⁵ combine to form -S-;

G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S or O;

G4 is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O;

G5 is CH(X3-R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O;

G ₆ is CH(X4-R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent;

where, when G ₅ is N, or (i) at least one of G ₃ , G4 and G ₆ is not CH or (ii) R ⁴ and R ⁵ combine to form -S-;

X1, X ₂ , X3 and X4 are each independently absent, ^or ' m is 1-6;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen or -C(O)R ^h where C1-C ₆ is alkyl from R ^6a , R ^6b , R ^6c and R ^6d are independently unsubstituted or substituted with C ₃ -C ₈ cycloalkyl or halogen;

R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl;

where, except where otherwise indicated, each heteroaryl independently has up to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and from 3 to 12 ring atoms;

where, except where indicated otherwise, each heterocyclyl or heterocycloalkyl independently has 1 to 10 heteroatoms selected from nitrogen, oxygen and sulfur, and has 3 to 20 ring atoms; and where the connection is not a connection from the table. 1X.

In an additional aspect, this document provides pharmaceutical compositions containing at least one compound of formula (A), (I), such as the compound from table. 1, or a tautomer, or a pharmaceutically acceptable salt of any of the above, optionally further containing a pharmaceutically acceptable excipient.

In another aspect, provided herein is a method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound of formula (A), (I), such as the compound of Table . 1, or a tautomer, or a pharmaceutically acceptable salt of any of the above, and/or a pharmaceutical composition containing at least one compound of formula (A), (I), such as a compound from table. 1.

In some embodiments of any of the methods described herein, the disease or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body dementia (Lewy body disease), Parkinson's disease with dementia, multiple systemic atrophy, amyotrophic lateral sclerosis, Huntington's disease, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy), atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, trauma horn sheep, corneal disorders, Stargardt's disease (juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus (HSV), and fungal, bacterial, viral, and neoplastic diseases or conditions.

In some embodiments of any of the methods described herein, the disease or condition is selected from the group consisting of progressive supranuclear palsy (PNP), Niemann-Pick type C disease, irritable bowel syndrome, osteoarthritis, corneal HSV, stroke, and coronary heart disease. .

In yet another aspect, provided herein is a method of interfering with TLR2 heterodimerization in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound of formula (A), (I), such as the connection from the table. 1, or its tautomer, or a pharmaceutically acceptable salt of any of the above, and/or at least one pharmaceutical composition containing at least one compound of formula (A), (I), such as the compound from table. 1, and bringing into contact occurs in vitro, ex vivo or in vivo.

Additional embodiments, features and advantages of the present disclosure will become apparent from the following detailed description and by practicing the present disclosure.

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For the sake of brevity, descriptions of publications cited in this specification, including patents, are incorporated herein by reference.

Detailed Description of the Invention

The present invention relates to compounds, pharmaceutical compositions containing such compounds, and to the use of such compounds in methods of treatment or in drugs for the treatment of inflammatory diseases and certain neurological disorders that are associated with inflammatory signaling, including, without limitation, misfolded proteins.

It is to be appreciated that this description is not limited to the specific embodiments described as they may vary. It is also to be understood that the terminology used herein is for the sole purpose of describing particular embodiments and is not intended to limit the scope of the description.

Unless otherwise indicated, all technical and scientific terms used in this document have the generally accepted meanings understood by a person skilled in the art to which the present invention belongs. All patents, applications, published applications and other publications referenced in this document are incorporated by reference in their entirety. If a definition in this section is inconsistent with or otherwise inconsistent with a definition in a patent, application, or other publication that is incorporated herein by reference, the definition in this section takes precedence over the definition incorporated herein by reference. links.

The use in the present description and in the appended claims of the singular forms includes reference to the plural, unless the context clearly indicates otherwise. It should also be noted that the claims may be amended to remove any optional elements. Therefore, this statement should serve as a preliminary basis for the use of such exhaustive terminology as exclusively, only, etc. in connection with the indication of the elements of the claims, or the use of a negative feature.

In the context of this document, the terms including, containing, and consisting of are used in their open, non-restrictive sense.

To provide a more concise description, some quantitative expressions given in this document are not defined using the term about. It should be understood that whether the term about is used explicitly or not, each quantity given herein is intended to indicate an actual setpoint, and is also intended to indicate an approximation to such a setpoint that is objectively expected by one of ordinary skill in the art. , including equivalents and approximations due to experimental and/or measurement conditions for such a given value. Whenever a yield is expressed as a percentage, that yield refers to the weight of the compound for which the yield is specified relative to the maximum amount of the same compound that could be obtained under the particular stoichiometric conditions. Concentration values expressed as a percentage refer to mass ratios unless otherwise indicated.

Unless otherwise indicated, all technical and scientific terms used in this document have the generally accepted meanings understood by a person skilled in the art to which the present invention belongs. Although any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present disclosure. All publications mentioned in this document are incorporated herein by reference for the purpose of disclosing and describing the methods and/or materials in connection with which these publications are cited.

Unless otherwise indicated, the methods and techniques of the present embodiments are generally performed in accordance with conventional methods well known in the art and described in the various general and more specific references cited and discussed herein. See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, p. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

The nomenclature used herein to name the compounds of the present invention is illustrated in the examples in this document. This nomenclature has generally been generated using the commercially available ChemBioDraw Ultra software, version 14.0.

It should be understood that certain features of the present disclosure, which are described in the context of separate embodiments for clarity, may also be presented in combination as a single embodiment. Conversely, various features of the present disclosure, which for brevity are described in the context of one embodiment, may also be presented separately or in any suitable subcombination. All combinations of embodiments that refer to the chemical groups represented by the variables are expressly included herein.

- 7 042453 description and are described herein in the same way as if all combinations without exception were separately and explicitly described to the extent that such combinations cover compounds that are stable compounds (i.e. compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables are also expressly included in the present description and are described herein in the same way as if all subcombinations of chemical groups without exception were separately and explicitly described.

Connections

The compounds and their salts (such as pharmaceutically acceptable salts) are described in detail herein, including a summary of the invention and the appended claims. Also provided is the use of all compounds described herein, including any and all stereoisomers, including geometric isomers (e.g., cis/trans isomers or E/Z isomers), enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts and solvates of the compounds described herein, as well as methods for preparing such compounds. Any compound described herein may also be referred to as a drug.

In one aspect, compounds of formula (A) are provided.

or a tautomer, or a pharmaceutically acceptable salt of any of the above, G' where indicates that the ring is saturated, partially unsaturated or completely unsaturated;

T

Y _X G ₇ .R ^{5 G} O ^G 6 ,, , ? indicates that ^G s attached to the E - or Z-configuration;

G1 and G2 are each independently CR ^x or N;

R ^x is hydrogen or halogen;

one of R1 and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NR ^J , -S(O)R ^b , -S(O)2R ^c , - NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C6-alkenyl-R ⁸ , unsubstituted or substituted C3-C ₈ -cycloalkyl, unsubstituted or substituted C ₃ -C ₈ -cycloalkenyl and unsubstituted or substituted heterocycloalkyl;

R ^a , R ^b , R ^c and R ^e each independently represent H, C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C 1 -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^d is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl;

R ^f and R ^g are each independently -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl or styryl;

R ^m and R ⁿ are each independently H, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or unsubstituted or substituted cycloalkyl;

R ^J is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, -OR ^k , -NHR ^k , -NHC(O)R ^k , -NHS(O) 2 R ^k , or -NHC(NH)NH 2 ;

R ^k is C 1 -C ₆ alkyl, C ₂ -C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl;

R ³ is H, C1-C ₆ alkyl, C1-C ₆ alkoxy, or halo, where C1-C ₆ alkyl and C1-C ₆ alkoxy of R ³ are each independently unsubstituted or substituted with one or more halogens;

Where:

when R ¹ or R ² is -C1-C6 alkyl-OH or -C1-C6 alkyl-NR ^m R ⁿ , where R ^m and R ⁿ are each C1-C6 alkyl, R ³ is selected from a group consisting of C 1 -C ₆ -alkyl, C ₂ -C ₆ -alkoxy and halogen;

when R ¹ or R ² is unsubstituted or substituted C3-C8 cycloalkyl, -NHC(O)CH3 or -S(O)2-R ^c , where R ^c is unsubstituted or substituted heterocyclyl, R ³ is selected from the group, consisting of C1-C6 alkyl, C1-C ₆ alkoxy and halogen;

- 8 042453 when R ¹ or R ² represents -CHO, R ³ is selected from the group consisting of hydrogen, C ₂ -C ₆ -alkoxy and halogen;

when R ¹ or R ² is -C(O)CH3, R ³ is selected from the group consisting of C2-C ₆ -alkoxy and halogen;

when R ¹ or R ² is -C(O)CH(Br)CH ₃ or -C(O)CH(Br)CH ₂ CH ₃ , G ₇ is C or CH;

when R ³ is hydrogen, no more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CF ₃ , no more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CH3 and no more than one of R ^6a , R ^6b , R ^6c and R ^6d is -OH,

Y is -C(O)- or absent, and R ⁴ and R ⁵ are each H or

Y is absent, and R ⁴ and R ⁵ combine to form -S-;

G3 is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S or O;

G4 is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O;

G5 is CH(X3-R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O;

G6 is CH(X4-R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent;

G ₇ is N, C or CH;

where, when G ₅ is N, at least one of (i), (ii) and (in) applies:

(i) at least one of G3, G4 and G6 is not CH;

(ii) R ⁴ and R ⁵ combine to form -S-;

(iii) R ³ is -OCH3 or halo;

X1, X ₂ , X3 and X4, each independently absent, are m equal to 1-6;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, -C1 -C ₆ -alkyl-heterocyclyl, -OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 where C1-C6 alkyl and C1-C6 alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; aryl and heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, -OH and C1 -C6-alkyl-OH; and heterocyclyl, -C1-C6-alkyl-heterocyclyl and -OC(O)-heterocyclyl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl, _C1 - _C6 alkoxy, -OH, _C1 - _C6 alkyl-OH, ═O and ═S;

R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl and -NR ^r R ^s ;

R ^p represents H or C ₁ -C ₆ -alkyl;

R ^q is C ₂ -C ₃ -alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ;

R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C ₁ -C ₆ alkyl;

And ¹ ' R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl; or

G ₅ is CH(X ₃ -R ^6c ) or C(X ₃ -R ^6c );

G6 is CH(X4-R ^6d ) or C(X4-R ^6d );

R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring, where 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl ring , each independently, are unsubstituted or substituted;

where no more than one of R ^6a , R ^6b , R ^6c and R ^6d is C ₁ -C ₆ -alkoxy or -OH;

where the connection is not a connection from the table. 1X.

In some embodiments of formula (A)

G' indicates that the ring is saturated, partially unsaturated or completely unsaturated;

indicates attached to E- or Z-configuration;

G1 and G2 are each independently CR ^x or N;

R ^x is hydrogen or halogen;

one of R1 and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NR ^j , -S(O)R ^b , -S(O)2R ^c , - NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g unsubstituted or substituted C ₃ -C ₈ -cycloalkyl, unsubstituted or substituted C ₃ -C ₈ -cycloalkenyl and unsubstituted or substituted heterocycloalkyl;

- 9 042453

R ^a , R ^b , R ^c and R ^e are each independently H, C ₁ -C ₆ alkyl, C ₂ -C 6 alkenyl, C ₂ -C 6 alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^d is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl;

Rf and R ^g are each independently -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl or styryl;

R ^m and R ⁿ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or unsubstituted or substituted cycloalkyl;

R ^j is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, -OR ^k , -NHR ^k , -NHC(O)R ^k , -NHS(O) 2 R ^k , or -NHC(NH)NH 2 ;

R ^k is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl;

R ³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or halo, where C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy of R ³ are each independently unsubstituted or substituted with one or more halogens;

Y is -C(O)- or absent, and R ⁴ and R ⁵ are each H or

Y is absent, and R ⁴ and R ⁵ combine to form -S-;

G3 is CH(X _r R ^6a ), C(XrR ^6a ), N,N(XrR ^6a ), S or O;

G ₄ is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O;

G5 is CH(X3-R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O;

G6 is CH(X4-R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent;

G7 is N, C or CH;

where, when G ₅ is N, at least one of (i), (ii) and (iii) applies:

(i) at least one of G3, G4 and G6 is not CH;

(ii) R ⁴ and R ⁵ combine to form -S-;

(iii) R ³ is -OCH3 or halo;

X1, X ₂ , X3 and X ₄ are each independently absent, ^or ' m is 1-6;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, -C1-C ₆ -alkyl-heterocyclyl, -OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 , where C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen ;

aryl and heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, -OH and C1 -C6-alkyl-OH; and heterocyclyl, -C1-C6-alkyl-heterocyclyl and -OC(O)-heterocyclyl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl, _C1 - _C6 alkoxy, -OH, _C1 - _C6 alkyl-OH, ═O and ═S;

R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, and -NR ^r R ^s ;

R ^p represents H or C ₁ -C ₆ -alkyl;

R ^q is C ₂ -C ₃ -alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ;

R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C ₁ -C ₆ alkyl;

Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl; or

G5 is CH(X3-R ^6c ) or C(X3-R ^6c );

G6 is CH(X4-R ^6d ) or C(X4-R ^6d );

R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring, where 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl ring , each independently, are unsubstituted or substituted;

where no more than one of R ^6a , R ^6b , R ^6c and R ^6d is C ₁ -C ₆ -alkoxy or -OH;

where the connection is not a connection from the table. 1X.

In some embodiments of formula (A), one or more of the following apply:

(1) when R ¹ or R ² is -C1-C6 alkyl-OH or -C1-C6 alkyl-NR ^m R ⁿ , where R ^m and R ⁿ are each C1-C ₆ alkyl, R ³ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkoxy and halogen;

(2) when R ¹ or R ² is unsubstituted or substituted C3-C8-cycloαalkyl, -NHC(O)CH3 or -S(O)2-R ^c , where R ^c is unsubstituted or substituted heterocyclyl, R ³ is selected from the group consisting of C1- _C6 alkyl, _C1 - _C6 alkoxy and halo;

(3) when R ¹ or R ² is -CHO, R ³ is selected from the group consisting of hydrogen, C ₂ -C ₆ -alkoxy and halogen;

- 10 042453 (4) when R ¹ or R ² represents -C(O)CH 3 , R ³ is selected from the group consisting of C 2 -C ₆ -alkoxy and halogen;

(5) when R ¹ or R ² is -C(O)CH(Br)CH ₃ or -C(O)CH(Br)CH ₂ CH ₃ , G7 is C or CH; and (6) when R ³ is hydrogen, no more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CF3, no more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CH3 and not more than one of R ^6a , R ^6b , R ^6c and R ^6d is -OH.

In some embodiments of formula (A), Y is -C(O)- and R ⁴ and R ⁵ are each H. In some embodiments, Y is absent and R ⁴ and R ⁵ are each H In other embodiments, Y is absent and R ⁴ and R ⁵ combine to form -S-.

In some embodiments of Formula (A), G1 and G2 are each independently CR ^x , where R ^x is H or halogen. In some embodiments, G1 and G2 are each independently CH, CF, CCl, or CBr. In some embodiments, G1 and G2 are each CH. In a particular embodiment, G1 is CF and G2 is CH. In another embodiment, G1 is CH and G2 is CF. In some embodiments, G1 is CR ^x and G2 is N. For example, in some embodiments, G1 is CH, CF, CCl, or CBr, and G ₂ is N. In some embodiments, G1 is N, a G ₂ is CR ^x . For example, in some embodiments, G ₁ is N and G ₂ is CH, CF, CCl, or CBr. In other embodiments, G1 and G2 are each N.

In some embodiments, when any particular group is substituted, said group is substituted with one or more substituents selected from the group consisting of oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , halogen, -CN, -OR ^A1 , -SR ^A1 , -NR ^A2 R ^A3 , -NO ₂ , -C=NH(OR ^a1 ), -C(O)R ^a1 , -OC(O)R ^a1 , - C(O)OR ^a1 , -C(O)NR ^A2 R ^A3 , -OC(O)NR ^A2 R ^A3 , -NR ^a1 C(O)R ^A2 , -NR ^a1 C(O)OR ^A2 , -NR ^A1 C(O)NR ^A2 R ^A3 , -S(O)R ^a1 , -S(O)2R ^a1 , -NR ^a1 S(O)R ^A2 , -C(O)NR ^a1 S(O)R ^A2 ,

-NR ^a1 S(O)2R ^A2 , -C(O)NR ^a1 S(O)2R ^A2 , -S(O)NR ^A2 R ^A3 , -S(O)2NR ^A2 R ^A3 , -P(O)( OR ^A2 )(OR ^A3 ), C3-C8-cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C6-C14-aryl, -(C1-C3-alkylene)CN, -(C1-C3- alkylene)OR ^A1 , -(C1-C ₃ -alkylene)SR ^A1 , -(C1-C3-alkylene)NR ^A2 R ^A3 , -(C1-C ₃ -alkylene)CF ₃ ,

-(C1-C3-alkylene)NO2, -C=NH(OR ^A1 ), -(C1-C3-alkylene)C(O)R ^A1 , -(C1-C3-alkylene)OC(O)R ^A1 ,

-(C1-C3-alkylene)C(O)OR ^A1 , -(C1-C3-alkylene)C(O)NR ^A2 R ^A3 , -(C1-C3-alkylene)OC(O)NR ^A2 R ^A3 ,

-(C1-C3-alkylene)NR ^A1 C(O)R ^A2 , -(C1-C3-alkylene)NR ^A1 C(O)OR ^A2 , -(C1-C3-alkylene)NR ^A1 C(O)NR ^A2 R ^A3 , -(C1-C3-alkylene)S(O)R ^A1 , -(C1-C3-alkylene)S(O)2R ^A1 , -(C1-C3-alkylene)NR ^A1 S(O)R ^A2 , -C(O)(C1-C3-alkylene)NR ^A1 S(O)R ^A2 , -(C1-C3-alkylene)NR ^A1 S(O)2R ^A2 , -(C1-C3-alkylene)C(O) NR ^A1 S(O)2R ^A2 , -(C1-C3-alkylene)S(O)NR ^A2 R ^A3 , -(C1-C3-alkylene)S(O)2NR ^A2 R ^A3 , -(C1-C3-alkylene )P(O)(OR ^A2 )(OR ^A3 ), -(C1-C3-alkylene)(C3-C8cycloalkyl), -(C1-C3-alkylene)(3-12-membered heterocyclyl), -(C1-C3 -alkylene)(5-10 membered heteroaryl) and -(C1-C3-alkylene)(C6-C14-aryl), where one or more substituents are each independently unsubstituted or substituted with one or more additional substituents selected from the group , consisting of halogen, oxo, -OR ^A4 , -NR ^A4 R ^A5 , -C(O)R ^A4 , -CN, -S(O)R ^A4 , -S(O)2R ^A4 , -P(O)( OR ^A4 )(OR ^A5 ), -(C1-C3-alkylene)OR ^A4 , -(C1-C3-alkylene)NR ^A4 R ^A5 , -(C1-C3-alkylene)C(O)R ^A4 , -(C1 -C3-alkylene)S(O)R ^A4 , -(C1-C3-alkylene)S(O)2R ^A4 , -(C1-C3-alkylene)P(O )(OR ^A4 )(OR ^A5 ), C3-C8 cycloalkyl, C1-C6 alkyl and C1-C6 alkyl substituted with oxo, -OH or halogen; where each R ^A1 is independently hydrogen, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, 5-6 -membered heteroaryl or 3-6-membered heterocyclyl, where C1-C ₆ is alkyl, C ₂ -C ₆ is alkenyl, C ₂ -C ₆ is alkynyl, C ₃ -C ₈ is cycloalkyl, C ₆ -C ₁₄ is aryl , 5-6 membered heteroaryl and 3-6 membered heterocyclyl are independently unsubstituted or substituted with halogen, oxo, -CN, -OR ^A6 , -NR ^A6 R ^A 7, -P(O)(OR ^A6 )(OR ^A6 ) , phenyl, phenyl substituted with halogen, C1-C6 alkyl or C1-C6 alkyl substituted with halogen, -OH or oxo; R ^A2 and R ^A3 are each independently hydrogen, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl , 5-6-membered heteroaryl or 3-6-membered heterocyclyl, where C1-C ₆ is alkyl, C ₂ -C ₆ is alkenyl, C ₂ -C ₆ is alkynyl, C ₃ -C ₈ is cycloalkyl, C ₆ - C ₁₄ -aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are each independently unsubstituted or substituted with halo, oxo, -CN, -OR ^A6 , -NR ^A6 R ^A 7 , C1-C6 alkyl or C1-C6 alkyl substituted with halogen, -OH or oxo; a R ^A4 , R ^A5 , R ^A6 and R ^A 7 are each independently hydrogen, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C ₆ alkyl, substituted with one or more halogens, C ₂ -C ₆ alkenyl substituted with one or more halogens, or C ₂ -C ₆ alkynyl substituted with one or more halogens.

In some embodiments, R ³ is C2-C6 alkoxy or halogen and R ¹ , R ² , R ⁴ , R ⁵ , Y, Gi, G2, G ₃ , G ₄ , G5, G ₆ and G7 are as defined for formula (A) or any variation or embodiment thereof.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -CH=NR ⁱ , -S(O)R ^b , -NHS(O)2R ^e , -C2-C ₆ -alkenyl^ ⁶ , unsubstituted or substituted C3-C8-cycloalkenyl and unsubstituted or substituted heterocycloalkyl, a R ¹ , R ³ , R ⁴ , R ⁵ , Y, G1, G2,

- 11 042453

G ₃ , G ₄ , G ₅ , G ₆ and G7 are as defined for formula (A) or any variation or embodiment thereof.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NR ^j , -S(O)R ^b , -S(O )2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f ', -C2-C ₆ -alkenyl-R ^s , unsubstituted or substituted C ₃ -C ₈ -cycloalkenyl and unsubstituted or substituted heterocycloalkyl;

R ^a is C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^c is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^d is H, C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl;

R ^f is unsubstituted heteroaryl, benzoyl or styryl; a

R ³ , R ⁴ , R ⁵ , Y, G1, G ₂ , G ₃ , G ₄ , G ₅ , G ₆ and G7 are as defined for formula (A) or any variation or embodiment thereof.

In some embodiments

R ³ is C ₂ -C ₆ alkoxy or halogen;

G ₅ is CH(X ₃ -R ^6c ), C(X3-R ^6c ), S or O; R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C ₆ -alkyl, halogen, -NRpR ^q , aryl, heterocyclyl, heteroaryl, -C1-C6-alkylheterocyclyl, -OC(O) -heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 ; a

R ¹ , R ² , R ⁴ , R ⁵ , Rp, R ^q , R ^h , R ^w1 , R ^w2 , R ^y , R ^z1 , R ^z2 , Y, G1, G2, G3, G4, G6 and G7 are , as defined for formula (A) or any variation or embodiment thereof.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -CH=NR ^j , -S(O)R ^b , -NHS(O)2R ^e , -C2-C ₆ -alkenyl-R ^s , unsubstituted or substituted C ₃ -C ₈ -cycloalkenyl and unsubstituted or substituted heterocycloalkyl;

G ⁵ is CH(X3-R ^6c ), C(X3-R ^6c ), S or O;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, halogen, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, -C1-C ₆ alkyl-heterocyclyl, - OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 ; a

R ¹ , R ³ , R ⁴ , R ⁵ , Rp, R ^q , R ^h , R ^w1 , R ^w2 , R ^y , R ^z1 , R ^z2 , Y, G _b G ₂ , G ₃ , G ₄ , G ₆ and G7 are as defined for formula (A) or any variation or embodiment thereof.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NR ^j , -S(O)R ^b , -S(O )2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f ', -C2-C ₆ -alkenyl-R ^s , unsubstituted or substituted C ₃ -C8- cycloalkenyl and unsubstituted or substituted heterocycloalkyl;

R ^a is C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^c is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^d is H, C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl;

R ^f is unsubstituted heteroaryl, benzoyl or styryl;

G5 is CH(X3-R ^6c ), C(X3-R ^6c ), S or O;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, halogen, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, -C1-C ₆ alkyl-heterocyclyl, - OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 ;

R ³ , R ⁴ , R ⁵ , Rp, R ^q , R ^h , R ^w1 , R ^w2 , R ^y , R ^z1 , R ^z2 , Y, G1, G ₂ , G ₃ , G ₄ , G ₆ and G7 are as defined for formula (A) or any variation or embodiment thereof.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NR ^J , -S(O)R ^b , -S(O )2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl^, -C2-C6-alkenyl^ ^E ,

C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl and 5 - or 6-membered heterocycloalkyl, where C ₃ -C ₈ -cycloalkyl and C ₃ -C ₈ -cycloalkenyl, each independently, are unsubstituted or substituted with one or more than =O, and 5- or 6-membered heterocycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, \u003d 0 and -C (O) O-C ₁ -C ₆ -alkyl;

R ^a , R ^b , R ^c and R ^e are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, benzoyl, or styryl, wherein the 3-10 membered heterocyclyl of R ^a , R ^b , R ^c and R ^e are each independently selected from the group consisting of C1-C6 alkyl, C ₃ -C ₈ - cycloalkyl, =0 and -C(O)O-C ₁ -C ₆ -alkyl, and 5-10-membered heteroaryl of R ^a , R ^b , R ^c and R ^e each independently selected from the group consisting of C 1 -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and

- 12 042453

-C(O)O-C1-C ₆ alkyl;

R ^d is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or benzoyl, where 3-10 -membered heterocyclyl from R ^d is selected from the group consisting of C 1 -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, =O and -C (O)OC ₁ -C ₆ -alkyl, and 5-10-membered heteroaryl R ^d is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and -C(O)OC ₁ -C ₆ -alkyl;

Rf and R ^g are each independently -OH, unsubstituted 5-6 membered heteroaryl, -NR ^m R ⁿ , benzoyl or styryl;

R ^m and R ⁿ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₃ -C ₈ cycloalkyl, where C ₃ -C ₈ -cycloalkyl is unsubstituted or substituted with one or more groups selected from C ₁ -C ₆ -alkyl and halogen;

Rj is 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 6-12 membered aryl, -OR ^k , -NHR ^k , -NHC(O)R ^k , -NHS(O)2R ^k , or -NHC (NH)NH2 wherein the 5-6 membered heterocyclyl of Rj is unsubstituted or substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, =O and -C (O)OC ₁ -C ₆ -alkyl, and 5-6 membered heteroaryl and 6-12 membered aryl of Rj are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and -C(O)OC ₁ -C ₆ -alkyl; And

R ^k is C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ -cycloalkyl or 6-12-membered aryl, where C ₁ -C ₆ - alkyl is unsubstituted or substituted with 5-6 membered heterocyclyl or 5-6 membered heteroaryl.

In some embodiments

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpR ^q , C6-C ₁₂ -aryl, 3-10 -membered heterocyclyl, 5-10-membered heteroaryl, -C ₁ -C ₆ -alkyl 5-6-membered heterocyclyl, -OC(O)-5-6-membered heterocyclyl, -C(O)R ^h , -S(O ) ₂ NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 , where C ₁ -C ₆ -alkyl and C ₁ -C ₆ alkoxy from R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C3-C8 cycloalkyl and halo; C6-C12-aryl and 5-10 membered heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C ₆ alkyl, C ₁ -C ₆ -alkoxy, -OH and C ₁ -C ₆ -alkyl-OH; and 3-10-membered heterocyclyl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl and -OC(O)-5-6-membered heterocyclyl from R ^6a , R ^6b , R ^6c and R ^6d , each are independently unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -OH, C ₁ -C ₆ alkyl-OH, =O, and = S;

R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl and -NR ^r R ^s ;

R ^p represents H or C ₁ -C ₆ -alkyl;

R ^q is C ₂ -C ₃ -alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ;

R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C ₁ -C ₆ alkyl;

Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl; or

G ₅ is CH(X ₃ -R ^6c ) or C(X3-R ^6c ), G6 is CH(X ₄ -R ^6d ) or C(X4-R ^6d ), and R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring; where the 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl rings are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl and -C(O)OC ₁ - C ₆ -alkyl; and where no more than one of R ^6a , R ^6b , R ^6c and R ^6d is C ₁ -C ₆ alkoxy or -OH.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NRj, -S(O)R ^b , -S(O) 2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C6-alkenyl-R ^s , unsubstituted or substituted C3-C ₈ -cycloalkyl, unsubstituted or substituted C ₃ -C ₈ -cycloalkenyl and unsubstituted or substituted heterocycloalkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -CH=NRj, -S(O)R ^b , -S(O) 2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^s , C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl and heterocycloalkyl, where C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl and heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ - C ₆ -haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl.

In some embodiments, R ^a , R ^b , R ^c and R ^e are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl.

In some embodiments, R ^a , R ^b , R ^c and R ^{e ,} each independently; are H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, heterocyclyl, heteroaryl, benzoyl or styryl, where heterocyclyl and heteroaryl are optionally substituted one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH,

- 13 042453

-C(O)OC1- _C6 alkyl, -OC1- _C6 alkyl and _C3 - _C8 cycloalkyl.

In some embodiments, R ^d is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl. In some embodiments, R ^d is H, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C6 alkynyl, C1-C ₆ haloalkyl, heterocyclyl, heteroaryl, or benzoyl, where heterocyclyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl.

In some embodiments, R ^f and R ^g are each independently -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl, or styryl, where R ^m and R ⁿ are each independently H, C1- _C6 - alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, where C ₃ -C ₈ -cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C ₆ -alkyl, C1-C ₆ -haloalkyl, halogen, -OH, -C (O) H, -C (O) OH, -C (O) OC ₁ -C _{6 -α} alkyl, -OC ₁ -C ₆ - alkyl and C ₃ -C ₈ -cycloalkyl.

In some embodiments, R ^J is heterocyclyl, aryl, -OR ^k , -NHR ^k , -NHC(O)R ^k , -NHS(O)2R ^k , or -NHC(NH)NH ₂ where heterocyclyl and aryl are optionally substituted one or more substituents selected from the group consisting of C1- _C6 alkyl, C1- _C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -αkyl and C ₃ -C ₈ -cycloalkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -C(O)R ^a , where R ^a is 3-18 membered heterocyclyl. In some embodiments, R ^a is 3-10 membered heterocyclyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, ═O, and —C(O)O -C1-C6-alkyl. In some embodiments, one of R ¹ and R ² is -OH and the other is -C(O)R ^a , where R ^a is 5-18 membered heteroaryl. In some embodiments, R ^a is 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C ₃ -C ₈ cycloalkyl, and -C(O)OC ₁ -C ₆ -alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where R ^J is 3-18 membered heterocyclyl. In some embodiments, R ^J is 5-6 membered heterocyclyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1- _C6 alkyl, _C3 - _C8 cycloalkyl, ═O, and —C( O)O-C1-C6-αkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where R ^J is 5-18 membered heteroaryl. In some embodiments, R ^J is 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1- _C6 alkyl, _C3 - _C8 cycloalkyl, and -C(O)O -C1-C6-αkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where R ^J is 6-14 membered aryl. In some embodiments, R ^J is phenyl or naphthyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C1- _C6 alkyl, _C3 - _C8 cycloalkyl, and -C(O)OC1 _- C ₆ -alkyl. In some embodiments, R ^J is phenyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where -CH=NR ^J is selected from the group consisting of n.Ν^ΝΗ ₂

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where -CH=NR ^J is selected from the group consisting of

- 14 042453

About I

In some embodiments, one of R ¹ and R ² is -OH and the other is -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d or -NHS(O)2R ^e , where R ^b , R ^c , R ^d and R ^e each independently represent an unsubstituted 3-18 membered heterocyclyl or an unsubstituted 5-18 membered heterocyclyl.

In some embodiments, R ^b , R ^c , R ^d and R ^e are each independently 3-18 membered heterocyclyl or 5-18 membered heterocyclyl, each independently substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloαalkyl and -C(O)O-C1-C6 -alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -C1-C6-alkyl-R ^f , where R ^f is -OH or NR ^m R ⁿ , where R ^m and R ⁿ , each independently is H, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or unsubstituted or substituted C ₃ -C ₆ cycloalkyl. In some embodiments, R ^f is NR ^m R ⁿ , where R ^m is H and R ⁿ is C ₃ -C ₆ -cycloalkyl, where C ₃ -C ₆ -cycloalkyl is unsubstituted or substituted with one or more groups, selected from C1- _C6 alkyl and halo.

In some embodiments, one of R ¹ and R ² is -OH and the other is -C2-C6-alkenyl-R ^g , where R ^g is benzoyl. In some embodiments, one of R ¹ and R ² is -OH and the other is -Cl-C6-alkenyl-R ^g where R ^g is -OH or NR ^m R ⁿ where R ^m and R ⁿ , each independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R ^g is NR ^m R ⁿ , where R ^m is H and R ⁿ is C 3 -C ₆ cycloalkyl, where C ₃ -C ₆ cycloalkyl is unsubstituted or substituted with one or more groups selected from from C ₁ -C ₆ -alkyl and halogen. In some embodiments, R ^m is unsubstituted or substituted C3-C8 cycloalkyl and R ⁿ is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R ^m is C ₃ -C ₈ cycloalkyl and R ⁿ is H.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, -OR ^k , -NHR ^k , -NHC (O) ^Rk , -NHS(O) ^2Rk or -NHC(NH)NH2.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is unsubstituted or substituted 4-12 membered heterocyclyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is an unsubstituted 4-12 membered heterocyclyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is a 4-12 membered heterocyclyl substituted with one or more groups selected from the group consisting of C1 -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and oxo.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is unsubstituted or substituted 5-6 membered heterocyclyl.

In certain embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is unsubstituted heterocyclyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl or thiomorpholinyl.

In other embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ^J , where NRj is heterocyclyl substituted with one or more substituents selected from the group consisting of C1- _C6 alkyl , C ₃ -C ₈ -cycloalkyl and oxo. In some embodiments, Rj is a heterocyclyl, where the nitrogen and/or sulfur atoms of the heterocyclyl are optionally oxidized to form -N-oxide, -S(O)-, or -SO ₂ moieties.

In some embodiments, one of R ¹ and R ² is -OH and the other is C3-C8 cycloalkyl or C3-C8 cycloalkenyl, each being unsubstituted or substituted with one or more groups selected from the group consisting of halo , C1-C ₆ -alkyl, C1-C ₆ -alkoxy, -C(O)OC ₁ -C ₆ -alkyl and oxo.

In some embodiments, one of R ¹ and R ² is -OH and the other is

- 15 042453 is a C ₃ -C ₈ -cycloalkenyl substituted with one or more oxo.

In some embodiments, one of R ¹ and R ² is -OH and the other is unsubstituted or substituted 3-18 membered heterocycloalkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is unsubstituted or substituted 5-6 membered heterocycloalkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is 5-6 membered heterocycloalkyl, unsubstituted or substituted with one or more groups selected from C1- _C6 alkyl, _C3 - _C8- cycloalkyl, =0 and -C(O)O-C ₁ -C ₆ -alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where NRj is unsubstituted or substituted aryl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where NRj is an unsubstituted or substituted 6-14 membered aryl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where NRj is unsubstituted phenyl or naphthyl.

In other embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where NRj is phenyl or naphthyl substituted with one or more substituents selected from the group consisting of C1- _C6 - alkyl, C ₃ -C ₈ -cycloalkyl and oxo.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -OR ^k .

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NR ⁱ , where Rj is -0-C ₁ -C ₆ alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -0-C ₁ -C6 alkenyl or -0-C ₁ -C6 alkynyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -0-C ₃ -C ₈ cycloalkyl.

In other embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -0-aryl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHR ^k

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NH-C ₁ -C ₆ alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NH-C ₁ -C ₆ alkenyl or -NH-C ₁ -C ₆ alkynyl .

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NH-C ₃ -C ₈ cycloalkyl.

In other embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NH-aryl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHC(0)R ^k .

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHC(O)-C ₁ -C ₆ alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHC(O)-C ₁ -C ₆ -alkenyl or -NHC(O)-C ₁ -C ₆ -alkynyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHC(O)-C ₃ -C ₈ cycloalkyl.

In other embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHC(O)-aryl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHS(O) ₂ R ^k .

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHS(O) ₂ -C ₁ -C ₆ alkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHS(O) ₂ -C ₁ -C ₆ alkenyl or -NHS(O) ₂ -C ₁ -C ₆ alkynyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHS(O) ₂ -C ₃ -C ₈ cycloalkyl.

In other embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHS(O) ₂ -aryl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -CH=NRj, where Rj is -NHC(NH)NH ₂ .

In some embodiments, one of R ¹ and R ² is -OH and the other is -C1-C6-alkyl-R ^f ', where R ^f is selected from the group consisting of -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl or styryl, and R ^m and R ⁿ , each independently, represent H, C1-C6-alkyl,

- 16 042453

C ₂ -C ₆ -alkenyl, C ₂ -Cb-alkynyl or unsubstituted or substituted ^-^-cycloalkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is -C2-C6-alkenyl-R ^s , where R ^g is selected from the group consisting of -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl or styryl, and R ^m and R ⁿ each independently represent H, C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or unsubstituted or substituted C ₃ -C ₈ -cycloalkyl. In some embodiments, R ^m and R ⁿ are each independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or unsubstituted C ₃ -C ₈ cycloalkyl , or C ₃ -C ₈ cycloalkyl substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2 -C6 alkynyl, C1 -C6 alkoxy, C1-C6 haloalkyl, -OH and halogen.

In some embodiments, one of R ¹ and R ² is -OH and the other is unsubstituted C3-C8 cycloalkyl. In other embodiments, one of R ¹ and R ² is -OH and the other is a substituted C3- _C8 cycloalkyl.

In some embodiments, one of R ¹ and R ² is -OH and the other is an unsubstituted C3-C8 cycloalkenyl. In other embodiments, one of R ¹ and R ² is -OH and the other is a substituted C3- _C8 cycloalkenyl.

In some embodiments, R ³ is H. In some embodiments, R ³ is unsubstituted C1-C6 alkyl. In some embodiments, R ³ is C1- _C6 alkyl substituted with one or more halogens. In some embodiments, R ³ is an unsubstituted C1-C6 alkoxy. In some embodiments, R ³ is C1- _C6 alkoxy substituted with one or more halogens. In other embodiments, R ³ is halogen.

In some embodiments, one of R ¹ and R ² is -OH and the other is -C(O)H. In some embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is H. In some embodiments, R ¹ is -OH, R ² is -C(O)H , and R ³ is unsubstituted C1-C6 alkyl. In some embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is C1- _C6 haloalkyl. In some embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is unsubstituted C1-C6 alkoxy. In some embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is C1- _C6 alkoxy substituted with one or more halogens. In other embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is halogen. In certain embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is fluoro. In certain embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is methyl. In some embodiments, R ¹ is -OH, R ² is -C(O)H, and R ³ is methoxy.

In some embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is H. In some embodiments, R ² is -OH, R ¹ is -C(O)H , and R ³ is unsubstituted C1-C6 alkyl. In some embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is C1- _C6 haloalkyl. In some embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is unsubstituted C1-C6 alkoxy. In some embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is C 1 -C ₆ alkoxy substituted with one or more halogens. In other embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is halogen. In certain embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is fluorine. In certain embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is methyl. In some embodiments, R ² is -OH, R ¹ is -C(O)H, and R ³ is methoxy.

In some embodiments, G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S, or O; G4 is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O; G5 is CH(X3-R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O; G6 is CH(X4-R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent; a G7 is N, C or CH, where G1, G ₂ , G ₃ , G ₄ , G ₅ , G ₆ and G7 each have zero charge (e.g. nitrogen in G1, G ₂ , G ₃ , G ₄ , G ₅ , G ₆ and G7 is not cationic).

and a In some embodiments, θ ⁵ is ^R where one or more of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, - NR ^p R ^q , C6-C ₁₂ -aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C ₁ -C ₆ -alkyl-5-6 membered heterocyclyl, -OC(O)-5- 6-membered heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y and -NR ^z1 S(O) ₂ R ^z2 .

- 17 042453

In some embodiments

where R ^6c is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, -NRpR ^q , C ₆ -C ₁₂ -aryl, 3-10-membered hetero cyclyl, 5-10-membered heteroaryl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl, -OC(O)-5-6-membered heterocyclyl, -C(O)R ^h , -S(O )2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 .

In some embodiments, R ^6c is unsubstituted C ₁ -C ₆ alkyl. For example, in some embodiments, R ^6c is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl.

In some embodiments, R ^6c is C ₁ -C ₆ alkyl substituted with one or more groups selected from the group consisting of C ₃ -C ₈ cycloalkyl and halo.

In some embodiments, R ^6c is C ₁ -C ₆ alkoxy. For example, in some embodiments, R ^6c is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

In some embodiments, R ^6c is C ₁ -C ₆ alkoxy substituted with one or more groups selected from the group consisting of C ₃ -C ₈ cycloalkyl and halo.

In some embodiments, R ^6c is halo. For example, in some embodiments, R ^6c is fluorine, chlorine, or bromine.

In other embodiments, R ^6c is C ₁ -C ₆ haloalkyl. For example, in some embodiments, R ^6c is fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and trichloromethyl.

In some embodiments, R ^6c is -C(O)R ^h , where R ^h is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or -NR ^r R ^s . For example, in some embodiments, R ^6c is -C(O)H, -C(O)CH3, -C(O)OC(CH ₃ ) ₃ , or -C(O)-cyclopropyl.

In some embodiments, R ^6c is an unsubstituted 5-6 membered heterocycle. In some embodiments, R ^6c is a 5-6 membered heterocycle substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S.

In some embodiments, R ^6c is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl. In some embodiments, R ^6c is pyrrolidinyl. In certain embodiments, R ^6c is 4-pyrrolidin-1-yl.

In some embodiments, R ^6c is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R ^6c is 5-10 membered heteroaryl substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -OH, and C ₁ -C ₆ -alkyl-OH.

In some embodiments, R ^6c is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.

.G?.

In some embodiments, is where R ^6b is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , C6-C ₁₂ -aryl, 3-10 membered heterocyclyl, 5-10-membered heteroaryl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl, -OC(O)-5-6-membered heterocyclyl, -C(O)R ^h , -S(OhNR ^w1 R ^w2 , -S(OhR ^y or -NR ^z1 S(OhR ^z2 .

In some embodiments, R ^6b is unsubstituted C ₁ -C ₆ alkyl. For example, in some embodiments, R ^6b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl.

In some embodiments, R ^6b is C ₁ -C ₆ alkyl substituted with one or more groups selected from the group consisting of C ₃ -C ₈ cycloalkyl and halo.

In some embodiments, R ^6b is C ₁ -C ₆ alkoxy. For example, in some embodiments, R ^6b is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

In some embodiments, R ^6b is C ₁ -C ₆ alkoxy substituted with one or more groups selected from the group consisting of C ₃ -C ₈ cycloalkyl and halo. In some embodiments, R ^6b is halo. For example, in some embodiments, R ^6b is fluorine, chlorine, or bromine.

In other embodiments, R ^6b is C ₁ -C ₆ haloalkyl. For example, in some

- 18 042453 In other embodiments, R ^6b is fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl and trichloromethyl.

In some embodiments, R ^6b is -C(O)R ^h , where R ^h is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or -NR ^r R ^s . For example, in some embodiments, R ^6b is -C(O)H, -C(O)CH3, -C(O)OC(CH ₃ ) ₃ , or -C(O)-cyclopropyl.

In some embodiments, R ^6b is an unsubstituted 5-6 membered heterocycle. In some embodiments, R ^6b is a 5-6 membered heterocycle substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S.

In some embodiments, R ^6b is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl.

In some embodiments, R ^6b is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R ^6b is 5-10 membered heteroaryl substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -OH, and C ₁ -C ₆ -alkyl-OH.

In some embodiments, R ^6b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.

R"

In some embodiments, is where R ^6a is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, -NRpR ^q , C ₆ -C ₁₂ -aryl, 3- 10-membered heterocyclyl, 5-10-membered heteroaryl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl, -OC(O)-5-6-membered heterocyclyl, -C(O)R ^h , - S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 .

In some embodiments, R ^6a is unsubstituted C ₁ -C ₆ alkyl. For example, in some embodiments, R ^6a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl.

In some embodiments, R ^6a is C1-C6 alkyl substituted with one or more groups selected from the group consisting of C3-C8 cycloalkyl and halo. In some embodiments, R ^6a is C1-C ₆ alkoxy. For example, in some embodiments, R ^6a is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and t-butoxy.

In some embodiments, R ^6a is C ₁ -C ₆ alkoxy substituted with one or more groups selected from the group consisting of C ₃ -C ₈ cycloalkyl and halo. In some embodiments, R ^6a is halo. For example, in some embodiments, R ^6a is fluorine, chlorine, or bromine.

In other embodiments, R ^6a is C ₁ -C ₆ haloalkyl. For example, in some embodiments, R ^6a is fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and trichloromethyl.

In some embodiments, R ^6a is -C(O)R ^h , where R ^h is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or -NR ^r R ^s . For example, in some embodiments, R ^6a is -C(O)H, -C(O)CH3, -C(O)OC(CH ₃ ) ₃ , or -C(O)-cyclopropyl.

In some embodiments, R ^6a is an unsubstituted 5-6 membered heterocycle. In some embodiments, R ^6a is a 5-6 membered heterocycle substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S.

In some embodiments, R ^6a is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl.

In some embodiments, R ^6a is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R ^6a is 5-10 membered heteroaryl substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -OH, and C ₁ -C ₆ -alkyl-OH.

In some embodiments, R ^6a is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.

- 19 042453 .G ₇ ,

O ^G <> ^G 6 _ „

In some embodiments, ^G 5 is ^{to R6d} ' where R ^6b and R ^6d are each independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NRpR ^q , C ₆ -C ₁₂ -aryl, 3-10-membered heterocyclyl, 5-10-membered heterocyclyl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl, -OC(O)-5-6- membered heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 .

In some embodiments

represents

R

^r6c > where R ^6a and R ^6c are each independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , C6-C ₁₂ -aryl, 3- 10-membered heterocyclyl, 5-10-membered heteroaryl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl, -OC(O)-5-6-membered heterocyclyl, -C(O)R ^h , - S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 .

θ7.

^G4 "> ^G6

In some embodiments ^{, Gs} is

In some embodiments

represents

_R 6d ^r6c ' where one or more of

R ⁶ b, r ^6c and R ^6d are selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloαalkylα, halogen, C ₆ -C ₁₂ -aryl, 3-10-membered heterocyclyl and 5- 10-membered heteroaryl.

θ7.

θ4'>θ6

In some embodiments, ^G s is R ^6a , R ^6c and R ^6d are selected from the group consisting of C ₁ -C ₆ alkyl, C ₆ -C ₁₂ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl.

^R1

R ^{6d Rfic} > where one or more of

C ₁ -C ₆ -haloalkyl, halogen,

R

^G 4'”> ^G 6 R _R 6d

In some embodiments, ^Gs is ^N where one or more of R ⁶ a, R ⁶ b and R ^6d are selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkylα, halogen, C ₆ -C ₁₂ -aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl.

-G _A ^G 4'> ^G 6 _ ~ ov^.xA _6d _

In some embodiments, ^G s is ^N , where one or both of R ^6b and R ^6d are selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ -halogen α alkyl, halogen, C ₆ -C ₁₂ - aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl.

In some embodiments

R

is ^r6c > where one or both of R ^6a and

R ^6c is selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloαalkyl, halogen, C ₆ -C ₁₂ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl.

• ^G7 .

G<->G ₆ .

In some embodiments, ^G s is selected from the group consisting of

- 20 042453

In some embodiments

• ^G7 .

represents about or

_G4y- > _G6N

In some embodiments, ^Gs is ^r6c , where R ^6c is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , C6-C ₁₂ -αril, 3-10-membered heterocyclyl, 5-10-membered heteroaryl, -C ₁ -C ₆ -alkyl-5-6-membered heterocyclyl, -OC(O)-5-6-membered heterocyclyl, -C(O)R ^h , - S(O)2NR ^w1 R ^w2 , -S(O)2R ^y and -NR ^z1 S(O)2R ^z2 . In certain embodiments, R ^6c is -C(O)OC(CH ₃ ) ₃ .

- ^G7 .

^G O ^G 6 „ ^e 5 is

In certain embodiments

In some embodiments, the implementation is

In any of the above embodiments, one or more of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloαalkyl, halogen, C ₆ -C ₁₂ -aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl.

In some embodiments, one or more of R ^6a , R ^6b , R ^6c and R ^6d is C ₆ -C ₁₂ -aryl, unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ -αalkyl , C ₁ -C ₆ -alkoxy, -OH and C ₁ -C ₆ -alkyl-OH. For example, in some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is phenyl or naphthyl.

In some embodiments, one or more of R ^6a , R ^6b , R ^6c and R ^6d is a 3-10 membered heterocyclyl, unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1- C6-alkoxy, halogen, -OH, C1-C6-αkyl-OH, =O and =S. For example, in some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl , dithianyl, trithianyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indolinyl, isoindolinyl, tetrahydronaphthyridinyl, or hexahydrobenzoimidazolyl, each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S.

In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, C6-C12 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl. In certain embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of methyl, ethyl, F, Cl, -CF3, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, and triazolyl. In certain embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl and triazolyl, each optionally substituted with one or more groups selected from the group consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S. In some embodiments, two or three of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of methyl, ethyl, F, Cl, -CF ₃ , pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, and triazolyl.

In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of methyl, ethyl, methoxy, F, Cl, -CF3,

- 21 042453

In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of o I

ABOUT

In other embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each H.

In some embodiments, G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ) or N(X1-R ^6a ),

X1 is absent, is ^or ' and R ^6a is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, -C1-C6-alkylheterocyclyl, -OC(O)-heterocyclyl, -C(O )R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 , where C1-C ₆ is alkyl and C ₁ -C ₆ is alkoxy from R ^6a , each independently, are unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; aryl and heteroaryl of R ^6a are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, -OH, and C1-C6 alkyl-OH; and heterocyclyl, -C1-C6-alkyl-heterocyclyl and -OC(O)-heterocyclyl from R ^6a are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S; R ^h is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl and -NR ^r R ^s ; R ^p is H or C1- _C6 alkyl; R ^q is C2-C3 alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ; R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C1-C ₆ alkyl; a Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl.

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), where X1 is absent; R ^6a is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C ₆ is alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; and R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, and

C ₃ -C ₈ -cycloalkyl.

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), where X1 ..... xM/. 6a _ _ is ^or > m is 1-6; R represents hydrogen, C ₁ -C ₆ -alkyl,

C ₁ -C ₆ alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h , where C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted by C3 -C8-cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl. In some embodiments, G ₃ is N or N(X1-R ^6a ), where X1 is absent; R ^6a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl or -C(O)R ^h where C1- C6-alkyl and C1-C6-alkoxy are unsubstituted or substituted with C3-C8-cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G ₃ is N or N(X1-R ^6a ), where X1 is

..... ' ... 6a _ _ _ ^or ' m is 1-6; R is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C6 -alkyl and C1-C6-alkoxy are unsubstituted or substituted with C3-C8-cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some of any of the previous embodiments, R ^6a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some of any of the previous embodiments, R ^6a is C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6a is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy

- 22 042453 or tert-butoxy. In some of any of the preceding embodiments, R ^6a is C1-C6 alkoxy substituted with C3-C8 cycloalkyl or halogen. In some of any of the previous embodiments, R ^6a is fluorine, bromine, or iodine. In some of any of the previous embodiments, R ^6a is -N(CH2CH3)2, -N(CH ₂ CH ₂ CH ₃ ) _{2 ,} or -N(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ). In some of any of the preceding embodiments, R ^6a is phenyl or naphthyl. In some of any of the preceding embodiments, R ^6a is a 5-14 membered heterocyclyl. In some embodiments, R ^6a is a 5-6 membered heterocyclyl. In some of any of the preceding embodiments, R ^6a is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl. In some of any of the previous embodiments, R ^6a is 5-14 membered heteroaryl. In some embodiments, R ^6a is 5-6 membered heteroaryl. In some of any of the preceding embodiments, R ^6a is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl. In some of any of the preceding embodiments, R ^6a is aryl, heterocyclyl, or heteroaryl, each of which is substituted with C1-C6 alkyl. In some of any of the preceding embodiments, R ^6a is -C(O)H, -C(O)-C1-C ₆ alkyl, -C(O)-C ₁ -C ₆ alkoxy, or -C(O) -C ₃ -C ₈ -cycloalkyl. In some of any of the preceding embodiments, R ^6a is -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, unsubstituted C1-C6 alkoxy, or C1-C6 alkoxy substituted with C3-C8 cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6a is hydrogen, -CH3, -OH, -OCH ₃ , -C(O)OC(CH ₃ ) ₃ , -N(CH2CH ₃ )2, phenyl, morpholinyl, piperidinyl, piperazinyl , 4-ethylpiperazinyl, pyrrolidinyl, pyrazolyl, cyclopropylmethoxy or cyclopropanecarbonyl. In some embodiments, G ₃ is S. In other embodiments, G ₃ is O.

In some embodiments, G4 is CH(X2-R ^6b ), C(X2-R ^6b ), or N(X2-R ^6b ), . „ . . . . ____ . .._ .. 6b ____ . . ...

where X2 is absent, is ^or ' a R is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, -C1-C6-alkylheterocyclyl, -OC(O)-heterocyclyl, -C(O )R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 , where C1-C ₆ is alkyl and C ₁ -C ₆ is alkoxy from R ^6b , each independently, are unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; aryl and heteroaryl of R ^6b are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, -OH, and C1-C6 alkyl-OH; and heterocyclyl, -C1-C6-alkyl-heterocyclyl and -OC(O)-heterocyclyl of R ^6b are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S; R ^h is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl and -NR ^r R ^s ; R ^p is H or C1- _C6 alkyl; R ^q is C2-C3 alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ; R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C1-C ₆ alkyl; a Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl.

In some embodiments, G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), where X2 is absent; R ^6b is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C ₆ is alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; and R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), where X ₂ is ^m or ^m ; m is 1-6; R ^6b is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl or -C(O)R ^h where C1- C6-alkyl and C1-C6-alkoxy are unsubstituted or substituted with C3-C8-cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl. In some embodiments, G4 is N or N(X2-R ^6b ), where X2 is absent; R ^6b is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C6 -alkyl and C1-C6-alkoxy are unsubstituted or substituted with C3-C8-cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G4 is N or N(X2-R ^6b ), where X2 is

- 23 042453 is ^m or ^m ; m is 1-6; R ^6b is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl or -C(O)R ^h where C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl. In some of any of the preceding embodiments, R ^6b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some of any of the previous embodiments, R ^6b is C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6b is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. In some of any of the preceding embodiments, R ^6b is C1-C6 alkoxy substituted with C3-C8 cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6b is fluorine, bromine, or iodine. In some of any of the previous embodiments, R ^6b is N(CH2CH3)2, -N(CH2CH2CH ₃ )2 or -N(CH2CH ₃ )(CH2CH2CH ₃ ). In some of any of the previous embodiments, R ^6b is phenyl or naphthyl. In some of any of the previous embodiments, R ^6b is a 5-14 membered heterocyclyl. In some embodiments, R ^6b is a 5-6 membered heterocyclyl. In some of any of the preceding embodiments, R ^6b is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl. In some of any of the previous embodiments, R ^6b is 5-14 membered heteroaryl. In some embodiments, R ^6b is a 5-6 membered heteroaryl. In some of any of the preceding embodiments, R ^6b is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl. In some of any of the preceding embodiments, R ^6b is aryl, heterocyclyl, or heteroaryl, each of which is substituted with C1-C6 alkyl. In some of any of the preceding embodiments, R ^6b is -C(O)H, -C(O)-C1-C ₆ alkyl, -C(O)-C ₁ -C ₆ alkoxy, or -C(O) -C ₃ -C ₈ -cycloalkyl. In some of any of the previous embodiments, R ^6b is -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, unsubstituted C1-C6 alkoxy, or C1-C6 alkoxy substituted with C3-C8 cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6b is hydrogen, -CH3, -OH, -OCH ₃ , -C(O)OC(CH ₃ ) ₃ , -N(CH ₂ CH ₃ ) ₂ , phenyl, morpholinyl, piperidinyl , piperazinyl, 4-ethylpiperazinyl, pyrrolidinyl, pyrazolyl, cyclopropylmethoxy or cyclopropanecarbonyl. In some embodiments, G ₄ is S. In other embodiments, G ₄ is O.

In some embodiments, G5 is CH(X ₃ -R ^6c ), C(X3-R ^6c ), or N(X3-R ^6c ), where X3 is absent, is

4°· > R ^6c is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, -C1-C6-alkylheterocyclyl, -OC(O)-heterocyclyl, -C(O )R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 , where C1-C ₆ is alkyl and C ₁ -C ₆ is alkoxy from R ^6c , each independently, are unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; aryl and heteroaryl of R ^6c are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, -OH, and C1-C6 alkyl-OH; and heterocyclyl, -C1-C6-alkyl-heterocyclyl and -OC(O)-heterocyclyl of R ^6c are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S; R ^h is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl and -NR ^r R ^s ; Rp is H or C1- _C6 alkyl; R ^q is C2-C3 alkyl, -C(O)Rt, -C(O)0R ^u , -C(O)NR ^v ; R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C1-C ₆ alkyl; a Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl.

In some embodiments, G5 is CH(X ₃ -R ^6c ) or C(X3-R ^6c ), where X3 is absent; R ^6c is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C ₆ is alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; and R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G5 is CH(X ₃ -R ^6c ) or C(X3-R ^6c ), where X3

- 24 042453

........ ,, „6c......._ ,,,,.

is ^or > m is 1-6; R is hydrogen, C1- _C6 alkyl,

C ₁ -C ₆ -alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl or -C(O)R ^h , where C ₁ -C ₆ -alkyl and

C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C ₂ -C ₃ alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₃ -C ₈ cycloalkyl. In some embodiments, G5 is N or N(X ₃ -R ^6c ), where X3 is absent; R ^6c is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl or -C(O)R ^h where C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted with C3-C8 cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G5 is N or N(X ₃ -R ^6c ), where X ₃ is _M hM/. 6c _ „„ a ^or ' m equals 1-6; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NRpRq, aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C6 is alkyl and C1-C6 alkoxy are unsubstituted or substituted with C3-C8 cycloalkyl or halogen; Rp is H or C1-C6 alkyl; R ^q is C2- _C3 alkyl; a R ^h is selected from the group consisting of H,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or C ₃ -C ₈ -cycloalkyl.

In some of any of the previous embodiments, R ^6c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some of any of the preceding embodiments, R ^6c is C1-C6 alkyl substituted with C3-C8 cycloalkyl or halo. In some of any of the previous embodiments, R ^6c is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. In some of any of the preceding embodiments, R ^6c is C 1 -C ₆ alkoxy substituted with C ₃ -C ₈ cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6c is fluorine, bromine, or iodine. In some of any of the preceding embodiments, R ^6c is -N(CH2CH3)2, -N(CH2CH2CH3)2, or -N(CH2CH3)(CH2CH2CH3). In some of any of the preceding embodiments, R ^6c is phenyl or naphthyl. In some of any of the previous embodiments, R ^6c is a 5-14 membered heterocyclyl. In some embodiments, R ^6c is a 5-6 membered heterocyclyl. In some of any of the preceding embodiments, R ^6c is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl. In some of any of the previous embodiments, R ^6c is 5-14 membered heteroaryl. In some embodiments, R ^6c is a 5-6 membered heteroaryl. In some of any of the preceding embodiments, R ^6c is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl. In some of any of the preceding embodiments, R ^6c is aryl, heterocyclyl, or heteroaryl, each of which is substituted with C1- _C6 alkyl. In some of any of the preceding embodiments, R ^6c is -C(O)H, -C(O)-C1-C6-alkyl, -C(O)-C1-C6-alkoxy, or -C(O)-C3-C8- cycloalkyl. In some of any of the preceding embodiments, R ^6c is -OH, -NRpRq, aryl, heterocyclyl, heteroaryl, unsubstituted C1-C ₆ alkoxy, or C ₁ -C ₆ alkoxy substituted with C ₃ -C ₈ C ₃ -C ₈ -cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6c is hydrogen, -CH3, -OH, -OCH3, -C(O)OC(CH ₃ ) ₃ , -N(CH ₂ CH ₃ ) ₂ , phenyl, morpholinyl, piperidinyl, piperazinyl, 4-ethylpiperazinyl, pyrrolidinyl, pyrazolyl, cyclopropylmethoxy or cyclopropanecarbonyl.

In some embodiments, G5 is S. In other embodiments, G5 is O.

In some embodiments, G ₆ is CH(X ₄ -R ^6d ), CH(X ₄ -R ^6d ) or ^-^Jy

N(X4-R ^6d ) where X4 is absent is ^{m or m} R ^6d is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpRq, aryl, heterocyclyl, heteroaryl, -C1-C6-alkylheterocyclyl, -OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 where C1-C ₆ alkyl and C ₁ -C ₆ alkoxy of R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; aryl and heteroaryl of R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -OH, and C ₁ -C ₆ - alkyl-OH; and heterocyclyl, -C ₁ -C ₆ -alkyl-heterocyclyl and -OC(O)-heterocyclyl from R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of

- 25 042453

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S; R ^h is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl and -NR ^r R ^s ; Rp is H or C1- _C6 alkyl; R ^q is C2-C3 alkyl, -C(O)Rt, -C(O)OR ^u , -C(O)NR ^v ; R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C1-C ₆ alkyl; a Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from H, C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, and unsubstituted or substituted heterocyclyl.

In some embodiments, G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), where X4 is absent; R ^6d is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpRq, aryl, heterocyclyl, heteroaryl, or -C(O)R ^h where C1-C ₆ is alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; and R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl.

In some embodiments, G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), where ^m or

X ₄ is ^m; m is 1-6; R ^6d is hydrogen,

C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, or -C(O)R ^h , where C1-C6 alkyl and C ₁ -C ₆ alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G6 is N or N(X4-R ^6d ), where X4 is absent; R ^6d is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl or -C(O)R ^h where C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl.

In some embodiments, G6 is N or N(X4-R ^6d ), where X4 is or ^m ; m is 1-6; R ^6d is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -OH, -NRpRq, aryl, heterocyclyl, heteroaryl or -C(O)R ^h where C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; Rp is H or C ₁ -C ₆ alkyl; R ^q is C2-C3 alkyl; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl.

In some of any of the preceding embodiments, R ^6d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some of any of the preceding embodiments, R ^6d is C1-C6 alkyl substituted with C3-C8 cycloalkyl or halo. In some of any of the previous embodiments, R ^6d is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. In some of any of the preceding embodiments, R ^6d is C1- _C6 alkoxy substituted with _C3 - _C8 cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6d is fluorine, bromine, or iodine. In some of any of the preceding embodiments, R ^6d is -N(CH2CH3)2, -N(CH2CH2CH3)2, or N(CH2CH3)(CH2CH2CH3). In some of any of the preceding embodiments, R ^6d is phenyl or naphthyl. In some of any of the previous embodiments, R ^6d is a 5-14 membered heterocyclyl. In some embodiments, R ^6d is a 5-6 membered heterocyclyl. In some of any of the preceding embodiments, R ^6d is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl. In some of any of the previous embodiments, R ^6d is 5-14 membered heteroaryl. In some embodiments, R ^6d is a 5-6 membered heteroaryl. In some of any of the preceding embodiments, R ^6d is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl. In some of any of the preceding embodiments, R ^6d is aryl, heterocyclyl, or heteroaryl, each of which is substituted with C1- _C6 alkyl. In some of any of the preceding embodiments, R ^6d is -C(O)H, -C(O)-C1-C6-alkyl, -C(O)-C1-C6-alkoxy, or -C(O)-C3- C8-cycloalkyl. In some of any of the preceding embodiments, R ^6d is -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl, unsubstituted C1-C ₆ alkoxy, or C ₁ -C ₆ alkoxy substituted with C ₃ -C ₈ cycloalkyl or halogen. In some of any of the preceding embodiments, R ^6d is hydrogen, -CH ₃ , -OH, -OCH ₃ , -C(O)OC(CH3)3, -N(CH2CH3)2, phenyl, morpholinyl, piperidinyl, piperazinyl, 4-ethylpiperazinyl, pyrrolidinyl, pyrazolyl, cyclopropylmethoxy or cyclopropanecarbonyl.

In some embodiments, G ₆ is S. In other embodiments,

- 26 042453 G ₆ is O. In some embodiments, G ₆ is absent.

In some embodiments, G ₅ is CH(X ₃ -R ^6c ), G6 is CH(X4-R ^6d ), the ring is saturated, and R ^6c and R ^6d are taken together with the carbon atoms to which they are attached, for formation of a 6-membered heterocyclyl ring; where the heterocyclyl ring is unsubstituted or substituted with one or more groups selected from the group consisting of C 1 -C ₆ -alkyl and -C(O)OC ₁ -C ₆ -alkyl.

In some embodiments, G ₅ is C(X ₃ -R ^6c ), G6 is C(X4-R ^6d ), is partially unsaturated or fully unsaturated, and R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl, or 6-membered heteroaryl ring; where the 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl rings are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl and -C(O)-OC ₁ -C ₆ -alkyl.

In some embodiments, G ₅ is C(X ₃ -R ^6c ), G6 is C(X ⁴ -R ^6d ), is fully unsaturated, and R ^6c and R ^6d are taken together with the carbon atoms to which they are attached, to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring; where the 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl rings are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl and -C(O)OC ₁ - C ₆ -alkyl.

In some embodiments, R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a phenyl ring. In some embodiments, R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered heterocyclyl or 6-membered heteroaryl ring; where the 6-membered heterocyclyl or 6-membered heteroaryl ring each independently contains one, two, or three heteroatoms selected from the group consisting of N, S, and O. In some embodiments, R ^6c and R ^6d are taken together with carbon atoms, to which they are attached to form an unsubstituted 6-membered aryl, 6-membered heterocyclyl, or 6-membered heteroaryl ring. In some embodiments, R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl, or 6-membered heteroaryl ring; where the 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring is each independently substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH , -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl.

In some embodiments, G7 is N. In some embodiments, _G7 is C. In other embodiments, _G7 is CH.

In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, -C1-C ₆ -alkyl-heterocyclyl, -OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O )2R ^z2 where C1-C6 alkyl and C1-C6 alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen ; aryl and heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1- _C6 alkyl, _C1 - _C6 alkoxy, - OH and C ₁ -C ₆ -alkyl-OH; and aryl, heterocyclyl, heteroaryl, -C ₁ -C ₆ -alkyl-heterocyclyl and -OC(O)-heterocyclyl of R ⁶ a, R ^6b , r ^6c and R ^6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -OH, C ₁ -C ₆ -alkyl-OH, =O and =S; where each aryl of R ^6a , R ^6b , R ^6c and R ^6d is 6-12 membered, each heterocyclyl of R ^6a , R ^6b , R ^6c and R ^6d is 3-18 membered, and each heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are 5-18 members.

In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl and -C(O)R ^h where C1-C ₆ alkyl and C ₁ -C ₆ alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with C3-C8 cycloalkyl or halogen; and the remainder of R ^6a , R ^6b , R ^6c and R ^6d are each H. In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of C1-C ₆ alkyl , C ₁ -C ₆ -alkoxy, halogen, -OH, -NR ^p R ^q , 6-12-membered aryl, 3-12-membered heterocyclyl, 5-12-membered heteroaryl and -C(O)R ^h , where C1-C6 alkyl and C1-C6 alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with C3-C ₈ cycloalkyl or halogen; and the remainder of R ^6a , R ^6b , R ^6c and R ^6d are each H. In some embodiments, two of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C1-C6 alkyl, C1-C6-alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl and -C(O)R ^h , where C1-C ₆ is alkyl and C ₁ -C ₆ -alkoxy from R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with C3-C8 cycloalkyl or halogen; and the remainder of R ^6a , R ^6b , R ^6c and R ^6d are each H. In some embodiments, two of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C1- _C6 alkyl , C ₁ -C ₆ -alkoxy, halogen,

- 27 042453

-OH, -NRpR ^q , 6-12 membered aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl and -C(O)R ^h , where C1-C6 is alkyl and C1-C6 is alkoxy from R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with C3- _C8 cycloalkyl or halogen; and the rest of R ^6a , R ^6b , R ^6c and R ^6d are each H.

In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpR ^q , aryl, heterocyclyl, heteroaryl, and -C(O)R ^h where C1-C ₆ alkyl and C ₁ -C ₆ alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with C3-C8 cycloalkyl or halogen ; and the remainder of R ^6a , R ^6b , R ^6c and R ^6d are each H. In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of -C1-C ₆ - alkyl-heterocyclyl, -OC(O)-heterocyclyl, -S(O) ₂ NR ^w1 R ^w2 , -S(O)2R ^y and -NR ^z1 S(O)2R ^z2 ; where R ^w1 and R ^z1 are each independently selected from H and C1-C6 alkyl, and R ^w2 , R ^y and R ^z2 are each independently selected from H, C1-C ₆ alkyl, unsubstituted or substituted with C ₃ - C ₈ -cycloalkyl and unsubstituted or substituted 3-12-membered heterocyclyl.

In some embodiments, two of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NR ^p R ^q , aryl, heterocyclyl, heteroaryl and -C(O)R ^h where C1-C ₆ alkyl and C ₁ -C ₆ alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with C ₃ -C ₈ -cycloalkyl or halogen; and the rest of R ^6a , R ^6b , R ^6c and R ^6d are each H.

In some embodiments, one, two or three of R ^6a , R ^6b , R ^6c and R ^6d are 5-10 membered heterocyclyl unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6 alkyl, -OH, C1-C6-alkyl-OH, =O, =S. In some embodiments, one, two, or three of R ^6a , R ^6b , R ^6c , and R ^6d are monocyclic heterocyclyl, bicyclic heterocyclyl, or spirocyclic heterocyclyl, each being unsubstituted or substituted with one or more groups selected from the group consisting of C1 -C ₆ -alkyl, -OH, C ₁ -C ₆ -alkyl-OH, =O, =S. In some embodiments, one, two or three of R ^6a , R ^6b , R ^6c and R ^6d are 5-10 membered heteroaryl, unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ - alkyl, -OH, C ₁ -C ₆ -alkyl-OH, =O, =S.

A^r ⁴

( 1 ( In some embodiments In certain variants jwv JVMV σννν I € 4- € .U έ_ € Μ· / £ „ g ~ O _ O ¹³⁵ represents or. Ϊ , >3 ₇ .R |Г'У ^G <M ^G 6 implementation ^G s is Dk* Q l ₇ /R JL irA Ml

in some embodiments is

D A m In some embodiments, ⁴ ei ' Q / C] V ) Y * , M OR J . »azw ^wv I ' _Г ' 9 4 I «- -o-m r ^N ₃ Hm represents ^o , ι ι or

- 28 042453

In one aspect, compounds of formula (I) are provided.

or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, ( ' where indicates that the ring is saturated, partially unsaturated or fully unsaturated;

I A' ? indicates that ⁶ is attached to an E- or Z-configuration;

G1 and G2 are each independently CH or N;

one of R1 and R ² is -OH and the other is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6 alkyl-R ^f , -C2-C ₆ alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl;

R ^a , R ^b , R ^c and R ^e are each independently H, C ₁ -C ₆ -αlkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -haloαlkyl , unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl;

R ^d is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl or benzoyl;

R ^f and R ^g are each independently unsubstituted heteroaryl, benzoyl or styryl;

R ³ represents H, C1-C ₆ alkyl, C1-C ₆ alkoxy or halogen; And

R ⁴ and R ⁵ are each H or

R ⁴ and R ⁵ combine to form -S-;

G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S or O;

G4 is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O;

G5 is CH(X3-R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O;

G ₆ is CH(X ₄ -R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent;

where, when G5 is N, or (i) at least one of G ₃ , G4 and G6 is not CH, or (ii) R ⁴ and R ⁵ combine to form -S-;

X1, X ₂ , X ₃ and X4 are each independently m equal to 1-6;

R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen or -C(O)R ^h where C1-C ₆ alkyl is unsubstituted or substituted with cycloalkyl or halogen;

R ^h is selected from the group consisting of H, C ₁ -C ₆ -αkyl, C ₁ -C ₆ -alkoxy and C ₃ -C ₈ -cycloalkyl;

where the connection is not a connection from the table. 1X.

In some embodiments of Formula (I), G1 and G2 are each CH. In some embodiments, G1 is CH and G2 is N. In some embodiments, G ₁ is N and G ₂ is CH. In other embodiments, G ₁ and G ₂ are each N.

In some embodiments, R ¹ is -OH and R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6 alkyl-R ^f , -C2-C6 alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl.

In some embodiments, R ¹ is -OH and R ² is selected from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C ₂ -C ₆ -alkenyl-R ^g and unsubstituted or substituted cycloalkenyl.

In some embodiments, R ¹ is -OH and R ² is selected from the group consisting of -CHO, -C(O)CH ₃ , -C(O)CH ₂ F, -C(O)CH=CH ₂ , -S(O) ₂ CH=CH ₂ , -C(O)C=CH, -C(O)C<'CH;, -NHS(O)2CH=CH2, -NHC(O)CH=CH2, - C(O)C(=CH2)CH3,

- 29 042453

In some embodiments, R ¹ is -OH and R ² is selected from the group consisting of

In some embodiments, R ² is -OH and R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O) 2 R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C6-alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl. In some embodiments, R ² is -OH and R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C2-C ₆ -alkenyl-R ^g and unsubstituted or substituted cycloalkenyl.

In some embodiments, R of the group consisting of -CHO, -C(O)CH ₃ is -OH, and R ¹ is selected from

-C(O)CH= _CH2 ,

-C(O)CH ₂ F,

-C(O)C CH, -C(O)C CCIk -NHS(O)2CH=CH2, -NHC(O)CH=CH2,

In some embodiments, R ² is -OH and R ¹ is selected from the group consisting of

-S (O) ₂ CH \u003d CH ₂ ,

-C(O)C(=CH2)CH3,

And

In some embodiments, one of R ¹ and R ² is -OH and the other is -C(O)R ^a , where R ^a is H, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C 1 -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl. In some embodiments, one of R ¹ and R ² is -OH and the other is -C(O)R ^a , where R ^a is substituted heterocyclyl or substituted heteroaryl.

It should be understood that in any of the embodiments described herein, a substituent of a substituted cyclic group (e.g., a substituted heterocyclyl or substituted heteroaryl group) may be attached to the same atom of the cyclic group that

- 30 042453 about

connected to the remainder of the compound. For example, ⁰ is a particular embodiment of -C(O)R ^a when R ^a is an epoxy group substituted with methyl. In some embodiments, one of R ¹ and R ² is -OH and the other is -S(O)R ^b , where R ^b is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl. In some embodiments, one of R ¹ and R ² is -OH and the other is -S(O)2R ^c , where R ^c is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl. In some embodiments, one of R ¹ and R ² is -OH and the other is -NHC(O)R ^d , where R ^d is H, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl or benzoyl. In some embodiments, one of R ¹ and R ² is -OH and the other is -NHS(O)2R ^e , where R ^e is H, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl or styryl. In some embodiments, one of R ¹ and R ² is -OH and the other is -C1-C6-alkyl-R ^f , where R ^f is unsubstituted heteroaryl, benzoyl, or styryl. In some embodiments, one of R ¹ and R ² is -OH and the other is -C2-C ₆ -alkenyl-R ^g , where R ^g is unsubstituted heteroaryl, benzoyl, or styryl. In some embodiments, one of R ¹ and R ² is -OH and the other is unsubstituted or substituted cycloalkyl. In some embodiments, one of R ¹ and R ² is -OH and the other is unsubstituted or substituted cycloalkenyl. In other embodiments, one of R ¹ and R ² is -OH and the other is unsubstituted or substituted heterocycloalkyl.

In some embodiments, R ¹ is -OH and R ² is C(O)R ^a . In other embodiments, R ¹ is C(O)R ^a and R ² is -OH. In some embodiments, R ¹ is -OH and R ² is -CHO. In other embodiments, R ¹ is -CHO and R ² is -OH.

In some embodiments, R ³ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, and halo. In some embodiments, R ³ is methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R ³ is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R ³ is methoxy, ethoxy, propoxy, isopropoxy, butoxy, or t-butoxy. In some embodiments, R ³ is F, Cl, Br, or I. In some embodiments, R ³ is -OCH3. In some embodiments, R ³ is F. In other embodiments, R ³ is H.

In some embodiments, R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl- ^Rf , -C2-C6-alkenyl- ^Rg , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl; a R ³ is hydrogen, C ₁ -C ₆ -alkoxy or halogen.

In some embodiments, R ¹ is -OH and R ² is selected from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C2-C6-alkenyl-R ^g and unsubstituted or substituted cycloalkenyl; a R ³ is hydrogen, -OCH3 or F. In some embodiments, R ¹ is -OH; R ² is selected from the group consisting of -CHO, -C(O)CH ₃ , -C(O)CH ₂ F,

-C(O)CH=CH2, -S(O)2CH=CH2, -C(O)C CH, -C(O)C CCH3, -NHS(O)2CH=CH2, -NHC(O)CH= CH2,

-C(O)C(=CH2)CH3,

a R ³ is hydrogen, -OCH ₃ or F.

In some embodiments, R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl- ^Rf , -C2- _C6- alkenyl- ^Rg , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl; a R ³ is hydrogen, C1-C6 alkoxy or halogen. In some embodiments, R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O) ₂ R ^e , -C2-C6-alkenyl-R ^g and unsubstituted or substituted cycloalkenyl; a R ³ is hydrogen, -OCH3 or F. In some embodiments, R ² is -OH and R ¹ is selected from the group consisting of -CHO, -C(O)CH3, -C(O)CH2F,

-C(O)CH=CH ₂ , -S(O) ₂ CH=CH ₂ ,

-C(O)C(=CH2)CH3,

-C(O)C=CH, -C(O)C=CCH ₃ ,

-NHS(O)2CH=CH2,

-NHC(O)CH=CH2,

a R ³ is hydrogen, -OCH ₃ or F.

In some embodiments, R ¹ is -OH, R ² is -CHO, and R ³ is H. In some embodiments, R ¹ is -CHO, R ² is -OH, and R ³ is H. In some embodiments, R ¹ is -OH, R ² is -CHO, and R ³ is -OCH ₃ . In other embodiments, R ¹ is -CHO, R ² is -OH, and R ³ is -OCH3. In some embodiments, R ¹ is -OH, R ² is -CHO, and R ³ is F. In other embodiments, R ¹ is -CHO, R ² is -OH, and R ³ is F.

In some embodiments, R ⁴ and R ⁵ are each H. In some embodiments, R ⁴ and R ⁵ are combined to form -S- such that R ⁴ is taken together with R ⁵ and the atoms to which they are attached to form formation of a thiophene ring.

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), where X1 is absent; R ^6a is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or —C(O)R ^h , where C1-C ₆ alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), where .. .. ..... Y'-'Y . , „ 6a - .

X1 is ^or ' m is 1-6; R ^6a is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 -alkyl is unsubstituted or substituted by cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G ₃ is N or N(X1-R ^6a ), where X1 is absent; R ^6a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl.

In some embodiments, G ₃ is N or N(X1-R ^6a ), where X1 is ^m or ^m ; m is 1-6; R ^6a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G ₃ is S. In other embodiments, G ₃ is O.

In some embodiments, G ₄ is CH(X ₂ -R ^6b ) or C(X2-R ^6b ), where X2 is absent; R ^6b is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl.

In some embodiments, G ₄ is CH(X ₂ -R ^6b ) or C(X ₂ -R ^6b ), where ..... Mt . , „6b. .

X ₂ is ^or > m is 1-6; R is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 -alkyl is unsubstituted or substituted by cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G ₄ is N or N(X ₂ -R ^6b ), where X2 is absent; R ^6b is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or —C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl.

- 32 042453

In some embodiments, G4 is N or N(X2-R ^6b ), where X2 is ^{m or m} ' m is 1-6; R ^6b is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G4 is S. In other embodiments, G4 is O.

In some embodiments, G5 is CH(X ₃ -R ^6c ) or C(X3-R ^6c ), where X3 is absent; R ^6c is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or —C(O)R ^h , where C1-C ₆ alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G5 is CH(X ₃ -R ^6c ) or C(X ₃ -R ^6c ) where "" is .....M/. ., "" _.

X ₃ is ^or > m is 1-6; R is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 -alkyl is unsubstituted or substituted by cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G5 is N or N(X ₃ -R ^6c ), where X3 is absent; R ^6c is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or —C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl.

In some embodiments, the implementation of G5 represents N or N(X ₃ -R ^6c ), where X ₃ represents , „ h^ ^about 1y. . _ 6c , „ „ „ _ ^or ' m is 1-6; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G5 is S. In other embodiments, G5 is O.

In some embodiments, G ₆ is CH(X4-R ^6d ) or C(X4-R ^6d ), where X4 is absent; R ^6d is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or —C(O)R ^h , where C1-C ₆ alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl.

In some embodiments, G ₆ is CH(X4-R ^6d ) or C(X4-R ^6d ), where "M/.....M-.. " _i

X4 is ^or ' m is 1-6; R is hydrogen,

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 -alkyl is unsubstituted or substituted by cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₈ cycloalkyl. In some embodiments, G ₆ is N or N(X4-R ^6d ), where X4 is absent; R ^6d is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or —C(O)R ^h , where C1-C ₆ alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₃ -C ₈ cycloalkyl.

In some embodiments, G ₆ is N or N(X4-R ^6d ), where X ₄ is

...___ itself ^or ' m is 1-6; R represents hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or -C(O)R ^h , where Cl-C6 -alkyl is unsubstituted or substituted by cycloalkyl or halogen; a R ^h is selected from the group consisting of H, Cl-C6 alkyl, Cl-C ₆ alkoxy, and C ₃ -C ₈ cycloalkyl. In some embodiments, G ₆ is S. In other embodiments, G ₆ is O. In some embodiments, G ₆ is absent.

In some embodiments, the ring bearing ^<h -' is saturated, such that the ring is made up entirely of single bonds.

Examples of saturated rings include, but are not limited to,

In some embodiments, the ring bearing ''-L is partially unsaturated such that the ring is non-aromatic and contains at least one double bond, such as one or two double bonds.

Examples of partially unsaturated rings include, but are not limited to

- 33 042453

In other embodiments, the ring bearing * is completely unsaturated and contains two or three double bonds.

In certain embodiments, nom.

In certain embodiments, the implementation of nym and aromatic.

Examples of a fully unsaturated ring, a ring bearing *-', is a fully unsaturated * , is a fully unsaturated-

rings include, among other things,

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is CH(X ₃ -R ^6c ) or C(X3-R ^6c ), G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), and the ring bearing ''- ^; , is partially unsaturated.

In some embodiments, G ₃ is C(Xi-R ^6a ), G4 is C(X2-R ^6b ), G5 is C(X3-R ^6c ), G6 is C(X4-R ^6d ), and the ring bearing is completely unsaturated.

In some embodiments, G ₃ is CH(X1-R ^6a ), G4 is CH(X2-R ^6b ), G5 is CH(X3-R ^6c ), G6 is CH(X4-R ^6d ), and the ring bearing ^ is saturated.

In other embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is CH(X3- R ^6c ) or C(X3-R ^6c ), and G ₆ is absent.

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), G4 is N or N(X2-R ^6b ), G5 is CH(X ₃ -R ^6c ) or C (X3-R ^6c ), G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), and the ring bearing ^-^ is partially unsaturated.

In some embodiments, G ₃ is C(X1-R ^6a ), G4 is N, G5 is C(X3-R ^6c ), G6 is C(X4-R ^6d ), and the ring bearing ''- ^; , is completely unsaturated.

In some embodiments, G ₃ is CH(X1-R ^6a ), G4 is N(X2-R ^6b ), G5 is CH(X3-R ^6c ), G6 is CH(X4-R ^6d ), and the ring bearing ' is saturated.

In other embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), G4 is N or N(X2-R ^6b ), G5 is CH(X ₃ -R ^6c ) or C (X3-R ^6c ), and G6 is missing.

In some embodiments, G ₃ is N or N(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is CH(X ₃ -R ^6c ) or C (X3-R ^6c ), G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), and the ring bearing ^-^ is partially unsaturated.

In some embodiments, G ₃ is N, G4 is C(X2-R ^6b ), G5 is C(X3-R ^6c ), G6 is C(X4-R ^6d ), and the ring bearing '- ^; , is completely unsaturated.

In some embodiments, G ₃ is N(X1-R ^6a ), G4 is CH(X2-R ^6b ), G5 is CH(X3-R ^6c ), G6 is CH(X4-R ^6d ), and the ring bearing is saturated. In other embodiments, G3 is N or N(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is CH(X3-R ^6c ) or C(X3 -R ^6c ), and G6 is missing.

In some embodiments, G ₃ is CH(X1-R ^6a ) or C(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is N or N( X3-R ^6c ), G6 is CH(X4-R ^6d ) or C(X4-R ^6d ), and the ring bearing ^-^ is partially unsaturated.

In some embodiments, G ₃ is C(X1-R ^6a ), G4 is C(X2-R ^6b ), G5 is N, G ₆ is C(X4-R ^6d ), and the ring bearing ''-', is completely unsaturated.

In some embodiments, G ₃ is CH(X1-R ^6a ), G4 is CH(X2-R ^6b ), G5 is N(X3-R ^6c ), G6 is CH(X4-R ^6d ), and the ring bearing ^-^ is saturated. In other embodiments, G3 is CH(Xi-R ^6a ) or C(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is N or N(X3 -R ^6c ), and G6 is missing.

In other embodiments, G ₃ is N or N(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is N or N(X1-R ^6c ), G ₆ is CH(X4-R ^6d ) or

- 34 042453

C(X4-R ^6d ), and the ring bearing is partially unsaturated.

In some embodiments, G ₃ is N, G4 is C(X2-R ^6b ), G5 is N, G ₆ is C(X4-R ^6d ), and the ring bearing α is fully unsaturated.

In some embodiments, G ₃ is N(X ₁ -R ^6a ), G4 is CH(X2-R ^6b ), G5 is N(X1-R ^6c ), G6 is CH(X4-R ^6d ), and the ring carrying ^1χ -' is saturated. In other embodiments, G3 is N or N(X1-R ^6a ), G4 is CH(X2-R ^6b ) or C(X2-R ^6b ), G5 is N or N(X1-R ^6c ), a G ₆ is missing.

In certain embodiments, R ⁴ and R ⁵ combine to form -S-, G3 is CH(X1-R ^6a ), G4 is N(X2-R ^6b ), G5 is CH(X1-R ^6a ), G6 is CH(X1-R ^6a ) and the ring bearing ^1'- ' is a saturated ring.

In certain embodiments, R ⁴ and R ⁵ combine to form -S-, G ₃ , G5 and G ₆ are each CH2, G4 is N(X2-R ^6b ), and the ring bearing ^-^ is saturated ring.

In some of any of the above embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1 -C ₆ -alkyl is unsubstituted or substituted with cycloalkyl or halogen; R ^h is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy and C3-C8 cycloalkyl. In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1- _C6 alkyl, _C1 - _C6 alkoxy, or halogen.

In some embodiments, each R ⁶ is independently selected from the group consisting of Cl, o

F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3, -C(O)CH3, and .

In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of H, Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3,

-C(O)CH3, o

In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of H, -OH,

In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of H,

In some of any of the above embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1 -C ₆ -alkyl is unsubstituted or substituted with cycloalkyl or halogen, and the remaining three of R ^6a , R ^6b , R ^6c and R ^6d each represent hydrogen. In some embodiments, one of R ^6a , R ^6b , R ^6c and R ^6d is selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3)2, -C(O )OC(CH3)3,

- 35 042453

-C(O)CH3,

, and the remaining three of R ^6a , R ^6b , R ^6c and R ^6d each represent hydrogen.

In some embodiments, R ^6a , R ^6b and R ^6d are each H and R ^6c is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6a , R ^6b and R ^6d are each H and R ^6c is selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3)z , -C(O)OC(CH3)3, -C(O)CH3, o ^v and ^v .

In some embodiments, R ^6b , R ^6c and R ^6d are each H and R ^6a is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6b , R ^6c and R ^6d are each H and R ^6a is selected from the group consisting of Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH( CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ , o ^v and ^v .

In some embodiments, R ^6a , R ^6c and R ^6d are each H and R ^6b is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6a , R ^6c and R ^6d are each H and R ^6b is selected from the group consisting of Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH( CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ , o ^v and ^v .

In some embodiments, R ^6a , R ^6b and R ^6c are each H, and R ^6d is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6a , R ^6b and R ^6c are each H and R ^6d is selected from the group consisting of Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH( CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ , o ^v and ^v .

In some of any of the above embodiments, two of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1 -C ₆ -alkyl is unsubstituted or substituted with cycloalkyl or halogen, and the remaining two of R ^6a , R ^6b , R ^6c and R ^6d each represent hydrogen.

In some embodiments, two of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of

Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH(CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ , these are two of R ^6a , R ^6b , R ^6c and R ^6d each represent hydrogen.

and the rest In some embodiments, R ^6a and R ^6b are each H, and R ^6c and R ^6d are independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6a and R ^6b are each H, and R ^6c and R ^6d are independently selected from the group consisting of Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH (CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ ,

-C(O)CH3,

In some embodiments, R ^6a and R ^6c are each H, and R ^6b and R ^6d are independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen. In some embodiments, R ^6a and R ^6c are each H, and R ^6b and R ^6d are independently selected from the group consisting of Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH (CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ , o ^v and ^v .

In some embodiments, R ^6a and R ^6d are each H, and R ^6b and R ^6c are independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h where C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

- 36 042453

In some embodiments, R ^6a and R ^6d are each H, and R ^6b and R ^6c are independently selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3) 2, -C (O) OS (CH3) s, o

-C(O)CH3,

In some embodiments, R ^6b and R ^6c are each H, and R ^6a and R ^6d are independently selected from the group consisting of C1- _C6 alkyl, C1- _C6 alkoxy, halogen, or -C(O) R ^h , where

C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6b and R ^6c are each H, and R ^6a and R ^6d are independently selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3) 2, -C (O) OS (CH3) s, o

-C(O)CH3,

In some embodiments, R ^6b and R ^6d are each H, and R ^6a and R ^6c are independently selected from the group consisting of C1- _C6 alkyl, C1- _C6 alkoxy, halogen, or -C(O) R ^h , where

C1- _C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6b and R ^6d are each H, and R ^6a and R ^6c are independently selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3) 2, -C (O) OS (CH3) s, o

-C(O)CH3, and .

In some embodiments, R ^6c and R ^6d are each H, and R ^6a and R ^6b are independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6c and R ^6d are each H, and R ^6a and R ^6b are independently selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3) 2, -C (O) OS (CH3) s, o

-C(O)CH3, and .

In some of any of the above embodiments, three of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen or -C(O)R ^h where C1 -C6-alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, three of R ^6a , R ^6b , R ^6c and R ^6d are selected from the group consisting of o

Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH (CH _s ) ₂ , -C (O) OS (CH _s ) _s , -C (O) CH _s ,

In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d are each selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, or -C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, R ^6a , R ^6b , R ^6c and R ^6d each represent hydrogen.

In some embodiments, is or

is ^R6b-X2 > X2 absent, before ^m ; m is 1-6; R ^6b represents hydrogen, C1-C ₆ -alkyl,

C1- _C6 alkoxy, halogen or -C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C6 alkyl, C1-C ₆ alkoxy, or

C ₃ -C ₈ -cycloalkyl.

In some embodiments

is ^R6b ” ^X2 , X2 is absent, a

R ^6b _is selected from hydrogen Cl, F, -CH ₃ , -OCH ₃ , -CF ₃ , -CH2CH2F, -CH(CH 3 _{) 2} , -C(O)OC(CH ₃ ) 3 , -C(O)CH _h , o

In some embodiments

represents

X2 is absent, a

- 37 042453

R ^6b is selected from hydrogen, -CH3, -CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3, -C(O)CH

In some embodiments

represents

R6C

In some embodiments

represents

^k6 " ^or r ^6c where R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of is

In some embodiments

C1-C ₆ -alkyl, C1-C ₆ -alkoxy, halogen or -C(O)R ^h , where C1-C ₆ -alkyl is unsubstituted or substituted by cycloalkyl or halogen.

each independently selected from the group where R ^6a , R ^6b , R ^6c and R ^6d consisting of C1-C ₆ -alkyl, C1-C ₆ -alkoxy, halogen or

-C(O)R ^h , where C1-C ₆ alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments

is a group consisting of -CH ₃ , -CH ₂ CH ₂ F, -CH(CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ ,

In some embodiments

is a group consisting of -CH3, -CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3, -C(O)CH3

> where R ^6a is selected from ' where R ^6a is selected from

- 38 042453

In some embodiments

is a ny consisting of -CH3, -CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3, -C(O)CH3,

In some embodiments, independently, are selected from the group consisting of

In some embodiments, independently, are selected from the group consisting of

In some embodiments

In other embodiments

R ^6c > where R ^6c is selected from the group

represents ^{R6b R6d} > where R ^6b and R ^6d each of -CH ₃ , -CH2CH2F, -CH(CH 3 _{) 2} , -C(O)OC(CH 3 _{) 3} , -C(O)CH ₃ ,

represents

^R1

R ^6c ' where R ^6a and R ^6d , each of -CH ₃ , -CH2CH2F, -CH(CH _s ) ₂ , -C(O)OC(CH _s ) _s , -C(O)CH _s ,

represents

represents

In some embodiments, G1 and G2 are each CH; R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^C , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ is hydrogen, C1-C6 alkoxy or halogen; a R ⁴ and R ⁵ are each H. In some embodiments, G1 and G2 are each CH; R ¹ is -OH and R ² is selected from the group consisting of -C(O)R ^a , -S(O)2R ^C , -NHC(O)R ^d , -NHS(O)2R ^e , -C2 -C ₆ -alkenyl-R ^g and unsubstituted or substituted cycloalkenyl; R ³ is hydrogen, -OCH ₃ or F; a R ⁴ and R ⁵ are each H.

In some embodiments

G1 and G2 are each CH;

R ¹ is -OH;

R ² is selected from the group consisting of -CHO, -C(O)CH3, -C(O)CH2F, -C(O)CH=CH2, -S(OhCH=CH2 _;

-C(O)C CH, -C(O)C CCH ₃ , -NHS(O) ₂ CH=CH ₂ , -NHC(O)CH=CH ₂ , -C(O)C(=CH ₂ )CH _h ,

R ³ is hydrogen, -OCH ₃ or F;

R ⁴ and R ⁵ are each H.

In some embodiments, G1 and G2 are each CH; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(OhR ^C , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6 -alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl R ³ is hydrogen, C1-C ₆ alkoxy or halogen a R ⁴ and R ⁵ are each H. In some embodiments, G1 and G2 are each CH, R ² is -OH, R ¹ is selected

- 39 042453 from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C2-C6-alkenyl-R ^g and unsubstituted or substituted cycloalkenyl; R ³ is hydrogen, -OCH3 or F; a R ⁴ and R ⁵ are each H. In some embodiments, G1 and G2 are each CH; R ² is -OH and R ¹ is selected from the group consisting of -CHO, -C(O)CH ₃ , -C(O)CH2F,

-C(O)CH=CH2,

-S(OhCH=CH2, -C(O)C CH, -((OC CClh. -NHS(O)2CH=CH2, -NHC(O)CH=CH2,

-C(O)C(=CH2)CH3,

is hydrogen, -OCH ₃ or F; a R ⁴ and R ⁵ are each H.

R ³ pre-

In any of the above embodiments, ⁴ ' ^G ^ ⁶ represents

where R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen or -C(O)R ^h where C1-C ₆ - alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, G ₁ and G ₂ are each CH; R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ is hydrogen, C1-C6 alkoxy or halogen; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, G1 and G ₂ are each CH; R ¹ is -OH and R ² is selected from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C2 -C6-alkenyl-R ^g and unsubstituted or substituted cycloalkenyl; R ³ is hydrogen, -OCH3 or F; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, G1 and G2 are each CH; R ¹ is -OH; R ² is selected from the group consisting of -CHO, -C(O)CH3, -C(O)CH ₂ F, -C(O)CH=CH ₂ , -S(O) ₂ CH=CH ₂ , -C (O)C CH, -C(O)C CCH ₃ , -NHS(O) ₂ CH=CH ₂ ,

-NHC(O)CH=CH2, -C(O)C(=CH2)CH3, R ³ is hydrogen, -OCH3 or F; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, G1 and G2 _are each CH; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-I ^g , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ is hydrogen, C1-C6 alkoxy or halogen; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, G1 and G ₂ are each CH; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O) ₂ R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C2-C ₆ -alkenyl-R ^g and unsubstituted or substituted cycloalkenyl; R ³ is hydrogen, -OCH ₃ or F; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, G1 and G2 are each CH; R ² is -OH and R ¹ is selected from the group consisting of -CHO, -C(O)CH ₃ , -C(O)CH ₂ F, -C(O)CH=CH ₂ ,

- 40 042453

-S(O)2CH=CH2, -C(O)CCH, -C(O)C CCH3, -NHS(O)2CH=CH2, -NHC(O)CH=CH2, -C(O)C( \u003d CH2) CH3,

-OCH ₃ or F; a R ⁴ and R ⁵ combine to form -S-. In any of

R ³ is hydrogen, of the above embodiments

is ^{R6b X2} ' X2 is absent, a

R ^6b is selected from hydrogen, -CH ₃ ,

-CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3, -C(O)CH3,

In some embodiments, one of G ₁ and G2 is N and the other is CH; R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ is hydrogen, C1-C6 alkoxy or halogen; a R ⁴ and R ⁵ are each H. In some embodiments, one of G1 and G ₂ is N and the other is CH; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ represents hydrogen, C1-C ₆ -alkoxy or halogen; a R ⁴ and R ⁵ are each H.

In any of the above embodiments, is

where R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen or -C(O)R ^h where C1-C6-alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, one of G1 and G2 is N and the other is CH; R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ represents hydrogen, C1-C ₆ -alkoxy or halogen; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, one of G1 and G2 is N and the other is CH; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ represents hydrogen, C1-C ₆ -alkoxy or halogen; a R ⁴ and R ⁵ combine to form -S-.

- 41 042453

In any of the above embodiments

is ^{RSb X2} ' X2 is absent, and R ^6b is selected from hydrogen, -CH ₃ , -CH2CH2F, -CH(CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ ,

In some embodiments, G ₁ and G2 are both N; R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O) ₂ R ^e , - C1-C6 alkyl-R ^f , -C2-C ₆ alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl; R ³ represents hydrogen, C ₁ -C ₆ -alkoxy or halogen; a R ⁴ and R ⁵ are each H. In some embodiments, G1 and G2 are both N; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(OhR ^e , -C1-C6 -alkyl-R ^f , -C2-C6-alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl R ³ is hydrogen, C1-C ₆ alkoxy or halogen a R ⁴ and R ⁵ are each H.

G4' -^Gg

In any of the above embodiments, ' ^Gs is

where R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen or -C(O)R ^h where C1-C ₆ - alkyl is unsubstituted or substituted with cycloalkyl or halogen.

In some embodiments, G1 and G2 are both N; R ¹ is -OH; R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1 -C6-alkyl-R ^f , -C2-C ₆ -alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl; R ³ is hydrogen, C1-C6 alkoxy or halogen; a R ⁴ and R ⁵ combine to form -S-. In some embodiments, G1 and G ₂ are both N; R ² is -OH; R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(OhR ^c , -NHC(O)R ^d , -NHS(OhR ^e , -C1-C6-alkyl -R ^f , -C2-C6-alkenyl-R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl and unsubstituted or substituted heterocycloalkyl R ³ is hydrogen, C1-C ₆ alkoxy or halogen a R ⁴ and R ⁵ combine to form -S-.

In any of the above embodiments

is ^{R6b Xg} > X ₂ is absent, and R ^6b is selected from hydrogen, -CH ₃ , -CH2CH2F, -CH(CH ₃ ) ₂ , -C(O)OC(CH ₃ ) ₃ , -C(O)CH ₃ ,

In some embodiments, when R ¹ is -OH; R ² is -CHO; R ³ is H; G1, G2, G3, G4 and G6 are each CH; a R ⁴ and R ⁵ are each H, G5 is not CH, CBr, COCH ₃ , CCH ₃ , CCl or CF. In some variants, osu

- 42 042453 when R ¹ is -OH; R ² is -CHO; R ³ is H; Gb G2, G3, G5 and G6 are each CH; a R ⁴ and R ⁵ are each H, G4 is not -CF3. In some embodiments, when R ¹ is -CHO; R ² is -OH; R ³ is H; G ₁ , G ₂ , G4 and G6 each represent CH; R ⁴ and R ⁵ are each H; a G ₃ is -OCH ₃ , G5 is not n-propyl. In some embodiments, when R ¹ is -NHC(O)CH3; R ² is -OH; R ³ is H; G1 and G ₂ are each CH; a R ⁴ and R ⁵ are each H; at least one of G ₃ , G4, G5 and G6 is other than CH.

In one aspect, the compound of formula (I) is a compound of formula (Ia)

or a tautomer, or a pharmaceutically acceptable salt of any of the above, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , G _{1 , G 2 ,} G ₃ , G4, G5 and G6 are as defined for formula (I ) or any variation or embodiment thereof, and wherein the stereochemistry with respect to the double bond shown in formula (Ia) is as shown in formula.

In another aspect, the compound of formula (I) is a compound of formula (Ib)

R ^{1 G} k X> ^G 2 ^G 3 J γ r ⁴ R ⁵ (Ib) or a tautomer, or a pharmaceutically acceptable salt of any of the above, where R ¹ , R ² , R 3 , R ⁴ , ^{R 5 ,} G ₁ , G ₂ , G ₃ , G4, G5 and G ₆ are as defined for formula (I) or any variation or embodiment thereof, and where the stereochemistry with respect to the double bond shown in formula (Ib) is as shown in the formula.

It should be understood that, unless otherwise indicated, any of the embodiments described herein, such as those described with respect to formula (A), formula (A-1), formula (A-2), formula (I), formula (Ia) and formula (Ib) are also intended to apply to any other formula described herein, including formula (A), formula (A-1), formula (A-2), formula (I), formula ( Ia) and formula (Ib).

In some embodiments, provided herein are the compounds and their salts described in Table 1. 1.

Table 1

conn. no. Chemical structure chemical name 1 OH MeO_X, SNO TU 9 OMe (E)-2-hydroxy-3-methoxy-5-(4methoxystyryl)benzaldehyde

- 43 042453

2 O I and co ¹ /° ° \ /—/ \ Г f S (E)-2-hydroxy-3-methoxy-5-(3(trifluoromethyl)styryl)benzaldehyde d 3 3 f o I o 5-(4-chlorostyryl)-2-hydroxy-3 methoxybenzaldehyde 4 He MeO^A^CHO o 0 (E)-2-hydroxy-3-methoxy-5 styrylbenzaldehyde 5 He MeO^L^CHO y A, (E)-5-(3,5-difluorostyryl)-2hydroxy-3-methoxybenzaldehyde 6 He MeO^A^CHO y ¥ F (E)-5-(2,4-difluorostyryl)-2- hydroxy-3-methoxybenzaldehyde

-44042453

7 OH MeO^^L/CHO XY Q F (E)-5-(4-fluorostyryl)-2-hydroxy-3methoxybenzaldehyde 8 OH MeO.X.CHO XX 9 CF ₃ (E)-2-hydroxy-3-methoxy-5-(4(trifluoromethyl)styryl)benzaldehyde d 9 It 9 ome (E)-1-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)ethan-1-one 10 o I o (E)-3-fluoro-2-hydroxy-5-(4methoxystyryl)benzaldehyde AND HL /=( )=/ —( d-o i ¹ “ o x o (E) -3 -fluoro-2-hydroxy-5 - (3 - (trifluoromethyl)styryl)benzaldehydes D

- 45 042453

12 ABOUT X about ° \=/LH1 O o f m S tert-butyl 2-(3-formyl-4- hydroxy-5-methoxyphenyl)-6,7 dihydrothieno[3,2-c]pyridine in5(4H)-carboxylate 13 o X o °l=^lX2 o ¹ f S 2-hydroxy-3-methoxy-5-(4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)benzaldehyde hydrochloride 14 AoA o X about 5 - (5 - (cyclopropanecarbonyl) 4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-2-hydroxy-3-methoxybenzaldehyde 15 He MeO^A_CHO XY N—/ °h Me 5-(5-Acetyl-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-3-methoxybenzaldehyde

-46042453

16 OH MeO.X.SNO XU Xv N—/ F 5-(5-(2-fluoroethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-3methoxybenzaldehyde 17 OH MeO^X^CHO XX \ ^s 5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-3- methoxybenzaldehyde 18 he kX.CHO XX \ ^s N—/ Me 3-fluoro-2-hydroxy-5-(5-methyl- 4, 5,6,7-tetrahydrothieno[3,2с]pyridin-2-yl)benzaldehyde 19 OH kX.CHO XX \ ^s N—X °4 Me 5-(5-acetyl-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-3-fluoro-2- hydroxybenzaldehyde

- 47 042453

20 OH MeO^X, CHO y \ ^s N—/ Me—( Me 2-hydroxy-5-(5-isopropyl-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-3-methoxybenzaldehyde 21 About X ϋ --Λ 7=2 \—/ C_/ \ 5 (E)-2-hydroxy-5-(2-(6methylpyride in-3 yl)vinyl)benzaldehyde 22 LA / ^0Me MeO—/ /=< \=/ \ChTsnon / ⁰ (E)-1 - (2-hydroxy-3 -methoxy-5 - (4methoxystyryl) phenyl) prop-2-en-1 - He 23 LA / ^0Me MeO—/ /=( \=/ sf° c (E)-2-methoxy-4-(4methoxystyryl)-6(vinylsulfonyl)phenol 24 MeO-fH \=/ mu° ⁿ / ⁰ (E)-1 - (2-hydroxy-3 -methoxy-5 - (4methoxystyryl) phenyl) prop-2-yn-1 - He 25 O / ^0Me MeO-C y^x /=< \=/ /° / (E)-1-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)but-2-yn-1-one

- 48 042453

26 LA / ^OMe MeO—C y^ /=< O. , ^NH zS °? (E)^-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)ethensulfone amide 27 _Meo ^Y^ \=/ VQ-one /° (E)-1-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)-2methylprop-2-en-1-one 28 LA / ^OMe MeO—C y^x /=< \=/ \^>one /° O (E)-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)(2methyloxiran-2-yl)methanone 29 OH O I N N^O 1 n f OME (E)-6-(2-hydroxy-3-methoxy-5-(4methoxystyryl)benzoyl)-3 isopentyl-3,4-dihydropyrido[2,3<1]pyrimidin-2(1Н)-one thirty LA / ^0Me MeO—/ y^x /=< M^^ ^on / ⁰ W (E)-1-(2-hydroxy-3-methoxy-5-((E)4-methoxystyryl)phenyl)-3phenylprop-2-en-1-one 31 LA / ^0Me MeO—/ y^x /=( \=/ AnuGon / ⁰ W (E)-3-(2-hydroxy-3-methoxy-5-((E)4-methoxystyryl)phenyl)-1-phenylprop-2-en-1-one

- 49 042453

32 /ch / ^0Me MeO-C /=< \=/ ν-z # ^{he N} \ o. , ^NH zS (E)-X-(3-hydroxy-4-methoxy-6-(4methoxystyryl)pyridin-2yl)ethensulfonamide 33 m.o ^ Y ^ J * \u003d ⁷ VQ-OH / ° O (E)-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)(6methylpyride in-3-yl)methanone 34 /G\ / ^0Me MeO-6 /=< \=/ NH (E)-M-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)acrylamide 35 _ OMe / ⁰ 1 - (5 - (5 - (cyclopropylmethyl) 4,5,6,7-tetrahydrothieno[3,2s] pyridin-2-yl) -2-hydroxy-3 methoxyphenyl) prop-2-en-1 -one 36 _ OMe V 4-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-methoxy-6- (vinylsulfonyl)phenol 37 _ OMe <Α><λ ^0Η / ⁰ / 1 - (5 - (5 - (cyclopropylmethyl) 4,5,6,7-tetrahydrothieno[3,2s] pyridin-2-yl) -2-hydroxy-3 methoxyphenyl) prop-2-in-1 -one

- 50 042453

38 r\ OMe -^G ^he /° / 1 - (5 - (5 - (opylmethyl cycle) 4,5,6,7-tetrahydrothieno[3,2c] pyridin-2-yl) -2-hydroxy-3 methoxyphenyl) but-2-yn-1 -one 39 ome T4-(5-(5-(cyclopropylmethyl)- GU 4,5,6,7-tetrahydrothieno[3,2- ^nNH c]pyridin-2-yl)-2-hydroxy-3 - °*S °1 methoxyfenyl)etensu lfonamide 40 OH 0 6-(5 -(5 -(opylmethyl cycle)- T Ύ | n 4,5,6,7-tetrahydrothieno[3,2- 'N^O N H c]pyridin-2-yl)-2-hydroxy-3 - methoxybenzoyl)-3 -isopentyl-3,4- N—/ dihydropyrido[2,3-(1]pyrimidine- L 2(1Н)-one 41 ome 1 - (5 - (5 - (opylmethyl cycle) - GU ^43rOH 4,5,6,7-tetrahydrothieno[3,2- O \=O c]pyridin-2-yl)-2-hydroxy-3 - methoxyphenyl)-2-methylprop-2-en- 1-he ome (5 - (5 - (cyclopropylmethyl) -4,5,6,7- GU -^ ^CrOH tetrahydrothieno[3,2-c]pyridine-2- 42 /° yl)-2-hydroxy-3-methoxyphenyl)(2- ABOUT methyloxiran-2-yl) methanone 43 /V\ ome (E) -1 - (5 - (5 - (cyclopropylmethyl) - GU ^s ^4ZrOH 4,5,6,7-tetrahydrothieno[3,2- /=0 c]pyridin-2-yl)-2-hydroxy-3 - methoxyphenyl)-3-phenylprop-2-en- 1-he /----\ w

- 51 042453

44 ome / /° w (E)-3-(5-(5-(cyclopropylmethyl)4,5,6,7-tetrahydrothieno[3,2c]pyridin-2-yl)-2-hydroxy-3 methoxyphenyl)-1-phenylprop-2- en1-he 45 OMe ULH / X ^he N - 0., ^NH yS °? M-(6-(5-(cyclopropylmethyl)4,5,6,7-tetrahydrothieno[3,2c]pyridin-2-yl)-3-hydroxy-4methoxypyridin-2yl)ethensulfonamide 46 <Α><λ ^0Η / ⁰ о (5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-3-methoxyphenyl)(6methylpyride in-3-yl)methanone 47 OMe ^'Hul j=^ <DH^ ^OH NH ”7 M-(5-(5-(cyclopropylmethyl)4,5,6,7-tetrahydrothieno[3,2c]pyridin-2-yl)-2-hydroxy-3-methoxyphenyl)acrylamide 48 nGA / ^OMe MeO—C \—l /=< \=/ ν--<( b—CHO he (E)-2-hydroxy-6-methoxy-4-(4methoxystyryl)benzaldehyde 49 ^Ome he 4-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-6methoxybenzaldehyde

- 52 042453

50 OMe \=/ OMe MZr ^0H CHO (2)-2-hydroxy-3-methoxy-5-(4methoxystyryl)benzaldehyde 51 GL / ^OME \=/ /° F (E) -2-fluoro-1 - (2-hydroxy-3 methoxy-5- (4- methoxystyryl)phenyl)ethan-1-one 52 LA / ^0Me \=/ ° \ / (E)-2'-hydroxy-3'-methoxy-5'-(4methoxystyryl)-4,5-dihydro-[ 1, Hbiphenyl]-2(3H)-one 53 LA / ^0Me MeO—/ U—λ /=< \=/ ° \ / (E)-2'-hydroxy-3'-methoxy-5'-(4methoxystyryl)-5,6-dihydro-[ 1, Hbiphenyl] -2(1 H)-one 54 LA / ^0Me MeO—C /=< \=/ MC-one ° \ / ° (E)-2'-hydroxy-3'-methoxy-5'-(4methoxystyryl)-[1,G-biphenyl]-2,5- dion 55 he xk ^ ^CHO ί t 9 OMe (E)-4-fluoro-2-hydroxy-5-(4methoxystyryl)benzaldehyde

-53 042453

56 OH MeO^^CHO V r^N (E)-2-hydroxy-3-methoxy-5 -(2- (pyridin-2-yl)vinyl)benzaldehyde 57 HE J^CHO T r^N and (E)-2-hydroxy-5-(2-(pyridin-2yl)vinyl)benzaldehyde 58 it is MeO^X^CHO and o N (E)-2-hydroxy-3-methoxy-5 -(2- (pyridin-4-yl)vinyl)benzaldehyde 59 OH MeO^X^CHO XY ό Me (E)-2-hydroxy-3-methoxy-5-(2-(6methylpyride in-3 yl)vinyl)benzaldehyde 60 OH MeO.L.SNO HU Vos tert-butyl (E) -4- (3-formyl-4- hydroxy-5methoxystyryl)piperidine-1 carboxylate

- 54 042453

61 OH R±XHO XT rT^N and (E)-3-fluoro-2-hydroxy-5-(2- (pyridin-2-yl)vinyl)benzaldehyde 62 o z o (E)-3-fluoro-2-hydroxy-5-(2-(6methylpyride in-3 yl)vinyl)benzaldehyde 63 OH κΛ,ΟΗΟ XT ό N (E)-3-fluoro-2-hydroxy-5-(2- (pyridin-4-yl)vinyl)benzaldehyde 64 OH R^X/CHO XT 1 Sun tert-butyl (E)-4-(3-fluoro-5- formyl-4hydroxystyryl)piperidine-1 carboxylate 65 OH MeO.X, CHO XT Ql Ό (E)-2-hydroxy-3-methoxy-5-(2(naphthalene-2yl)vinyl)benzaldehyde

-55042453

66 ABOUT V ΛΆ o o f S (E)-2-hydroxy-3-methoxy-5-(3-oxo-3-phenylprop-1-en-1-yl)benzaldehyde 67 he is MeO^U.CHO XY OL ^^ome he (E) -2-hydroxy-5 - (4-hydroxy-3 - methoxystyryl)-3-methoxybenzaldehyde 68 He MeO^X.CHO ? Ο^Ν^ l^^o (E)-2-hydroxy-3-methoxy-5-(3-morpholino-3-oxoprop-1-en-1 yl)benzaldehyde 69 OH MeO^X^CHO XY I O (E)-5-(2-([1,1'-biphenyl]-4-yl)vinyl)-2hydroxy-3-methoxybenzaldehyde

- 56 042453

70 OH R±XHO XT 1 O (E)-5-(2-([1,1'-biphenyl]-4yl)vinyl)-3-fluoro-2hydroxybenzaldehyde 71 He MeO^X-CHO XT άγ^ο 5-(2-(2,3- dihydrobenzo[b][1,4]dioxin-6yl)vinyl)-2-hydroxy-3methoxybenzaldehyde 72 he κΧ,οηο XT (E)-5-(2-(2,3- dihydrobenzo[b][1,4]dioxin-6yl)vinyl)-3-fluoro-2hydroxybenzaldehyde Cl η^^ο o^D 73 He MeO^L^CHO XT (E)-2-hydroxy-3-methoxy-5-(4morpholinostyryl)benzaldehyde Q0

- 57 042453

74 HE (2)-2-hydroxy-3-methoxy-5-(4- „ . MeO > CHO 9 v W morpholinostyryl)benzaldehyde 75 He (E)-3-fluoro-2-hydroxy-5-(4- F^^L^CHO Ϋ morpholinostyryl)benzaldehyde 9 0 76 HE (2)-3-fluoro-2-hydroxy-5-(4- F. L, CHO 9 L W morpholinostyryl)benzaldehyde ai 77 He (E)-2-hydroxy-3-methoxy-5 -(3 - D G J 0m e f S morpholinostyryl)benzaldehyde ό !^o 78 He (E) -3 -fluoro-2-hydroxy-5 - (3 - ABOUT G o Em I. morpholinostyryl)benzaldehyde With Z-

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79 HE MeO^HyuNO tt A (E)-2-hydroxy-3-methoxy-5 -(3 - (pyrrolidin-1 -yl)styryl)benzaldehyde 80 GU-x /=( _GU M>s 0 s o (E) -3 -fluoro-2-hydroxy-5 - (3 - (pyrrolidin-1 -yl)styryl)benzaldehyde 81 he MeO^/khno 9 (E)-2-hydroxy-3-methoxy-5 -(4- (pyrrolidin-1 -yl)styryl)benzaldehyde 82 OH E/cno Y R (E)-3-fluoro-2-hydroxy-5-(4- (pyrrolidin-1 -yl)styryl)benzaldehyde

- 59 042453

83 HE _ R Lchio G^U uu (2)-3-fluoro-2-hydroxy-5-(4- (pyrrolidin-1yl)styryl)benzaldehyde 84 Oh _MeO. X /CHO G^V V.J. (2)-2-hydroxy-3-methoxy-5-(4- (pyrrolidine-1- yl)styryl)benzaldehyde 85 CHO MeO^X^OH Ύ 0 (E)-2-hydroxy-6-methoxy-4-(4- (pyrrolidine-1- yl)styryl)benzaldehyde 86 CHO F^/GoH Q (E)-2-fluoro-6-hydroxy-4-(4- (pyrrolidin-1yl)styryl)benzaldehyde 87 OH MeO^J^CHO 9 0 (E)-2-hydroxy-3-methoxy-5-(4-(2methoxyethoxy)styryl)benzaldehyde

- 60 042453

88 / oh z oh (E)-3-fluoro-2-hydroxy-5-(4-(2methoxyethoxy)styryl)benzal- dehyde 89 he MeO^L^CHO V 9 about (E)-5-(4-( 1 H-pyrazol-1 -yl)styryl)2-hydroxy-3-methoxybenzaldehyde 90 o X o (E)-5-(4-( 1 H-pyrazol-1 -yl)styryl)3-fluoro-2-hydroxybenzaldehyde 91 He MeO^xL^CHO THAT Ql nO (E)-2-hydroxy-3-methoxy-5 -(2- (quinolin-6-yl)vinyl)benzaldehyde

-61 042453

92 OH rX_CHO TU (E)-3-fluoro-2-hydroxy-5-(2- (quinolin-6-yl)vinyl)benzaldehyde Ol no 93 he MeO^X, CHO TU Ql W<DU tert-butyl (E) -6- (3-formyl-4- hydroxy-5-methoxystyryl)-3,4dihydroquinoline-1 (2Н)carboxylate 94 00 o xw 0= ⁷ o X o tert-butyl (E)-6-(3-fluoro-5- formyl-4-hydroxystyryl)-3,4dihydroquinoline-1 (2H) carboxylate 95 he ^XxNO TU Q •XY (E)-3-fluoro-2-hydroxy-5-(2-(1-methyl-1,2,3,4-tetrahydroquinolin6-yl)vinyl)benzaldehyde

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96 About I and /=x /— g lu f S (E)-5-(4-(diethylamino)styryl)-2hydroxy-3-methoxybenzaldehyde 97 o t o (E)-5-(4-(diethylamino)styryl)-3fluoro-2-hydroxybenzaldehyde 98 OH MeO^X, CHO o Q (E)-5-(4- (cyclopropylmethoxy)styryl)-2hydroxy-3-methoxybenzaldehyde 99 OUK /k gk I 0 (E)-5-(4- (cyclopropylmethoxy)styryl)-3 fluoro-2-hydroxybenzaldehyde

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100 He MeO^X/CHO XY (E)-5-(2-(chroman-6-yl)vinyl)-2- hydroxy-3-methoxybenzaldehyde Qo^J 101 He F.X.CHO XY Ql (E)-5-(2-(chroman-6-yl)vinyl)-3fluoro-2-hydroxybenzaldehyde 102 He MeO^X^CHO HU f (E)-2-hydroxy-3-methoxy-5 -(4- (piperidine-1- yl)styryl)benzaldehyde 103 o X o (E)-3-fluoro-2-hydroxy-5-(4(piperidin-1yl)styryl)benzaldehyde

- 64 042453

104 CHO FXX/OH XY Q0 (E)-2-fluoro-6-hydroxy-4-(4- (piperidine-1- yl)styryl)benzaldehyde 105 CHO κΑ,ΟΗ HU Q0 (E)-4-(4-(4-ethylpiperazin-1 yl)styryl)-2-fluoro-6hydroxybenzaldehyde 106 ΛΑ ° \ / φθ s (E)-3-(5-(5- (cyclopropanecarbonyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one 107 OH 0 MeoAlziX,^ XY and \ ^s nT (E)-1-(5-(5- (cyclopropanecarbonyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2yl)-2-hydroxy-3-methoxyphenyl)-3-phenylprop-2-en-1-one

- 65 042453

108 F, Ίί A Oh ) 0^ (E)-2-(1,3-dioxan-2-yl)-6-fluoro-4- (4-(pyrrolidin-1 -yl)styryl)phenol 109 fs Ίι A Oh 1] 2-fluoro-6-((E)-((4-methylpiperazine- 1 -yl)imino)methyl)-4-((E)-4(pyrrolidin-1-yl)styryl)phenol 110 R Ίι A Oh 1] H-v ^N _r o N'-((E)-3 -fluoro-2-hydroxy-5 -((E)-4(pyrrolidine-1- yl)styryl)benzylidene)acetohydrase id 111 R Ίι A Oh b 2-fluoro-6-((E)- (phenylimino)methyl)-4-((E)-4- (pyrrolidin-1 -yl)styryl)phenol

- 66 042453

112 he _s 1 P 'xX'O 9 2-φτορ-6-((Ε)-(2- phenylhydrazono)methyl)-4-((E)-4(pyrrolidin-1-yl)styryl)phenol FROM X ZI b Ν'-((Ε)-3-fluoro-2-hydroxy-5-((E)-4(πirpolidin-lyl)styryl)benzylidene)benzohydrazide 114 JUa/) Τι ^T _x o _h H J o' ^s o 9 ό Ν'-((Ε)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1yl)styryl)benzylidene)benzenesul phonohydrazide 115 he '9τ ^ν °Ό 9 0 (E)-3 -fluoro-2-hydroxy-5 -((E)-4- (pyrrolidine-1- yl) styryl) benzaldehyde 0- phenyloxime

- 67 042453

116 OH 'Ϋ Λ Η ^Ν' ^Ν γ ^ΝΗ2 ΝΗ 2-((E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidine-1- yl)styryl)benzylidene)hydrazine-1 carboximidamide ό 117 it MeO^X04 XT (E)-3-(3-cinnamoyl-4-hydroxy-5-methoxyphenyl)-1-phenylprop-2-en1-one ° and 118 He at -..-O 4-(((E)-3 -fluoro-2-hydroxy-5 -((E)-4(pyrrolidine-1- yl)styryl)benzylidene)amino)-1 methylpiperazine 1-oxide 9 119 o^y-v u. ^0 (E)-3-fluoro-2-hydroxy-5-(2-(6(pyrrolide in-1 -yl)pyride in-3 yl)vinyl)benzaldehyde 0

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120 OH y ⁰ An τ ύ (E)-3-fluoro-2-hydroxy-5-(2-(5(pyrrolidin-1-yl)pyridin-2yl)vinyl)benzaldehyde 121 ΟOH Anh -y-h 9 1 -(((E)-3 -fluoro-2-hydroxy-5 -((E)-4(pyrrolidine-1- yl)styryl)benzylidene)amino)imide azolide in-2,4-dione 122 ⁴⁼⁷ about m (E)-3 -fluoro-2-hydroxy-5 -((E)-4- (pyrrolidine-1- yl) styryl) benzaldehyde 0- ethyloxime 123 Hl o z (E)-2-fluoro-6-(hydroxymethyl)-4-(4(pyrrolidin-1-yl)styryl)phenol

- 69 042453

124 -π Η (E)-2-((cyclopropylamino)methyl)6-fluoro-4-(4-(pyrrolidin-1 yl)styryl)phenol CHO 125 Π ^'N'^ ^N- ^N ^ 2-((E)-((4-cyclopropylpiperazin1-yl)imino)methyl)-6-fluoro-4-((E)4-(pyrrolidin-1-yl)styryl)phenol 9 ό 126 he's at 2-((E)-((4-ethylpiperazin-1 yl)imino)methyl)-6-fluoro-4-((E)-4(pyrrolidin-1-yl)styryl)phenol 9 O 127 sh i Q 2-fluoro-6-((E)- (morpholinoimino)methyl)-4-((E)-4(pyrrolidin-1-yl)styryl)phenol 9 ό

- 70 042453

128 R [1 G U, N he wu At ) /° tert-butyl 4-(((E)-3-fluoro-2- hydroxy-5-((E)-4-(pyrrolidin-1 yl) styryl) benzylidene) amino) piperazine-1-carboxylate 129 he wu ^XNH 2-fluoro-6-((E)-(piperazine-1 - R V ll imino)methyl)-4-((E)-4(pyrrolidin-1-yl)styryl)phenol hydrochloride d J 130 OH.X.CHO IT JI (E)-2-hydroxy-5-(4-(3-hydroxypyrrolidin-1-yl)styryl)3-methoxybenzaldehyde (

- 71 042453

131 /h = ⁷ .CHO (E)-3-fluoro-2-hydroxy-5-(4-(3 hydroxypyrrolidin-1 yl)styryl)benzaldehyde He 132 HE .CHO (E)-2-hydroxy-5-(4-(2- V (hydroxymethyl)pyrrolidin-1 yl)styryl)-3-methoxybenzaldehyde Λ ,N._ HE 133 π CHO (E)-3-fluoro-2-hydroxy-5-(4-(5thioxo-1,5-dihydro-4H-1,2,4triazol-4-yl)styryl)benzaldehyde v' Ν-ΝΗ 134 HE V CHO (E)-3-fluoro-2-hydroxy-5-(4-(5oxo-1,5-d ihydro-4H-1,2,4-triazol4-yl)styryl)benzaldehyde V (V° Ν-ΝΗ

- 72 042453

135 OH ^O^D^CHO (E)-2-hydroxy-3-methoxy-5-(4-(2oxopyrrolidin-1 yl)styryl)benzaldehyde R 136 HE E) -5 - (4- (6,7-d ihydropyrano[4,3 - T1 o Z s c]pyrazol-1 (4H)-yl)styryl)-3 fluoro-2-hydroxybenzaldehyde V _Ζ Ν ML Vo 137 OH ^Dsno t t (E)-3-fluoro-2-hydroxy-5-(4-(2- oxotetrahydropyrimidine-1 (2H)- yl)styryl)benzaldehyde p C ^N r° ^NH 138 HE (E)-5-(4-(2,2-dimethyltetrahydro- \ With Z With 5Н-[1,3]dioxolo[4,5-с]pyrrol-5yl)styryl)-2-hydroxy-3-methoxybenzaldehyde $

- 73 042453

139 HE (E)-5-(4-(3,4dihydroxypyrrolidin-1 yl)styryl)-2-hydroxy-3-methoxybenzaldehyde \ O ,no 9 But he is ⁷ 140 He ^o XY 9 ,no (E)-2-hydroxy-3-methoxy-5-(4-(2oκcogeκcahydro-5H-πirpolo[3,4c!]oxazol-5yl)styryl)benzaldehyde th V about 141 He it (E)-2-hydroxy-3-methoxy-5 -(4- \ O (tetrahydro-1 H-furo[3,4-c]pyrrol5(3H)-yl)styryl)benzaldehyde 9 ό Q 142 He HNO (E)-5-(4-(2-oxa-7- ^o^Dx. and J azaspiro[4.4]nonan-7-yl)styryl)-2- 9 hydroxy-3-methoxybenzaldehyde f l & 143 He ,no (E)-2-hydroxy-3-methoxy-5-(4-(8- /O^Dx. And oxo-2-oxa-7-azaspiro[4.4]nonane- 7-yl)styryl)benzaldehyde f X° 144 ^e hul /= o 'f- \ ,no (E)-2-hydroxy-3-methoxy-5-(4(3,4,4-trimethyl-2,5dioxoimid azolidin-1 yl)styryl)benzaldehyde o^ ^N ^o m

- 74 042453

145 o \ /=< ^o o X o (Ε)-5-(4-(2,4-dioxo-1,3diazaspiro[4.4]nonan-3yl)styryl)-2-hydroxy-3-methoxybenzaldehyde 146 he ^o^Duno XT QQ HN'y^ ⁰ _O D (E)-5-(4-(2,4-dioxo-1,3,8- triazaspiro[4.5]decan-8yl)styryl)-2-hydroxy-3-methoxybenzaldehyde 147 he _/O 1,c XT Ύ O^O (E)-4-(3-formyl-4-hydroxy-5methoxystyryl)phenyl pyrrolidine 1-carboxylate

- 75 042453

148 /°' He (E)-2-hydroxy-3-methoxy-5-(4-(1-oxido-4,5-dihydro-3H-116isothiazol-1yl)styryl)benzaldehyde at E 1 .CHO 149 /°' he ώ .CHO (E)-4-(3-formyl-4-hydroxy-5methoxystyryl)benzamide 150 0' /°' e ^νη ₂ he ύ _ZCHO (E)-4-(3-formyl-4-hydroxy-5methoxystyryl)-misopropylbenzamide 0' □ ^ΝΗ 151 /°' OH ώ .CHO (E)-K-(4-(3-formyl-4-hydroxy-5methoxystyryl)phenyl)isobutyramide ψ ΗΝ^Ο

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152 o x o (E)-5 -(4-( 1 H-imidazol-1 yl)styryl)-2-hydroxy-3 methoxybenzaldehyde 153 ^z o I o (E)-5-(4-( 1 Η-1,2,4-triazol-1 yl)styryl)-2-hydroxy-3 methoxybenzaldehyde 154 he ^o^a^sno XY I Hmm m (E)-2-hydroxy-3-methoxy-5 -(4- (oxazol-4-yl)styryl)benzaldehyde 155 CHKHHCH about I o (E)-2-hydroxy-3-methoxy-5 -(4- (thiazol-4-yl)styryl)benzaldehyde

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156 HE /O^A Ύ .eno (E)-2-hydroxy-3-methoxy-5-(4-((4methylpiperazin-1 yl)methyl)styryl)benzaldehyde ό 157 ON Wu kA ,SNO (E)-3-fluoro-2-hydroxy-5-(4-(1 methyl-1 H-pyrazol-4yl)styryl)benzaldehyde o A N-N \ 158 HE ,SNO (E)-3-fluoro-2-hydroxy-5-(4-(1 methyl-1H-pyrazol-3 yl)styryl)benzaldehyde t 0 \ 159 he 'Ϋ ,SNO (E)-5-(4-(2H-tetrazol-5yl)styryl)-3-fluoro-2hydroxybenzaldehyde O Np N N-NH

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160 OH rA,CHO ethyl (E)-(4-(3-fluoro-5-formyl-4hydroxystyryl)phenyl)carbamate 9 0^ NH °Ί 161 He (E)-1-(4-(3-fluoro-5-formyl-4- b hydroxystyryl)phenyl)-3- 9 ΟγΝΗ ΗΝ^ isopropylurea 162 HE (E)-N-cycle oppropyl-4-(3-fluoro-5 - F./L. CHO H 1 formyl-4-hydroxystyryl)benzene- ω--λ Γ- ο ^Μ ο\=/ sulfonamide 163 He (E)-K-(4-(3-fluoro-5-formyl-4- f.X,cho ϊJ hydroxystyryl)phenyl)methane- ο sulfonamide 164 He F^XxHO (E) -3 -fluoro-2-hydroxy-5 - (4- (( 1 - n Τ methylpiperidine-4- Ο Ο ^=/ V— yl)sulfonyl)styryl)benzaldehyde

and their pharmaceutically acceptable salts.

- 79 042453

In some embodiments, the implementation of the connection is not a connection from the table. 1X.

Table 1X

XI HE at .clear Vg X2 HE OME .clear xs About Λ _ΝΗ He X4 CHO ? .He o 3 o X5 he dxno O ) X6 He .clear X7 He .clear x8 He CI .clear

- 80 042453

x9 HE F HYU HE _O^A T A wow he chi he A^clear

It is understood that any formula or compound proposed herein, such as formulas (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from table. 1 represent compounds having the structures depicted by the structural formula, as well as certain variations or forms. In particular, compounds according to any of the formulas presented herein may contain bonds with limited rotation and therefore exist in different geometric configurations. Where the connection from the table. 1 is depicted as a particular geometric isomer (for example, the E or Z isomer, or the cis or trans isomer), any alternative geometric configuration of the compound is also provided herein, as well as a mixture of geometric isomers of the compound in any ratio. For example, where the connection from Table. 1 is shown as the Z isomer, the E isomer of this compound is also provided herein. Similarly, where the connection from the table. 1 is shown as the E isomer, the Z isomer of this compound is also provided herein. Also provided are mixtures of the compound with the E and Z stereochemical configuration, the mixtures having any ratio.

Similarly, where the connection from the table. 1 is shown as the cis isomer, the present document also provides the trans isomer of this compound; and where a compound is depicted as the trans isomer, the cis isomer of that compound is also provided herein. Also provided are mixtures of a compound with a stereochemical configuration of cis and trans, the mixtures having any ratio. In addition, compounds according to any of the formulas presented herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of this formula. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms (eg, geoisomeric forms), and mixtures thereof in any ratio. Where the connection from the table. 1 is depicted with a specific stereochemical configuration, any alternative stereochemical configuration of a compound is also provided herein, as well as a mixture of compound stereoisomers in any ratio. It is understood that any connection from the table. 1 represents a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms (eg, geoisomeric forms), and mixtures thereof in any ratio. Moreover, certain structures may exist as tautomers or atropisomers. In addition, any formula presented herein is intended to refer to hydrates, solvates, and amorphous forms of such compounds and mixtures thereof, even if these forms are not explicitly stated. In some embodiments, the solvent is water and the solvates are hydrates.

Compounds of formulas (A), (A-1), (A-2), (I), (Ia) or (Ib) or from the table. 1 may be prepared and/or formulated as pharmaceutically acceptable salts. In some embodiments, pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like. These salts may be derived from inorganic or organic acids. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrogen phosphates, metaphosphates, pyrophosphate

- 81 042453 you, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 -dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates , phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates and mandelates.

In some embodiments, pharmaceutically acceptable salts are formed provided that the acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinate with an organic base. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2 -diethylaminoethanol, tromethamine, trimetamine, dicyclohexylamine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-ethylglucamine, N-methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, amino acids such as lysine, arginine, histidine, and the like. Examples of pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.

In some embodiments, the organic non-toxic bases are L-amino acids such as L-lysine, L-arginine, tromethamine, N-ethylglucamine, and N-methylglucamine. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

Lists of suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, ^17th Edition, Mack Publishing Company, Easton, Pa., 1985.

For a compound described herein that contains a nitrogenous base, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid and the like, or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidilic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as almond nic acid, citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid , methanesulfonic acid, benzenesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids, such as those exemplified herein, as well as any other acid or mixture thereof that are considered equivalents or acceptable substituents in the light of ordinary skill in the art.

The compounds described herein may be present in the form of salts, even if salts are not described, and it should be understood that the compositions and methods presented herein include all salts and solvates of the compounds described herein, as well as non-salt and non-solvate the form of this compound, as is well known to a person skilled in the art. In some embodiments, salts of the compounds provided herein are pharmaceutically acceptable salts.

Illustrative examples of the compounds detailed herein, including intermediates and final compounds, are presented in the tables and elsewhere in this document. It should be understood that, in one aspect, any compound can be used in the methods detailed herein, including, where applicable, intermediates that can be isolated and administered to an individual.

In one embodiment, the compounds herein are synthetic compounds prepared for administration to an individual. In another embodiment, compositions are provided containing the compound in substantially pure form. In another embodiment, pharmaceutical compositions are provided comprising a compound as described in detail herein and a pharmaceutically acceptable carrier. In another embodiment, methods for administering a compound are provided. Purified forms, pharmaceutical compositions, and routes of administration of the compounds are suitable for any compound or form thereof detailed herein.

- 82 042453

Any embodiment or embodiment of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, Gi, G2, G3, G4, G5, G6, G7, R ^a , R ^{b , R c ,} R ^d , R ^e , R ^f , R ^g , R ^h , R ^j , R ^k , R ^m , R ⁿ , Rp, R ^q , R ^r , R ^s , Rt, R ^u , R ^v , R ^w1 , R ^w2 ,R ^x , R ^y , R ^z1 , R ^z2 , X1, X2, X3, X4, m, R ^6a , R ^6b , R ^6c and R ^6d provided herein may be combined with any other embodiment or embodiment of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, G1, G2, G3, G4, G5, G6, G7, R a , R b , R ^c , R ^d , ^{R e ,} R ^f , ^{R g ,} R ^h , R ^j , R ^k , R ^m , R ⁿ , Rp, R ^q , R ^r , R ^s , R', R ^u , R ^v , R ^w1 , R ^w2 , R ^x , R ^y , R ^z1 , R ^z2 , X1, X2, X ₃ , X ₄ , m, R ^6a , R ^6b , R ^6c and R ^6d as if each combination was separately and specifically described. Any embodiment or embodiment of R ¹ , R ² , R ³ , R 4 , R ⁵ , G1, G2, G3, ^G4 , G5, G6, R ^a , R ^b , Rc, Rd, Re, R ^f , R ^g , R ^h , X1, X2, X3, X, m, R ^6a , R ^6b , R ^6c and R ^6d provided herein may be combined with any other embodiment or embodiment of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , G1, G2, G3, G4, G5, G6, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , X1, X2, X3, X4, m , R ^6a , R ^6b , R ^6c and R ^6d as if each combination were separately and specifically described.

Embodiments also relate to pharmaceutically acceptable prodrugs of the compounds described herein, and to methods of treatment that use such pharmaceutically acceptable prodrugs.

The term prodrug means a precursor of the designated compound which, after administration to a subject, yields the compound in vivo by a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., by adjusting to physiological pH, the prodrug is converted to the compound of formula (I)) . A pharmaceutically acceptable prodrug is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically acceptable for administration to a subject. Exemplary procedures for selecting and preparing suitable prodrugs are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Embodiments also relate to pharmaceutically active metabolites of the compounds described herein and to the use of such metabolites in the methods provided herein. Pharmaceutically active metabolite means the pharmacologically active product of metabolism in the body of the compound described herein, or its salt. Prodrugs and active metabolites of a compound can be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., J. Med. Chem. 1997, 40, 20112016; Shan et al., J. Pharm. sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. DrugRes. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985) and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

Chemical definitions

The following compounds have the following meanings unless otherwise noted. All undefined terms have meanings known in the art.

The term alkyl refers to a linear or branched monovalent saturated hydrocarbon group, or a combination thereof, having a given number of carbon atoms (ie, C1-C10 means from one to ten carbon atoms). Examples of alkyl groups include, without limitation, methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl (tBu), pentyl, isopentyl, t-pentyl, hexyl , isohexyl, as well as groups which, in the light of ordinary skill in the art and the ideas presented herein, will be considered equivalent to any of the above examples.

The term alkoxy refers to -O-alkyl. Examples of alkoxy include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term alkenyl refers to an unsaturated straight or branched chain hydrocarbon group, or a combination thereof, having a given number of carbon atoms and having one or more double bonds. Examples of alkenyl groups include, without limitation, ethenyl (or vinyl), allyl, and but-3-en-1-yl. The term also covers cis and trans isomers and mixtures thereof.

The term alkynyl refers to an unsaturated straight or branched hydrocarbon group having a given number of carbon atoms (eg, 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Examples of alkynyl groups include, without limitation, acetylenyl (-C^CH) and propargyl (-CH ₂ C=CH).

The term alkylene refers to a divalent group which is an alkane radical. Alkylene may be a straight or branched divalent alkyl radical, C _1-4 alkylene refers to alkylene groups containing from 1 to 4 carbon atoms.

The term aryl refers to a monovalent aromatic carbocyclic group containing from 6 to 18 ring carbon atoms and having one ring (phenyl group) or multiple fused rings (e.g. naphthyl, anthracenyl or indanyl), the fused rings being optionally aromatic provided that the dot the addition of an aryl group to the parent structure is located on an atom of the aromatic ring. Aryl, as defined herein, encompasses groups such as phenyl and fluorenyl.

The term cycloalkyl refers to cyclic hydrocarbon groups with 3-10 ring carbon atoms having one or more cyclic rings, including fused, bridged

- 83 042453 ring and spiro systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, by way of example, single chain structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or multiple ring structures such as adamantanyl and the like. In some cases, cycloalkyl is a monocyclic ring. In some cases, cycloalkyl is a 3-6 membered ring.

The term cycloalkenyl refers to a cyclic alkenyl group containing from 4 to 10 ring carbon atoms and having one cyclic ring and at least one point of internal unsaturation, which may optionally be substituted with 1-3 alkyl groups. Examples of suitable cycloalkenyl groups include, for example, cyclopent-3-enyl, cyclohex-2enyl, cyclooct-3-enyl, and the like.

The term haloalkyl refers to an alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been replaced by a halogen group. Examples of such groups include, without limitation, fluoroalkyl groups such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

The term heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having ring atoms selected from carbon atoms and no more than four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms each heterocycle. Illustrative examples of heteroaryl groups include the following entities as appropriately linked moieties:

The terms heterocyclyl or heterocycloalkyl refer to a saturated or partially unsaturated group having one or more fused rings, including fused, bridged or spiro ring systems, and having 3 to 20 ring atoms including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of carbon, nitrogen, sulfur or oxygen. In certain embodiments, the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to form -N-oxide, -S(O)-, or -SO ₂ - moieties. Illustrative examples of heterocyclic groups include the following entities as appropriately linked moieties:

The term halogen represents chlorine, fluorine, bromine or iodine. The term halogen represents the fluorine, chlorine, bromine or iodine groups.

The term oxo represents carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

Those skilled in the art will appreciate that the species listed or illustrated above are not exhaustive, and that additional species may also be selected to be within the scope of these specified terms.

The term substituted means that said group or moiety bears one or more substituents, including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halogen, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, and the like.

The term unsubstituted means that the specified group does not bear substituents.

The term "optionally substituted" means that the specified group is unsubstituted or

- 84 042453 substituted with one or more substituents.

When the term substituted is used to describe a structural system, it is understood that the substitution occurs in any position of the system allowed by the valency. When a group or fragment bears more than one substituent, it should be understood that the substituents may be the same or different from each other. In some embodiments, the substituted group or moiety carries one to five substituents. In some embodiments, the substituted group or moiety bears one substituent. In some embodiments, the substituted group or moiety carries two substituents. In some embodiments, the substituted group or moiety carries three substituents. In some embodiments, the substituted group or moiety carries four substituents. In some embodiments, the substituted group or moiety carries five substituents.

Any formula described herein is intended to represent a compound with such a structural formula, as well as certain variations or forms. For example, a formula provided herein is intended to encompass the racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Furthermore, any formula presented herein is also intended to refer to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

Any formula described herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound. Isotopically labeled compounds have structures depicted by the formulas presented herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H, ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, respectively. Such isotopically labeled compounds are useful in metabolism studies (preferably ¹⁴ C), reaction kinetics studies (e.g. ² H or ³ H), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) ], including drug or substrate tissue distribution assays, or for radioactive treatment of patients. In particular, ^{a 18} F or 11C labeled compound may be particularly preferred for PET or SPECT studies. PET and SPECT studies may be performed as described, for example, in Brooks, DJ, Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development, NeuroRx 2005, 2(2), 226-236 and references cited in German Moreover, substitution with heavier isotopes such as deuterium (ie ² H) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by following the procedures described in the Schemes or in the Examples and Preparations below, substituting a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

The nomenclature Ci-j, where j>i, when applied herein to a substituent class, is meant to refer to embodiments of the present invention for which each and every one of carbon elements i to j, including i and j, are independently implemented. By way of example, the term C _1-3 independently refers to embodiments that have one carbon element (C1), to embodiments that have two carbon elements (C ₂ ), and to embodiments that have three carbon elements (C3) .

Any disubstituent referred to herein is intended to cover various attachment possibilities if more than one such possibility is allowed. For example, as used herein, the di-substituent -A-B-, where A^B, refers to such a di-substituent in which A is attached to the first substituted element and B is attached to the second substituted element, and also refers to those di-substituents in which A is attached to the second substituted element. element and B is attached to the first replaced element.

The present invention also covers pharmaceutically acceptable salts of compounds represented by formula (A), (A-1), (A-2), (I), (Ia) or (Ib), or compounds from table. 1, pharmaceutical compositions containing these salts and methods of using these salts.

A pharmaceutically acceptable salt is intended to mean a free acid or base salt of a compound provided herein that is non-toxic, biologically tolerable, and otherwise biologically acceptable for administration to a subject. See, in general, S.M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977, 66, 1-19. Particular pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with the tissues of a subject without undue toxicity, irritation, or allergic reaction. The compound described herein may have a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and the corresponding

- 85 042453 react with a variety of inorganic or organic bases, as well as inorganic or organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates. , propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates , propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates and mandelates. Lists of suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, ^17th Edition, Mack Publishing Company, Easton, Pa., 1985.

For compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from the table. 1, which contains a nitrogenous base, a pharmaceutically acceptable salt can be obtained by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid and the like, or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidilic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid, citric acid or tartaric acid one, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, a sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids, such as those exemplified herein, as well as any other acid or mixture thereof that are considered equivalents or acceptable substituents in the light of ordinary skill in the art.

The present description also relates to pharmaceutically acceptable prodrugs of compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from table. 1, as well as to methods of treatment that use such pharmaceutically acceptable prodrugs.

The term prodrug means a precursor of the designated compound which, after administration to a subject, yields the compound in vivo by a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., by adjusting to physiological pH, the prodrug is converted to the compound of the formula). A pharmaceutically acceptable prodrug is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically acceptable for administration to a subject. Exemplary procedures for selecting and preparing suitable prodrugs are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

The present description also relates to pharmaceutically active metabolites of compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from table. 1, as well as the use of such metabolites in the methods presented herein. Pharmaceutically active metabolite means a pharmaceutically active product of metabolism in the body of the compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib), or compounds from table. 1, or salts of any of the above. Prodrugs and active metabolites of a compound can be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. DrugRes. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

pharmaceutical compositions.

For therapeutic purposes, pharmaceutical compositions containing the compounds described herein may additionally contain one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient is one that is non-toxic and otherwise biologically acceptable for administration to a subject. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers, or flavor modifying agents. In specific embodiments, pharmaceutical companies

- 86 042453 positions in accordance with the present description are sterile compositions. Pharmaceutical compositions can be prepared using mixing techniques known or available to those skilled in the art.

Sterile compositions are also contemplated by the present invention, including compositions that comply with national and local regulations governing such compositions.

The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution or capsules together with solid carriers in accordance with conventional methods known in the art for obtaining various dosage forms. The pharmaceutical compositions of the present invention may be administered by a suitable delivery route such as oral, parenteral, rectal, nasal, topical or ocular, or by inhalation. In some embodiments, the compositions are formulated for intravenous or oral administration.

For oral administration, the compounds of the present invention may be provided in solid form such as tablets or capsules, or as a solution, emulsion or suspension. For oral compositions, the compounds of the present invention may be formulated to provide a dosage of, for example, about 0.01 to about 50 mg/kg daily, or about 0.05 to about 20 mg/kg daily, or about 0.1 up to about 10 mg/kg daily. Additional dosages include about 0.1 mg to 1 g daily, about 1 to about 10 mg daily, about 10 to about 50 mg daily, about 50 to about 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may contain active ingredients mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavors, colors and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of liquid oral excipients include ethanol, glycerin, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are examples of disintegrants. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glycerol monostearate or glycerol distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredients may be mixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, an oil such as peanut or olive oil, liquid paraffin, a mixture of mono- and diglycerides of short chain fatty acids, polyethylene glycol 400 or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups, may be lyophilized, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically acceptable adjuvants such as suspending agents (eg, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oil (eg, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (eg methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and optionally flavorings or colorants.

Compositions of the invention may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present disclosure may be provided in sterile aqueous solutions or suspensions buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride solution. Such forms may be presented in unit dosage form, such as ampoules or disposable injection devices, in multi-dose forms, such as vials, from which the appropriate dose can be obtained, or in solid form or in the form of a primary concentrate, which can be used to obtain an injectable composition. Exemplary infusion doses range from about 1 to 1000 μg/kg/min. agent mixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For nasal, inhalation or oral administration, the pharmaceutical compositions of the invention may be administered via, for example, a spray also containing a suitable carrier.

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For topical use, the compounds of the present invention may be formulated as creams or ointments, or as a similar carrier suitable for topical administration. For topical administration, the compounds of the invention may be mixed with a pharmaceutical carrier at a concentration of from about 0.1% to about 10% of the drug, based on the carrier. In another method of administering the agents of the present invention, a transdermal delivery patch may be used.

The term treatment or treatment process in the context of this document refers to an approach to obtain a useful or desired result, including clinical results. For the purposes of this disclosure, a useful or desired result includes, without limitation: reducing the severity or keeping the worsening of a disease, symptom, or condition; relieving a symptom and/or reducing the severity of a symptom and/or preventing worsening of a symptom associated with the condition; stopping the development of the disease, symptom or condition; alleviate the disease, symptom or condition; causing regression of the disease, disorder, or symptom (in terms of severity or frequency of negative symptoms), or cessation of symptoms of the disease or condition. Beneficial or desired results may also be slowing, stopping or reversing the progression of a disease or condition. For example, beneficial effects may include slowing the progression of Parkinson's disease from an early stage (eg, prodromal stage or stage 1, 2, or 3) to a later stage (eg, stage 4 or 5) or stopping Parkinson's disease at a prodromal or early stage.

In the context of this document, the term delaying the development of a disease or condition means delaying, preventing, slowing down, inhibiting, stabilizing and/or delaying the development of a disease or condition. This delay may be of varying length, depending on the medical history and/or the individual being treated. As will be apparent to one of skill in the art, a sufficient or significant delay may, in essence, include prevention, as long as the individual does not develop the disease or condition. For example, a method that delays the development of Parkinson's disease (for example, at the prodromal stage in an individual) is a method that reduces the likelihood of developing the disease in a given time period and/or reduces the severity of the disease in a given time period compared to not using this method.

The term subject refers to a mammalian patient in need of such treatment, such as a human. The subject may be a human, or may be a cat, dog, cow, rat, mouse, horse, or other domesticated mammal.

Examples of diseases that are characterized by protein aggregation include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body dementia (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis (such as hepatitis B or C), gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy), atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, corneal trauma, corneal disorders, Stargardt's disease (juvenile macular i degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and fungal, bacterial, viral, and neoplastic diseases or conditions. Additional examples of diseases include progressive supranuclear palsy (PNP), Niemann-Pick type C disease, irritable bowel syndrome, osteoarthritis, corneal HSV, stroke, and coronary heart disease.

In one aspect, the compounds and pharmaceutical compositions of the present invention specifically target TLR2 protein dimers. Thus, these compounds and pharmaceutical compositions can be used to prevent, slow, reverse or inhibit the dimerization of TLR2 proteins with other natural protein ligands, and they are also used in the methods of the present invention to treat neurological and inflammatory diseases associated with or caused by such dimerization. . In some embodiments, the treatments target Parkinson's disease, Alzheimer's disease, Lewy body disease, multiple system atrophy, atopic dermatitis, traumatic brain injury, or multiple sclerosis. The compounds, compositions and methods of the present invention are also used to mitigate the deleterious effects that are secondary to protein dimerization and/or misfolding, such as neuronal cell death.

In some aspects, the compounds, compositions and methods of the present invention are used to inhibit TLR2 dimerization. In alternative aspects, the compounds, compositions, and methods of the present invention are used to inhibit TLR2 dimerization by TLR1, or by TLR6, or both.

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In the methods of inhibition of the present invention, an effective amount means an amount sufficient to reduce, slow the progression or reverse the dimerization of TLR2. Measurement of the degree of dimerization can be performed using conventional analytical methods, such as, for example, described below. Such modulation is useful in a variety of settings, including in vitro assays. In some embodiments of such methods, the cell is a nerve cell, or a HEK or THP cell.

In the methods of treatment in accordance with the present invention, an effective amount means an amount or dose sufficient to generally result in the desired therapeutic benefit in a subject in need of such treatment. Effective amounts or doses of the compounds of the present invention may be determined by conventional means, such as modeling, dose escalation, or clinical studies, taking into account conventional factors, such as the mode or route of administration or delivery of the drug, the pharmacokinetics of the agent, the severity and course of the infection, the state of health, the condition and weight of the subject, as well as the judgment of the attending physician. An exemplary dose is in the range of about 1 μg to 2 mg of the active substance per 1 kg of the subject's body weight per day, for example, from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day, or from about 0.1 to 10 mg/kg/day. In alternative embodiments, an exemplary dose is in the range of about 1 mg to about 1 g per day, or about 1-500, 1-250, 1-100, 1-50, 50-500, or 250-500 mg per day. The total dose may be administered as a single dose or in divided doses (eg, twice a day, three times a day, four times a day).

Once the patient's disease has improved, the dose may be adjusted for prophylactic or maintenance treatment. For example, the dosage or frequency of administration, or both, may be reduced depending on the symptoms to a level that maintains the desired therapeutic or prophylactic effect. Of course, if the symptoms have decreased to an appropriate level, treatment may be discontinued. However, with any recurrence of symptoms, patients may need long-term intermittent therapy. Patients may also need long-term chronic treatment.

Combinations of drugs.

The compounds of the invention described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients for the treatment of neurodegenerative disorders. Additional active ingredients for anticancer use include other anticancer therapeutic agents or agents that mitigate the adverse effects of anticancer chemotherapeutic agents. Such combinations may serve to improve efficacy, alleviate other symptoms of the disease, reduce one or more side effects, or reduce the required dose of a compound of the invention. Additional active ingredients may be administered in a pharmaceutical composition separate from the compound of the present invention, or may be included together with the compound of the present invention in a single pharmaceutical composition. Additional active ingredients may be administered simultaneously with, before or after administration of the compound of the present invention.

Combination agents, including additional active ingredients, are those known or found to be effective in the treatment of the diseases, disorders, conditions, and symptoms described herein, including those agents that are active on another target associated with the disease. , disorder, or symptom, such as, without limitation, a) compounds that reverse the misfolding of proteins (eg, drugs that reduce the production of these proteins, that increase their clearance, or that alter their aggregation and/or reproduction); b) compounds that treat the symptoms of such disorders (eg dopamine replacement therapies); and c) drugs that act as neuroprotective agents through a complementary mechanism (eg, drugs that target autophagy, that are antioxidants, and that act by other mechanisms, eg, adenosine A2A receptor antagonists).

For example, compositions and compositions of the present invention, as well as methods of treatment, may further include other drugs or pharmaceutical preparations, such as other active substances useful for the treatment or palliative treatment of neurological or inflammatory diseases associated with or caused by TLR2 dimerization, such as diseases Parkinson's disease, Alzheimer's disease (AD), Lewy body disease (LWB), and multiple system atrophy (MSA), as well as associated symptoms or conditions. For example, the pharmaceutical compositions of the present invention may further comprise one or more of these active agents, and the methods of treatment may further comprise administering an effective amount of one or more of these active agents. In certain embodiments, additional actives may be antibiotics (e.g., antibacterial or bacteriostatic peptides or proteins), e.g., those that are effective against Gram-positive or Gram-negative bacteria, fluids, cytokines, immunoregulatory agents, anti-inflammatory agents.

- 89 042453 va, complement-activating agents such as peptides or proteins containing collagen-like domains or fibrinogen-like domains (eg ficolin), carbohydrate-binding domains, and the like, as well as combinations thereof. Additional active agents, including those that may be used in such compositions and methods, include dopamine therapy drugs, catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase inhibitors, cognitive impairment correctors (such as acetylcholinesterase inhibitors or memantine), antagonists adenosine 2A receptor, beta-secretase inhibitors, or gamma-secretase inhibitors. In specific embodiments, at least one compound of the present invention may be combined in a pharmaceutical composition or method of treatment with one or more drugs selected from the group consisting of tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), galantamine ( Reminyl), Physostigmine, Neostigmine, Icopezil (CP-118954, 5,7-dihydro-3-[2-[1-(phenylmethyl)-4piperidinyl]ethyl]-6H-pyrrolo-[4,5-f]-1, 2-benzisoxazol-6-one maleate), ER-127528 (4-[(5,6-dimethoxy-2-fluoro-1-indanone)-2-yl]methyl-1-(3-fluorobenzyl)piperidine hydrochloride), zanapezil (TAK-147; 3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1 propane fumarate), Metrifonate (T-588; (-)-R-.alpha.-[[2-(dimethylamino)ethoxy]methyl]benzo[b]thiophene5-methanol hydrochloride), FK-960 (N-(4-acetyl-1- piperazinyl)-p-fluorobenzamide hydrate), TCH-346 (N-methyl-N-2-pyropynyldibenz[b,f]oxepin-10-methanamine), SDZ-220-581 ((S)-alpha-amino-5 (phosphonomethyl)-[1,1'-biphenyl]-3-propy onic acid, memantine (Namendy/Exibs) and 1,3,3,5,5pentamethylcyclohexane-1-amine (Neramexane), tarenflurbil (Flurizan), tramiprosate (Alzhemed), clioquinol, PBT-2 (derivative of 8-hydroxyquinilone), 1 -(2-(2-Naphthyl)ethyl)-4-(3trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, Huperzine A, Pozatirelin, Leuprolide or its derivatives, Ispronicline, (3-aminopropyl)(n-butyl) phosphinic acid (SGS-742), N-methyl-5-(3-(5isopropoxypyridinyl))-4-penten-2-amine (ispronicline), 1-decanaminium, N-(2-hydroxy-3sulfopropyl)-N-methyl -N-octyl-, internal salt (zt-1), salicylates, aspirin, amoxiprin, benorylate, choline and magnesium salicylate, diflunisal, faislamin, methyl salicylate, magnesium sapicylate, salicyl salicylate, diclofenac, aceclofenac, acemethacin, bromfenac, etodolac, indomethacin, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, thiaprofenic acid, suprofen, mefenamic acid, m eclofenamic acid, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinpyrazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, arylalkanoic acids, 2-arylpropionic acids), (phenamic acids), pyrazolidine derivatives, oxicams, COX-2 inhibitors, sulfanilides, essential fatty acids and Minozac (2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine dihydrochloride hydrate ) or combinations thereof.

Application methods.

The compounds and pharmaceutical compositions of this document can be used to treat or prevent a disease or condition in an individual. In some embodiments, methods of treating a disease or condition associated with TLR2 heterodimerization are provided, comprising administering to an individual in need thereof a compound of formula (A), (A-1), (A-2), (I), (Ia ) or (Ib) or compounds from the table. 1, or their tautomer, or a pharmaceutically acceptable salt of any of the above. In some embodiments, methods for treating a disease or condition associated with TLR2 heterodimerization are provided, comprising administering to a subject a therapeutically effective amount of at least one chemical, as described herein.

In some embodiments, the proposed compositions containing one or more compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from table. 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of a disease or condition associated with TLR2 heterodimerization. In some embodiments, compositions containing at least one chemical as described herein are provided for use in the treatment of a disease or condition associated with TLR2 heterodimerization.

Also provided herein is the use of a compound of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or a compound of Table 1. 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing in the manufacture of a medicament for the treatment of a disease or condition associated with TLR2 heterodimerization. In some embodiments, the use of at least one chemical as described herein in the manufacture of a medicament for the treatment of a disease or condition associated with TLR2 heterodimerization is provided.

In some embodiments, the disease or condition is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body dementia (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral gluteal

- 90 042453 rose, Huntington's disease, progressive supranuclear palsy (PNP), Niemann-Pick type C disease, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, irritable bowel syndrome, tuberculosis, rheumatoid arthritis, osteoarthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy ), stroke, coronary heart disease, atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, corneal trauma, corneal disorders, corneal HSV, Stargardt's disease (juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus and fungal, bacterial, viral and neoplastic diseases or conditions.

In some embodiments, the disease or condition is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body dementia (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, inflammatory diseases, asthma , chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions , multiple sclerosis, Crohn's disease and traumatic brain injury.

Also provided are methods of interfering with TLR2 heterodimerization in a cell or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from the table. 1, or its tautomer, or a pharmaceutically acceptable salt of any of the above. In some embodiments, methods are provided for interfering with TLR2 heterodimerization in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one chemical as described herein. .

Also provided herein are compositions containing one or more compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) or compounds from Table. 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in interfering with TLR2 heterodimerization in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell. In some embodiments, compositions are provided comprising at least one chemical as described herein for use in interfering with TLR2 heterodimerization in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell.

In addition, this document provides the use of at least one chemical as described herein, such as a compound of formula (A), (A-1), (A-2), (I), (Ia) or ( Ib), or a compound from table. 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for interfering with TLR2 heterodimerization, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization.

Sets.

Also proposed industrial products and kits containing any of the compounds or pharmaceutical compositions presented in this document. An industrial product may contain a container with a label. Suitable containers include, for example, bottles, vials and test tubes. Containers can be made from various materials such as glass or plastic. The container may contain the pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or control the condition described herein, and may also contain indications for in vivo or in vitro use.

In one aspect, provided herein are kits containing the compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of a disease or condition associated with TLR2 heterodimerization in an individual in need thereof. The kit may further comprise any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or intravenous infusion bags. The kit may also contain sterile packaging.

General methods of synthesis.

The compounds of the present invention can be prepared using a number of processes, as described generally below and more specifically in the examples below (e.g., the schemes presented in note

- 91 042453 rax below). In the following process descriptions, the symbols, when used in the depicted formulas, are to be understood as representing the groups described above with respect to the formulas herein.

Where a particular enantiomer of a compound is desired, this can be done from the appropriate mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be obtained by reacting a mixture of enantiomers, such as a racemate, with the appropriate chiral compound. The diastereomers can then be separated by any conventional means, such as crystallization, to isolate the desired enantiomer. In another resolution process, the racemate can be separated using chiral high performance liquid chromatography. Alternatively, a particular enantiomer, if necessary, can be obtained using the appropriate chiral intermediate in one of the described processes.

Chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or end products when it is desired to obtain a particular isomer of a compound or otherwise purify the reaction product.

Also contemplated are solvates of the compound provided herein, or a pharmaceutically acceptable salt thereof. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

In some embodiments, compounds of formula (A), (A-1) or (A-2) may be synthesized according to scheme A.

Scheme A

^R1

RR ²

Hal

_BRt

A _r4 /G ₇ .R ⁵ ίγΛ ^G < -/G ₆ ^G 5

G I G

^R1

^R2

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, Gi, G2,

G ₃ , G ₄ , G ₅ , G6 and G ₇ are as defined for formula (A) or any variation thereof as detailed herein;

Hal is halogen;

t is 2 or 3;

R is -OH, -O-alkyl, or halo, or \

N

BRt is ' ^or

In some embodiments, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 1.

Scheme 1

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , G1, G ₂ , G ₃ , G ₄ , G ₅ and G ₆ are as defined for formula (I) or any variation thereof detailed in this document;

Hal is halogen, t is 2 or 3;

R is -OH, -O-alkyl, or halo, or

-BR _t represents

In some embodiments of the above scheme 1, the compounds of formula (I) can be synthesized in accordance with scheme 1a.

- 92 042453

Scheme 1a

where R ³ , R ^a , G1, G ₂ , G ₃ , G4, G5, G ₆ and G ₇ are as defined for formula (I) or any variation thereof detailed herein;

Hal is halogen;

t is 2 or 3;

R is -OH, -O-alkyl, or halo, or \

N

-BRt represents ' ^or

In some embodiments, the compounds of formula (A), (A-1) or (A-2) can be synthesized according to scheme B.

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, G1, G2,

Scheme B

G ₃ , G4, G5, G ₆ and G ₇ are as defined for formula (A) or any variation thereof as detailed herein;

Hal is halogen;

t is 2 or 3;

R is -OH, -O-alkyl, or halo, or \

N

-BRt represents ' ^or

In some embodiments, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 2.

Scheme 2

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , G1, G ₂ , G ₃ , G4, G5 and G ₆ are as defined for formula (I) or any variation thereof detailed herein ;

Hal is halogen;

t is 2 or 3; R is -OH, -O-alkyl, or halo, or \

N^h

-BRt represents ' or o .

In some embodiments, the compounds of formula (A), (A-1) or (A-2) can be synthesized according to scheme C.

- 93 042453

Scheme C

^R1

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, G1, G ₂ , G3, G ₄ , G ₅ , G6 and G ₇ are as defined for formula (A) or any variation thereof, detailed in this document;

Hal is a halogen.

In some embodiments, a compound of formula (A), (A-1), or (A-2) is synthesized via a Heck coupling reaction.

In some embodiments, compounds of formula (I), (Ia) or (Ib) may be synthesized according to Scheme 3.

Scheme 3

^R1

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , G1, G ₂ , G ₃ , G ₄ , G ₅ and G6 are as defined for formula (I) or any variation thereof detailed herein document;

Hal is a halogen.

In some embodiments, a compound of formula (I), (Ia), or (Ib) is synthesized via a Heck coupling reaction.

In some embodiments of Scheme 3 above, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 3a.

Scheme 3a

where R ³ , R ⁴ , R ⁵ , R ^a , G1, G ₂ , G ₃ , G ₄ , G ₅ , G ₆ and G ₇ are as defined for formula (I) or any variation thereof detailed in herein, a Hal is halogen.

In some embodiments of Scheme 3 above, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 3b.

Scheme 3b

where R ³ , R ⁴ , R ⁵ , R ^a , G1, G ₂ , G ₃ , G4, G ₅ , G ₆ and G ₇ are as defined for formula (I) or any variation thereof detailed herein document;

Hal is a halogen.

In some embodiments, intermediates used to synthesize compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib) can be synthesized according to Scheme 4.

- 94 042453

Scheme 4

[(Ar) ₃ P(Me)] ⁺ NaG +

where G ₃ , G ₄ , G5, G6, G7 and Y are as defined for formula (A) or any of its variations described in detail herein;

Hal is halogen;

Ar is aryl.

In some embodiments, compounds of formula (A) may be synthesized according to Scheme 5.

Scheme 5

where R ³ , R ⁴ , R ⁵ , G1, G2, G ₃ , G ₄ , G ₅ , G6, G7 and Y are as defined for formula (A) or any variation thereof detailed herein.

In some embodiments, compounds of formula (A) may be synthesized according to Scheme 6.

Scheme 6 he he

ό ₅ ό ₅ where R ³ , R ⁴ , R ⁵ , R ^j , G1, G ₂ , G ₃ , G ₄ , G ₅ , G ₆ , G ₇ and Y are as defined for formula (A) or any its variations, described in detail in this document.

In some embodiments of Scheme 6 above, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 6a.

Scheme 6a he

where R ^j is as defined for formula (A) or any variation thereof as detailed herein.

In one embodiment of the procedure as described in Scheme 6a, (E)-3-Fluoro-2-hydroxy-5-(4(pyrrolidin-1-yl)styryl)benzaldehyde (1 eq.) and the amine compound R ^j -NH ₂ (1 eq.) is dissolved in ethanol or methanol. The reaction mixture is refluxed for 2 hours. The solvent is mostly removed and the residue is filtered. The precipitate is washed with ethanol and dried in vacuo to give the desired product.

In some embodiments of Scheme 6, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 6b.

- 95 042453

Scheme 6b

where R ^j is as defined for formula (A) or any variation thereof as detailed herein.

In one embodiment of the procedure as described in scheme 6b, (E)-3-fluoro-2-hydroxy-5-(4(pyrrolidin-1-yl)styryl)benzaldehyde (1 eq.), HCl salt of compound R ^j - NH ₂ (1.5 eq or 2 eq) and TEA (2 or 3 eq) are dissolved in ethanol. The reaction mixture is refluxed for 2 hours. The solvent is mostly removed and the residue is filtered. The precipitate is washed with ethanol and dried under vacuum to give the desired compound.

In another embodiment of the procedure as described in Scheme 6b, (E)-3-fluoro-2-hydroxy-5-(4(pyrrolidin-1-yl)styryl)benzaldehyde (1 eq) and free amine R ^j -NH2 or the HCl salt of the amine R ^j -NH2 (2 or 1.2 eq.) is dissolved in ethanol with or without TEA (2 or 3 eq.). The reaction mixture is refluxed for 2 hours. The resulting precipitate is filtered, washed with methanol and dried under vacuum to obtain the desired compound.

In some embodiments, compounds of formula (A) may be synthesized according to Scheme 7.

Scheme 7

^G 5 where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , G1, G ₂ , G ₃ , G4, G ₅ , G ₆ , G ₇ and Y are as defined for formula (A) or any its variations, described in detail in this document;

Hal is a halogen.

In some embodiments of Scheme 7 above, compounds of formula (I), (Ia) or (Ib) can be synthesized according to Scheme 7a.

Scheme 7a

^G <y ^{G 6 G} 5 where R ¹ , R ² , R ³ , R 4 , R ⁵ , G1, G ₂ , G ₃ , G4, G ₅ , G ₆ , G ₇ and Y are as defined for the formula (A) or any variation thereof as detailed herein.

Chemical synthesis.

Exemplary chemicals used in the methods of the present invention will now be described with reference to the following specific examples. Those skilled in the art will appreciate that, to prepare the various compounds herein, the starting materials can be appropriately selected such that the ultimately desired substituents will be carried through the reaction scheme with or without a protecting group, as appropriate, to obtain the desired product. . Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group which can be carried through the reaction scheme and replaced if necessary by the desired substituent. Moreover, one skilled in the art will appreciate that the transformations shown in the diagrams below may be

- 96 042453 are made in any order that is compatible with the functionality of specific side groups. Each of the reactions depicted in the general schemes can be carried out at a temperature from about 0°C to the reflux temperature of the organic solvent used. Isotopically labeled compounds as described herein are prepared according to the methods described below, using appropriately labeled starting materials. Such materials are generally available from commercial suppliers of radioactively labeled chemicals.

Examples

The following examples are provided by way of illustration only, and not by way of limitation of the present description. One skilled in the art will appreciate that the following reactions and synthetic schemes can be modified by selection of suitable starting materials and reagents to provide other compounds of formula (A), (A-1), (A-2), (I), (Ia) or (Ib). Compounds are prepared using the general methods described above.

The following abbreviations are used in the examples: Ac - acetate,

Boc - tert-butyloxycarbonyl, dba - dibenzylideneacetone, DCM - dichloromethane, DMF - N,N-dimethylformamide, DMSO - dimethyl sulfoxide, dppf - 1,1'-bis-(diphenylphosphino)ferrocene, EA or EtOAc - ethyl acetate, Et - ethyl, EtOH - ethanol, HPLC - high performance liquid chromatography, LAH - lithium aluminum hydride, mCPBA - meta-chloroperoxybenzoic acid, Me - methyl, MeOH - methanol, n-BuLi - n-butyl lithium, OMe - methoxy, PdCl ₂ (dppf) - 1.1 '-bis-(diphenylphosphino) ferrocene) palladium (P) dichloride, Pd ₂ (dba) ₃ - tris- (dibenzylideneacetone) dipalladium (0), Pd (OAc) ₂ - palladium (P) acetate,

Pd (PPh ₃ ) ₄ - tetrakis-(triphenylphosphine)palladium(0), PPh3 - triphenylphosphane, PinB - bis-(pinacolato)diborone, PMB - 4-methoxybenzyl, PMB-Cl - 4-methoxybenzyl chloride, TEA - trimethylamine, TFA - trifluoroacetic acid, THF - tetrahydrofuran and

TLC - thin layer chromatography).

Example 1 (E)-2-Hydroxy-3-methoxy-5-(4-methoxystyryl)benzaldehyde

OME

In a 30 ml glass vial sealed with a cap, 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol), (E)-(4-methoxystyryl)boronic acid (214 mg, 1.2 mmol) and Na ₂ CO ₃ (666 mg, 6.0 mmol) was suspended in DMF-water (10 ml). Then sparged with argon gas for 1-2 min, Pd(PPh ₃ ) ₄ (63 mg, 0.05 mmol) was added to the reaction flask, sealed with a sealed cap and continued at 105°C for 16 h on a stirrer with a cup containing metal granules. Then cooled to room temperature, diluted with water (20 ml) and transferred to a separating funnel with dichloromethane. The aqueous layer was acidified with 2.0N. HCl to pH ~4.0 and was extracted with additional dichloromethane (2x50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and completely evaporated. The resulting crude product was purified by silica gel column chromatography (hexane through hexane-EtOAc (0-100%)) to give the title compound as a gel solid.

- 97 042453 of that color (52 mg, 18% yield).

1H NMR (500 MHz, chloroform-d) δ 11.06 (s, 1H), 9.95 (s, 1H), 7.55-7.35 (m, 2H), 7.27 (d, J= 6.3 Hz, 2H), 6.97 (d, J=16.3 Hz, 1H), 6.94-6.87 (m, 3H), 3.99 (s, 3H), 3.84 ( s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₇ H ₁₆ O ₄ , 285; found, 285.

Example 2 (E)-2-Hidroxy-3-methoxy-5-(3-(trifluoromethyl)styryl)benzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (B)-4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)styryl )-1,3,2-dioxaborolane (358 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (92 mg, 29% yield).

1H NMR (500 MHz, chloroform-d) δ 11.14 (s, 1H), 9.96 (s, 1H), 7.75 (s, 1H), 7.70-7.61 (m, 1H) , 7.50 (dt, J=15.3, 7.8 Hz, 2H), 7.36-7.29 (m, 2H), 7.13 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.3 Hz, 1H), 4.00 (s, 3H);

LC-MS m/z [M+H]+ calc. for C17H13F3O3, 323; found, 323.

Example 3 5-(4-Chlorostyryl)-2-hydroxy-3-methoxybenzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (E)-2-(4-chlorostyryl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (318 mg, 1.2 mmol) as described in Example 1 to give a cis/trans mixture of the title compound as a yellow solid (58 mg, 20% yield).

'll NMR (500 MHz, chloroform-d) δ 11.22-10.92 (m, 1H), 10.04-9.73 (m, 1H), 7.53-7.36 (m, 1H) , 7.367.32 (m, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.28 (s, 1H), 7.21-7.17 (m, 1H), 7. 12 (m, 1H), 7.06-6.93 (m, 2H), 3.99-3.92 (s, 3H);

LC-MS m/z [M+Na]+ calc. for C ₁₆ H ₁₃ ClO ₃ , 311; found, 311.

Example 4 (E)-2-Hydroxy-3-methoxy-5-styrylbenzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (E)-styryl6-oronic acid (178 mg, 1.2 mmol) as described in Example 1, with affording the title compound as a brownish yellow solid (122 mg, 48% yield).

1H NMR (500 MHz, chloroform-d) δ 11.10 (s, 1H), 9.95 (s, 1H), 7.57-7.43 (m, 2H), 7.38 (t, J= 7.6 Hz, 2H), 7.29 (dd, J=5.3, 3.2 Hz, 3H), 7.06 (d, J=16.3 Hz, 1H), 7.01 (d, J=16.3 Hz, 1H), 4.00 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₆ H ₁₄ O ₃ , 255; found, 255.

Example 5 (E)-5-(3,5-Difluorostyryl)-2-hydroxy-3-methoxybenzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (E)-2-(3,5-difluorostyryl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (319 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (38 mg, 13% yield).

1H NMR (500 MHz, chloroform-d) δ 11.15 (s, 1H), 9.96 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.27 (d , J=2.0 Hz, 1H), 7.05 (d, J=16.3 Hz, 1H), 7.01 (dt, J=7.0, 2.1 Hz, 2H), 6.91 (d, J=16.2 Hz, 1H), 6.72 (tt, J=8.8, 2.3 Hz, 1H), 4.00 (s, 3H);

- 98 042453

LC-MS m/z [M+H]+ calc. for C^H^O3, 291; found, 291.

Example 6 (E)-5-(2,4-Difluorostyryl)-2-hydroxy-3-methoxybenzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (E)-2-(2,4-difluorostyryl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (319 mg, 1.2 mmol) as described in Example 1 to give the title compound as a tan solid (152 mg, 52% yield).

1H NMR (500 MHz, chloroform-d) δ 11.12 (s, 1H), 9.96 (s, 1H), 7.55 (td, J=8.6, 6.4 Hz, 1H), 7 .29 (q, J=2.0 Hz, 2H), 7.09 (d, J=16.2 Hz, 1H), 7.05 (d, J=16.2 Hz, 1H), 6.90 (td, J=8.4, 2.7 Hz, 1H), 6.85 (ddd, J=11.1, 8.7, 2.6 Hz, 1H), 4.00 (s, 3H);

LC-MS m/z [M+H]+ calc. for C16H12F2O3, 291; found, 291.

Example 7 (E)-5-(4-Fluorostyryl)-2-hydroxy-3-methoxybenzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (D)-(4-fluorostyryl)boronic acid (199 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (78 mg, 29% yield).

1H NMR (500 MHz, chloroform-d) δ 11.09 (s, 1H), 9.95 (s, 1H), 7.52-7.41 (m, 2H), 7.28 (s, 2H) , 7.107.02 (m, 2H), 6.97 (s, 2H), 3.99 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₆ H ₁₃ FO ₃ , 273; found, 273.

Example 8 (D)-2-Hydroxy-3-methoxy-5-(4-(trifluoromethyl)styryl)benzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and (D)-(4-(trifluoromethyl)styryl)boronic acid (259 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (58 mg, 18% yield).

1H NMR (500 MHz, chloroform-d) δ 11.14 (s, 1H), 9.97 (s, 1H), 7.65-7.57 (m, 4H), 7.33-7.28 ( m, 2H), 7.14 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.4 Hz, 1H), 3.96 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₇ H ₁₃ F ₃ O ₃ , 323; found, 323.

Example 9 (E)-1-(2-Hydroxy-3-methoxy-5-(4-methoxystyryl)phenyl)ethan-1-one

The title compound was prepared from 1-(5-bromo-2-hydroxy-3-methoxyphenyl)ethan-1-one (245 mg, 1.0 mmol) and (E)-(4-methoxystyryl)boronic acid (214 mg , 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (58 mg, 19% yield).

1H NMR (500 MHz, chloroform-d) δ 12.59 (s, 1H), 7.51-7.41 (m, 2H), 7.38 (d, J=1.9 Hz, 1H), 7 .25 (d, J=1.9 Hz, 1H), 6.96-6.85 (m, 4H), 3.97 (s, 3H), 3.84 (s, 3H), 2.68 ( s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₈ H ₁₈ O ₄ , 299; found, 299.

- 99 042453

Example 10 (E)-3-Fluoro-2-hydroxy-5-(4-methoxystyryl)benzaldehyde

K±XH0 U t

OME

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and (E)-(4-methoxystyryl)boronic acid (214 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (69 mg, 19% yield).

1H NMR (500 MHz, chloroform-d) δ 10.90 (s, 1H), 9.95 (s, 1H), 7.53 (dd, J=11.8, 2.1 Hz, 1H), 7 .46-7.41 (m, 3H), 6.97 (d, J=16.3 Hz, 1H), 6.94-6.90 (m, 2H), 6.87 (d, J=16 .1 Hz, 1H), 3.84 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₆ H ₁₃ FO ₃ , 273; found, 273.

Example 11 (E)-3-Fluoro-2-hydroxy-5-(3-(trifluoromethyl)styryl)benzaldehyde

F.1.CHO

Ύ

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and (E)-4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)styryl )-1,3,2-dioxaborolane (358 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (67 mg, 22% yield).

1H NMR (500 MHz, chloroform-d) δ 10.99 (s, 1H), 9.97 (s, 1H), 7.74 (s, 1H), 7.66 (d, J=7.6 Hz , 1H), 7.57 (dd, J=11.6, 2.1 Hz, 1H), 7.55-7.46 (m, 3H), 7.09 (d, J=16.3 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H);

LC-MS m/z [M+H]+ calc. for C ₁₆ H ₁₀ F ₄ O ₂ , 311; found, 311.

Example 12 tert-Butyl 2-(3-formyl-4-hydroxy-5-methoxyphenyl)-6,7-dihydrothieno[3,2-c]niridine5(4H)-carboxylate one

MeO^G,CHO y\ ^s

N—%

Vos

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (462 mg, 2.0 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-carboxylate (876 mg, 2.4 mmol) as described in Example 1 to give the title compound as a solid yellow (476 mg, 61% yield).

1H NMR (500 MHz, chloroform-d) δ 11.06 (s, 1H), 9.95 (s, 1H), 7.33 (d, J=2.0 Hz, 1H), 6.94 (s , 1H), 4.50 (s, 2H), 3.97 (s, 3H), 3.75 (s, 2H), 2.86 (s, 2H), 1.50 (s, 9H);

ESI-MS m/z [M+Na]+ calc. for C ₂₀ H ₂₃ NO ₅ S, 412; found, 412.

Example 13 2-Hydroxy-3-methoxy-5-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)benzaldehyde hydrochloride

MeO_G,CHO y\ ^s

HN—/

The title compound was prepared from Example 12 above, tert-butyl 2-(3-formyl-4-hydroxy-5-methoxyphenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (97 mg, 0.25 mmol), in dichloromethane (2.0 ml) treated with 4N. HCl in dioxane (2.0 ml) for 3 h at room temperature in a glass vial (30 ml) sealed with a cap. The volatiles were then completely evaporated and dried completely with a lyophilizer to give the title compound as a yellow solid (48 mg).

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 10.31 (s, 1H), 9.48 (s, 2H), 7.43 (d, J=2.2 Hz, 1H), 7.37

- 100 042453 (d, J=2.2 Hz, 1H), 7.31 (s, 1H), 4.17 (s, 2H), 3.94 (s, 3H), 3.57 (s, 1H ), 3.43 (d, J=7.3 Hz, 2H), 3.05 (t, J=6.1 Hz, 2H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₅ H ₁₅ NO ₃ S, 290; found, 290.

Example 14 5-(5-(Cyclopropanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-hydroxy3-methoxybenzaldehyde

Step 1. 2-Bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.HCl

A solution of bromine (0.51 ml, 10.0 mmol) in acetic acid (1 ml) was added to a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (1.75 g, 10.0 mmol) in acetic acid (5 ml). The reaction mixture was stirred for 1.5 hours. The reaction was quenched with sat. sodium bicarbonate (20 ml) and extracted with ethyl acetate (3x30 ml). The three organic extracts were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate. Added 6n. HCl (gas)/dioxane (10 ml) and the mixture was concentrated in vacuo to give the desired product (1.7 g, 67% yield) as a yellow solid.

LC-MS m/z [M+H]+ calc. for C7H8BrNS, 219; found, 219.

Step 2. (2-Bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(cyclopropyl)methanone

TEA (1.65 ml, 11.9 mmol) and cyclopropanecarbonyl chloride (0.39 ml, 4.3 mmol) were added successively to a solution of 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.HCl (1 g, 3.95 mmol) in THF (10 ml) at 0°C. The reaction mixture was stirred for 1 h at 0°C. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-1:1) to obtain the desired product (0.97 g, 86% yield).

LC-MS m/z [M+H] ⁺ calc. for C ₁₁ H ₁₂ BrNOS, 287; found, 287.

Step 3. 2-Hydroxy-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

A mixture of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1.15 g, 5.0 mmol), bis-(pinacolato)diborone (1.4 g, 5.5 mmol), potassium acetate (1.5 g, 15.0 mmol) and PdCl ₂ (dppf (0.4 g, 0.5 mmol) in dioxane (30 ml) was heated at 110°C for 4 h. The reaction was quenched with water (50 ml) and extracted with ethyl acetate (3x50 ml The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to give the desired product (310 mg, yield 22%) as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 11.37 (s, 1H), 9.93 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 3.96 (s, 3H), 1.35 (s, 12H).

Step 4 2-hydroxy-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde mixture (50 mg, 0.18 mmol), (2 -bromo-6,7-dihydrothieno[3,2-c]pyridin-5 (4H) -yl) (cyclopropyl) methanone (51 mg, 0.18 mmol), Na ₂ CO ₃ (96 mg, 0.9 mmol ) and Pd(PPh ₃ ) ₄ (10 mg, 0.01 mmol) in DMF (2 ml) and H2O (2 ml)

- 101 042453 was stirred at 95°C for 2 hours under N2 atmosphere. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organics were washed with brine (10 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (13 mg, 20% yield).

¹ H NMR (400 MHz, chloroform-d) δ 11.07 (s, 1H), 9.95 (s, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 6, 95 (s, 1H), 4.74 (m, 2H), 3.98 (s, 5H), 2.93 (m, 2H), 1.82 (m, 1H), 1.04 (m, 2H ), 0.84 (m, 2H);

LC-MS m/z [MH] ^- calc. for C ₁₉ H ₁₉ NO ₄ S, 356; found, 356.

Example 15 5-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-hydroxy-3-methoxybenzaldehyde

Step 1. 1-(2-Bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone

TEA (1.65 ml, 11.9 mmol) and acetyl chloride (0.35 ml, 4.3 mmol) were added successively to a solution of 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (1 g, 3.95 mmol) obtained in accordance with example 14, in THF (10 ml) at 0°C. The reaction mixture was stirred for 1 hour at 0°C. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1-1:1) to obtain the desired product (0.93 g, 91% yield).

LC-MS m/z [M+H] ⁺ calc. for C ₉ H ₁₀ BrNOS, 261; found, 261.

Step 2: Mixture of 1-(2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone (259 mg, 1.0 mmol), 2-hydroxy-3-methoxy -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (278 mg, 1.0 mmol) obtained in accordance with example 14, Na ₂ CO ₃ (530 mg, 5.0 mmol) and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) in DMF (10 ml) and H2O (10 ml) were stirred at 95°C for 2 h under N2 atmosphere. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (52 mg, 16% yield).

1H NMR (400 MHz, chloroform-d) δ 11.07 (s, 1H), 9.95 (s, 1H), 7.33 (s, 1H), 7.24 (s, 1H), 6.94 (s, 1H), 4.68 (s, 1H), 4.55 (s, 1H), 3.98 (s, 3H), 3.94 (m, 1H), 3.78 (m, 1H) , 2.94 (m, 2H), 2.19 (m, 3H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₇ H ₁₇ NO ₄ S, 332; found, 332.

Example 16 5-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-hydroxy-3methoxybenzaldehyde

Step 1. 2-Bromo-5-(2-fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

KOH (1.1 g, 19.75 mmol) and 1-bromo-2-fluoroethane (4.98 g, 39.5 mmol) were added to a solution of 2-bromo-4,5,6,7-tetrahydrothieno[3, 2-c]pyridine hydrochloride (1 g, 3.95 mmol) prepared according to Example 14 in MeOH (40 ml). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (3x100 ml). The organic extracts were combined, washed with brine (2x100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1-10:1) to obtain the desired product (0.88 g, 85% yield).

1H NMR (400 MHz, chloroform-d) δ 6.68 (s, 1H), 4.69 (m, 1H), 4.57 (m, 1H), 3.60 (s, 2H), 2.80 -2.94 (m, 6H);

LC-MS m/z [M+H]+ calc. for C ₉ H11BrFNS, 265; found, 265.

Step 2. 3-Methoxy-2-(4-methoxybenzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzaldehyde

- 102 042453

CHO X.OPMB

PinB'^^O^

PMB-Cl (0.54 ml, 4.0 mmol) was added to a mixture of 2-hydroxy-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzaldehyde ( 532 mg, 2.0 mmol) prepared according to example 14 and potassium carbonate (552 mg, 4.0 mmol) in DMF (10 ml). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (2x30 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1-10:1) to obtain the desired product (0.63 g, 82% yield).

Step 3. 5-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-methoxy-2-((4methoxybenzyl)oxy)benzaldehyde

OME _f ^nYXT ^opmb CHO

2-bromo-5-(2-fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine mixture (263 mg, 1.0 mmol), 3-methoxy-2-(4-methoxybenzyloxy) )-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (398 mg, 1.0 mmol), Na ₂ CO ₃ (320 mg, 3.0 mmol ) and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) in DMF (10 ml) and H ₂ O (10 ml) was stirred at 95°C for 2 h under N ₂ atmosphere. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (160 mg, 36% yield).

1H NMR (400 MHz, chloroform-d) δ 10.20 (s, 1H), 7.53 (s, 1H), 7.36 (m, 2H), 7.27 (m, 1H), 7.05 (m, 2H), 6.95 (s, 1H), 5.14 (s, 2H), 4.72 (m, 1H), 4.60 (m, 1H), 3.99 (s, 3H) , 3.74 (m, 2H), 3.67 (m, 2H), 2.93 (m, 6H).

Step 4. 5-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]πiridin-2-yl)-3-methoxy-2-((4methoxybenzyl)oxy)benzaldehyde (160 mg, 0.36 mmol) was dissolved in DCM (2 ml) and TFA (1 ml) was added. The reaction mixture was stirred for 30 minutes. The solution was concentrated under vacuum. The residue was dissolved in sat. sodium bicarbonate (5 ml) and extracted with ethyl acetate (3x5 ml). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (88 mg, 75% yield) as a yellow solid.

1H NMR (400 MHz, chloroform-d) δ 11.10 (br, 1H), 9.94 (s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 6.89 (s, 1H), 4.79 (m, 1H), 4.67 (m, 1H), 3.97 (s, 3H), 3.76 (s, 2H), 3.00 (m, 6H) ;

LC-MS m/z [M+H]+ calc. for C ₁₇ H ₁₈ FNO ₃ S, 336; found, 336.

Example 17

N—/

V

Step 1. Cyclopropyl (6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl) methanone

TEA (4.77 ml, 34.3 mmol) and cyclopropanecarbonyl chloride (1.14 ml, 12.6 mmol) were added successively to a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (2 g, 11.4 mmol) in THF (10 ml) at 0°C. The reaction mixture was stirred for 1 h at 0°C. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1-1:1) to give the title compound (2.2 g, 93% yield).

LC-MS m/z [M+H]+ calc. for C11H ₁₃ NOS, 208; found, 208.

Step 2. 5-(Cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

LAH (700 mg, 18.4 mmol) was added to a solution of cyclopropyl(6,7-dihydrothieno[3,2-e]pyridin5(4H)-yl)methanone (1 g, 4.8 mmol) in THF (10 ml) at 0°C. The reaction mixture was heated at 60°C for

- 103 042453 1 h. The reaction mixture was cooled to RT, quenched with water (30 m) and extracted with ethyl acetate (3x30 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100:1-20:1) to obtain the desired product (0.64 g, 69% yield).

LC-MS m/z [M+H]+ calc. for C11H15NS, 194; found, 194.

Step 3. 2-bromo-5-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

Bromine (0.13 ml, 2.59 mmol) was added to a solution of compound 2 (500 mg, 2.59 mmol) in DMF/water (6 ml/12 ml) at 0°C. The reaction mixture was stirred for 30 minutes. at 0°C. The reaction was quenched with sat. sodium bicarbonate (20 m) and was extracted with ethyl acetate (3x30 ml). The three organic extracts were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100:1-30:1) to obtain the desired product (0.41 g, 58% yield).

LC-MS m/z [M+H] ⁺ calc. for C _n H ₁₄ BrNS, 272; found, 272.

Step 4. 5-(5-(Cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-methoxy-2-((4methoxybenzyl)oxy)benzaldehyde

OME /=( sno

A mixture of 2-bromo-5-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (271 mg, 1.0 mmol), 3-methoxy-2-(4-methoxybenzyloxy)- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (398 mg, 1.0 mmol) prepared according to Example 16, Na ₂ CO ₃ (320 mg , 3.0 mmol) and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) in DMF (10 ml) and H2O (10 ml) were stirred at 95°C for 2 h under N2 atmosphere. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (90 mg, 19% yield).

Step 5. 5-(5-(Cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-methoxy-2-((4methoxybenzyl)oxy)benzaldehyde (90 mg, 0.19 mmol) was dissolved in DCM (2 ml) and TFA (1 ml) was added. The reaction mixture was stirred for 30 minutes. The solution was concentrated under vacuum. The residue was dissolved in sat. sodium bicarbonate (5 ml) and extracted with ethyl acetate (3x5 ml). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (57 mg, 85% yield) as a yellow solid.

1H NMR (400 MHz, chloroform-d) δ 10.31 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 3.94 (s, 3H), 3.27 (m, 4H), 3.03 (m, 4H), 1.09 (m, 1H), 0.61 (m, 2H), 0.29 (m, 2H) ;

LC-MS m/z [M+H] ⁺ calc. for C19H21NO3S, 344; found, 344.

Example 18 3-Fluoro-2-hydroxy-5-(5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2yl)benzaldehyde

Step 1. 2-Bromo-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

A mixture of an aqueous solution of formaldehyde (3.93 ml, 39.5 mmol, concentration 37%), acetic acid (2 ml), 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride ( 1 g, 3.95 mmol) prepared according to Example 14 and NaBH ₃ CN (0.50 g, 79.0 mmol) in MeOH (12 ml) were stirred overnight at RT. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=20:1:1-5:1:1) to obtain the desired product (0.32 g, 35% yield).

LC-MS m/z [M+H] ⁺ calc. for C ₈ H ₁₀ BrNS, 232; found, 232.

Step 2. 5-bromo-3-fluoro-2-(4-methoxybenzyloxy)benzaldehyde

- 104 042453

PMB-Cl (1.79 g, 11.5 mmol) was added to a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1 g, 4.6 mmol) and potassium carbonate (1.9 g, 13.8 mmol ) in DMF (10 ml). The reaction mixture was stirred for 3 hours at RT. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (2x30 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100:1-20:1) to obtain the desired product (1.37 g, 88% yield).

Step 3. 3-Fluoro-2-(4-methoxybenzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzaldehyde

A mixture of 5-bromo-3-fluoro-2-(4-methoxybenzyloxy)benzaldehyde (1.37 g, 4.1 mmol), bis-(pinacolato)diborone (1.1 g, 4.5 mmol), potassium acetate ( 1.2 g, 12.3 mmol) and PdCl ₂ (dppf) (0.3 g, 0.4 mmol) in dioxane (30 ml) were heated at 110°C for 4 h. The reaction was quenched with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1-5:1) to obtain the desired product (1.14 g, 73% yield).

Step 4: 2-bromo-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine mixture (84 mg, 0.36 mmol), 3-fluoro-2-(4-methoxybenzyloxy) -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (140 mg, 0.36 mmol), Na ₂ CO ₃ (192 mg, 1.81 mmol) and Pd(PPh ₃ ) ₄ (21 mg, 0.02 mmol) in DMF (7 ml) and H2O (1 ml) were stirred at 95° C. for 2 h under N ₂ atmosphere. PMB was removed during the course of the reaction. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (15 mg, 10% yield) as a yellow solid.

1H NMR (400 MHz, chloroform-d) δ 10.28 (s, 1H), 7.76 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.57 (d, J=1 .2 Hz, 1H), 7.20 (s, 1H), 3.60 (s, 2H), 3.27 (m, 4H), 2.88 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₅ H ₁₄ FNO ₂ S, 292; found, 292.

Example 19 5-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-fluoro-2-hydroxybenzaldehyde

A mixture of 1-(2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone (67 mg, 0.26 mmol) prepared according to Example 15, 3-fluoro -2-(4-methoxybenzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzaldehyde (100 mg, 0.26 mmol) obtained in accordance with example 18, Na ₂ CO ₃ (137 mg, 1.30 mmol) and Pd(PPh ₃ ) ₄ (15 mg, 0.01 mmol) in DMF (5 ml) and H ₂ O (1 ml) were stirred at 95°C for 2 h in an N2 atmosphere. PMB was removed during the course of the reaction. The reaction mixture was poured into water (30 ml) and extracted with dichloromethane (3x30 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give the desired product (39 mg, 47% yield) as a yellow solid.

1H NMR (DMSO-d6, 400 MHz) δ 11.12 (br, 1H), 10.30 (s, 1H), 7.80 (dd, J=12.0 Hz, 2.4 Hz, 1H), 7.60 (s, 1H), 7.28 (m, 1H), 4.52 (m, 2H), 3.74 (m, 2H), 2.76-2.88 (m, 2H), 2 .08-2.11 (m, 3H);

LC-MS m/z [MH] ^- calc. for C ₁₆ H ₁₄ FNO ₃ S, 318; found, 318.

Example 20 2-Hydroxy-5-(5-isopropyl-4,5,6,7-tetrahydrothieno[3,2-e]pyridin-2-yl)-3-methoxybenzaldehyde

Step 1. 2-Bromo-5-isopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

- 105 042453

Acetone (1.83 g, 31.6 mmol) and acetic acid (1.81 ml, 31.6 mmol) were added to a solution of 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (2 g, 7.9 mmol) prepared according to example 14 and triethylamine (2.2 ml, 15.8 mmol) in MeOH (20 ml). The reaction mixture was stirred for 20 minutes. and NaBH ₃ CN (2.49 g, 39.5 mmol) was added. The reaction mixture was then stirred overnight at RT. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The organic extracts were combined, washed with brine (2x20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane=20:1:1-5:1:1) to obtain the desired product (1.9 g, 93% yield).

LC-MS m/z [M+H]+ calc. for C ₁₀ H ₁₄ BrNS, 261; found, 261.

Step 2. A mixture of 2-bromo-5-isopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (100 mg, 0.39 mmol), 2-hydroxy-3-methoxy-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (107 mg, 0.39 mmol) prepared according to Example 13, Na ₂ CO ₃ (204 mg, 1 96 mmol) and Pd(PPh ₃ ) ₄ (22 mg, 0.02 mmol) in DMF (3 ml) and H ₂ O (2 ml) were stirred at 95°C for 2 h under N ₂ atmosphere. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to give the desired product (23 mg, 18% yield) as a yellow solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 10.29 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 3, 92 (s, 3H), 3.50 (m, 4H), 2.89 (m, 1H), 2.76 (m, 4H), 1.06 (d, J=6.4 Hz, 6H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₈ H ₂₁ NO ₃ S, 332; found, 332.

Example 21 (E)-2-Hidroxy-5-(2-(6-methylpyridin-3-yl)vinyl)benzaldehyde he ^khno ί J

Mr.

Me

In a 30 ml glass vial sealed with a cap, 5-bromo-2-hydroxybenzaldehyde (201 mg, 1.0 mmol), 2-methyl-5-vinylpyridine (119 mg, 1.0 mmol), 1,3-bis-(diphenylphosphino ) propane (dppp) (82.4 mg, 0.2 mmol), trimethylamine (278 mg, 2.0 mmol) was dissolved in DMF (5.0 ml), then palladium acetate (22.4 mg, 0 .1 mmol). Then closed with a sealed cap and continued at 95°C for 16 h on a stirrer with a cup containing metal granules. Then cooled to room temperature, diluted with water (20 ml), transferred to a separating funnel with dichloromethane and extracted with additional dichloromethane (2x50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and completely evaporated. The resulting crude product was purified by silica gel column chromatography (hexane through hexane-EtOAc (0-100%)) to give the title compound as a yellow solid (45 mg, 19% yield).

1H NMR (500 MHz, chloroform-d) δ 11.04 (s, 1H), 9.95 (s, 1H), 8.59 (d, J=2.3 Hz, 1H), 7.73 (dt , J=8.5, 2.4 Hz, 2H), 7.67 (d, J=2.2 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.07 (d, J=16.4 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.98 (d, J=16.3 Hz, 1H), 2.57 (s , 3H);

LC-MS m/z [M+H] ⁺ calc. for C15H13NO2, 240; found, 240.

Example 22 (E)-4-Fluoro-2-hydroxy-5-(4-methoxystyryl)benzaldehyde (compound 55) he

X/CHO ν’

OME

The title compound was prepared from 5-bromo-4-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and (E)-(4-methoxystyryl)boronic acid (214 mg, 1.2 mmol) as described in Example 1 to give the title compound as a yellow solid (45 mg, 16% yield).

¹ H NMR (500 MHz, chloroform-d) δ 11.22 (d, J=1.6 Hz, 1H), 9.89 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.51 7.37 (m, 2H), 7.07 (d, J=16.5 Hz, 1H), 7.00 (d, J=16.5 Hz, 1H), 6.95 -6.87 (m, 2H), 6.70 (d, J=11.9 Hz, 1H), 3.84 (s, 3H);

LC-MS m/z [M+H] ⁺ calc. for C1 ₆ H^O3, 273; found, 273.

Example 23 (E)-2-Hydroxy-3-methoxy-5-(2-(pyridin-2-yl)vinyl)benzaldehyde (compound 56)

- 106 042453 he

MeO^D^CHO

Ύ T

L and Tsu

Compound 56 was generally prepared as described in Scheme 3 a. In a 30 ml glass vial sealed with a cap, 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol), 2-vinylpyridine (105 mg, 1.0 mmol), 1,3-bis-(diphenylphosphino )propane (dppp) (82 mg, 0.2 mmol) and Et ₃ N (278 μl, 2.0 mmol) were suspended in DMF (5 ml). Pd(OAc) ₂ (22 mg, 0.1 mmol) was then added to the reaction vial, sealed with a cap, and continued at 95°C for 16 h on a stirrer with a cup containing metal granules. Then cooled to room temperature, evaporated the volatiles and transferred to a separating funnel with dichloromethane. The aqueous layer was acidified with 10% citric acid to pH ~5 and extracted with additional dichloromethane (2x50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (hexane through hexane-EtOAc (0-100%)) to give the title compound as a brown solid (36 mg, 13% yield).

1H NMR (500 MHz, chloroform-d) δ 11.17 (s, 1H), 9.95 (s, 1H), 8.61 (d, J=4.8 Hz, 1H), 7.68 (t , J=7.9 Hz, 1H), 7.59 (d, J=16.0 Hz, 1H), 7.38 (dd, J=14.3, 5.9 Hz, 3H), 7.17 (dd, J=7.5, 5.0 Hz, 1H), 7.09 (d, J=16.0 Hz, 1H), 3.99 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₅ H ₁₃ NO ₃ , 256; found, 256.

Example 24 (E)-2-Hydroxy-5-(2-(pyridin-2-yl)vinyl)benzaldehyde (compound 57)

The title compound was prepared from 5-bromo-2-hydroxybenzaldehyde (201 mg, 1.0 mmol) and (2-vinylpyridine (105 mg, 1.0 mmol) as described in Example 23 to give the title compound in as a yellow solid (37 mg, 16% yield).

¹ H NMR (500 MHz, chloroform-d) δ 11.07 (s, 1H), 9.94 (s, 1H), 8.71-8.53 (m, 1H), 7.88-7.75 (m, 2H), 7.73 (d, J=2.3 Hz, 1H), 7.68 (td, J=7.7, 1.9 Hz, 1H), 7.62 (d, J= 16.1 Hz, 1H), 7.50-7.39 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.20-7.13 (m, 1H), 7.09 (d, J=16.0 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₄ H _n NO ₂ , 226; found, 226.

Example 25 (E)-2-Hydroxy-3-methoxy-5-(2-(pyridin-4-yl)vinyl)benzaldehyde (compound 58)

Compound 56 was generally prepared as described in Scheme 3 a. In a 30 ml glass vial sealed with a cap, 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol), 4-vinylpyridine (105 mg, 1.0 mmol), 1,3-bis-(diphenylphosphino ) propane (dppp) (82 mg, 0.2 mmol) and K ₂ CO ₃ (414 mg, 3.0 mmol) were suspended in DMF-H ₂ O (3:1) (10 ml). Then Pd(OAc) ₂ (22 mg, 0.1 mmol) was added to the reaction flask, sealed with a cap and continued at 95°C for 5 h on a stirrer with a cup containing metal granules. Then cooled to room temperature, diluted with water and transferred to a separating funnel with ethyl acetate. The aqueous layer was acidified with 10% citric acid to pH ~5 and extracted with additional ethyl acetate (2x50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (hexane through hexane-EtOAc (0-100%)) to give the title compound as a brown solid (58 mg, 23% yield).

¹ H NMR (500 MHz, chloroform-d) δ 11.18 (s, 1H), 9.97 (s, 1H), 8.59 (d, J=5.1 Hz, 2H), 7.38- 7.35 (m, 2H), 7.34 (d, J=1.9 Hz, 1H), 7.31 (d, J=1.9 Hz, 1H), 7.25 (d, J=16 .3 Hz, 1H), 6.93 (d, J=16.3 Hz, 1H), 4.00 (s, 3H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₅ H ₁₃ NO ₃ , 256; found, 256.

Example 26 (E)-2-Hydroxy-3-methoxy-5-(2-(6-methylpyridin-3-yl)vinyl)benzaldehyde

- 107 042453 (compound 59) he MeO.X.CHO

T J

Mr.

Me

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 2-methyl-5-vinylpyridine (119 mg, 1.0 mmol) as described in Example 25, to give the title compound as a yellow solid (100 mg, 37% yield).

1H NMR (500 MHz, chloroform-d) δ 11.12 (s, 1H), 9.95 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 7.73 (dd , J=8.1, 2.3 Hz, 1H), 7.29 (s, 2H), 7.17 (d, J=8.1 Hz, 1H), 7.06 (d, J=16, 4 Hz, 1H), 6.96 (d, J=16.4 Hz, 1H), 4.00 (s, 3H), 2.58 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₆ H ₁₅ NO ₃ , 270; found, 270.

Example 27 tert-Butyl (E)-4-(3-formyl-4-hydroxy-5-methoxystyryl)piperidine-1-carboxylate (compound 60) he

MeO^X^CHO

Ύ J

N

Vos

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and t-butyl 4-vinylpiperidine-1-carboxylate (211 mg, 1.0 mmol) as described in Example 23 to give the title compound as a yellow solid (58 mg, 16% yield).

1H NMR (500 MHz, chloroform-d) δ 11.01 (s, 1H), 10.11-9.77 (m, 1H), 7.16-7.05 (m, 2H), 6.34 ( dd, J=15.9, 1.3 Hz, 1H), 6.06 (dd, J=16.0, 6.9 Hz, 1H), 3.94 (s, 3H), 2.77 (d , J=12.9 Hz, 3H), 2.29 (m, 1H), 1.76 (d, J=13.0 Hz, 2H), 1.59 (d, J=8.8 Hz, 1H ), 1.47 (s, 9H), 1.39 (m, 2H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₀ H ₂₇ NO ₅ , 362; found, 362.

Example 28 (E)-3-Fluoro-2-hydroxy-5-(2-(pyridin-2-yl)vinyl)benzaldehyde (compound 61) he

F.X.CHO y J

X N

G ί]

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 2-vinylpyridine (105 mg, 1.0 mmol) as described in Example 25 to give title compound as a yellow solid (70 mg, 29% yield).

1H NMR (500 MHz, chloroform-d) δ 10.97 (s, 1H), 9.96 (d, J=1.8 Hz, 1H), 8.61 (dd, J=4.8, 1, 7 Hz, 1H), 7.68 (td, J=7.7, 1.9 Hz, 1H), 7.62-.55 (m, 2H), 7.55-7.50 (m, 1H) , 7.35 (d, J=7.8 Hz, 1H), 7.23-7.14 (m, 1H), 7.06 (d, J=15.9 Hz, 1H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₄ H ₁₀ FNO ₂ , 244; found, 244.

Example 29 (E)-3-Fluoro-2-hydroxy-5-(2-(6-methylpyridin-3-yl)vinyl)benzaldehyde (compound 62) he

F.X.CHO J

G P

Me

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 2-methyl-5-vinylpyridine (119 mg, 1.0 mmol) as described in Example 25, to give the title compound as a yellow solid (38 mg, 15% yield) and its citrate salt (58 mg).

1H NMR (500 MHz, chloroform-d) δ 9.97 (d, J=1.8 Hz, 1H), 8.85-8.49 (m, 1H), 7.78 (dd, J=8, 1, 2.2 Hz, 2H), 7.56 (dd, J=11.5, 2.1 Hz, 1H), 7.49 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 6.97 (d, J=16.4 Hz, 1H), 2.61 (s, 3H);

LC-MS m/z [M+H] ⁺ calc. For C ₁₅ H ₁₂ FNO ₂ , 258; found, 258.

- 108 042453

Example 30 (E)-3-Fluoro-2-hydroxy-5-(2-(pyridin-4-yl)vinyl)benzaldehyde (compound 63)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 4-vinylpyridine (105 mg, 1.0 mmol) as described in Example 25 to give title compound as a pink solid (22 mg, 9% yield).

LC-MS m/z [M+H]+ calc. for C ₁₄ H ₁₀ FNO ₂ , 244; found, 244.

Example 31 tert-Butyl (E)-4-(3-fluoro-5-formyl-4-hydroxystyryl)piperidine-1-carboxylate (compound 64)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and tert-butyl 4-vinylpiperidine-1-carboxylate (211 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (48 mg, 14% yield).

1H NMR (500 MHz, chloroform-d) δ 10.88 (d, J=13.6 Hz, 1H), 9.92 (dd, J=12.6, 1.9 Hz, 1H), 7.42 -7.31(m, 1H), 7.29(t, J=1.4Hz, 1H), 6.30(d, J=15.9Hz, 1H), 6.07(dd, J= 15.9, 6.8 Hz, 1H), 4.39-4.01 (m, 2H), 2.78 (t, J=12.6 Hz, 2H), 2.29 (kt, J=7 .3, 3.5 Hz, 1H), 1.75 (dd, J=13.4, 3.7 Hz, 2H), 1.47 (d, J=4.4 Hz, 10H), 1.38 (cd, J=12.5, 4.2 Hz, 2H);

LC-MS m/z [M+H]+ calc. for C ₁₉ H ₂₄ FNO ₄ , 350; found, 350.

Example 32 (E)-2-Hydroxy-3-methoxy-5-(2-(naphthalen-2-yl)vinyl)benzaldehyde (compound 65) he

MeO.A, CHO

ΎJ

Li Ό

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 2-vinylnaphthalene (154 mg, 1.0 mmol) as described in Example 25 to give title compound as a yellow solid (54 mg, 18% yield).

1H NMR (500 MHz, chloroform-d) δ 11.12 (s, 1H), 9.97 (s, 1H), 7.90-7.79 (m, 4H), 7.73 (dd, J= 8.6, 1.8 Hz, 1H), 7.54-7.42(m, 2H), 7.39-7.31(m, 2H), 7.19(s, 2H), 4.02 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₂₀ H ₁₆ O ₃ , 305; found, 305.

Example 3 3. (E)-2-Hidroxy-3-methoxy-5-(3-oxo-3-phenylprop-1-en-1-yl)benzaldehyde (compound 66) he

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-phenylprop-2-en-1-one (132 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (68 mg, 24% yield).

1H NMR (499 MHz, chloroform-d) δ 11.35 (s, 1H), 9.98 (s, 1H), 8.15-7.95 (m, 2H), 7.77 (d, J= 15.6 Hz, 1H), 7.64-7.58 (m, 1H), 7.56-7.46 (m, 3H), 7.44 (d, J=15.5 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 4.01 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₇ H ₁₄ O ₄ , 283; found, 283.

Example 34 (E)-2-Hydroxy-5-(4-hydroxy-3-methoxystyryl)-3-methoxybenzaldehyde (compound 67)

- 109 042453

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 2-methoxy-4-vinylphenol (150 mg, 1.0 mmol) as described in Example 25, to afford the title compound as a yellow solid (62 mg, 21% yield).

1H NMR (499 MHz, chloroform-d) δ 11.06 (s, 1H), 9.94 (s, 1H), 7.27 (m, 2H), 7.05-7.00 (m, 2H) , 6.95 (d, J=16.3 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J=16.2 Hz, 1H), 5.67 (s, 1H) , 3.99 (s, 3H), 3.96 (s, 3H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₇ H ₁₆ O ₅ , 301; found, 301.

Example 35 (E)-2-Hydroxy-3-methoxy-5-(3-morpholino-3-oxoprop-1-en-1-yl)benzaldehyde (compound 68)

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-morpholinoprop-2-en-1-one (142 mg, 1.0 mmol) as described in Example 25 to give the title compound as a brown solid (165 mg, 21% yield).

1H NMR (499 MHz, chloroform-d) δ 11.22 (s, 1H), 9.95 (s, 1H), 7.66 (d, J=15.3 Hz, 1H), 7.36 (d , J=1.8 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.75 (d, J=15.4 Hz, 1H), 3.97 (s, 3H ), 3.74 (dd, J=4.0, 2.1 Hz, 8H);

LC-MS m/z [M+H]+ calc. for C ₁₅ H ₁₇ NO ₅ , 292; found, 292.

Example 36.

(compound 69) (E)-5-(2-([1,1'-biphenyl]-4-yl)vinyl)-2-hydroxy-3-methoxybenzaldehyde

The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 4-vinyl-1,1'-biphenyl (180 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (62 mg, 19% yield).

1H NMR (499 MHz, chloroform-d) δ 11.11 (s, 1H), 9.97 (s, 1H), 7.63 (dd, J=8.0, 2.3 Hz, 4H), 7 .58 (d, J=8.3 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.39-7.33 (m, 1H), 7.32 (q, J=2.0Hz, 2H), 7.11(d, J=16.4Hz, 1H), 7.05(d, J=16.2Hz, 1H), 4.01(s, 3H) ;

LC-MS m/z [M+H] ⁺ calc. for C ₂₂ H ₁₈ O ₃ , 331; found, 331.

Example 37 (E)-5-(2-([1,1'-Biphenyl]-4-yl)vinyl)-3-fluoro-2-hydroxybenzaldehyde (compound 70)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 4-vinyl-1,1'-biphenyl (180 mg, 1.0 mmol) as described in Example 25 to give the title compound as an off-white solid (18 mg, 6% yield).

1H NMR (499 MHz, chloroform-d) δ 10.95 (s, 1H), 9.97 (d, J=1.8 Hz, 1H), 7.63 (d, J=8.1 Hz, 4H ), 7.607.55 (m, 3H), 7.50-7.48 (m, 1H), 7.46 (t, J=7.7 Hz, 2H), 7.36 (t, J=7, 4 Hz, 1H), 7.06 (s, 2H);

LC-MS m/z [M+H] ⁺ calc. for C21H15FO2, 319; found, 319.

Example 38 5-(2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)vinyl)-2-hydroxy-3-methoxybenzaldehyde (compound 71)

- 110 042453

Stage 1. Synthesis of 6-vinyl-2,3-dihydrobenzo[b][1,4]dioxin

The intermediate 6-vinyl-2,3-dihydrobenzo[b][1,4]dioxin was prepared generally as described in Scheme 4. Methyltriphenylphosphonium bromide (7 .14 g, 20 mmol) suspended in tetrahydrofuran (40 ml) at 0° C. in an ice bath. The n-BuLi solution (2.0 M solution in THF) was then added to the reaction mixture using a syringe and stirring was continued for an additional 15 minutes. Then, 2,3-dihydrobenzo[b][1,4]dioxin-6-carbaldehyde (1.64 g, 10 mmol) in 10 ml THF was added dropwise using an addition funnel. The reaction was continued for 8 hours, then saturated aq. NH4Cl at 0°C and extracted into EtOAc (2x75 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (hexane through hexane-EtOAc (0-100%)) to give the title compound as a colorless oil (1.32 g, 81% yield).

LC-MS m/z [M+H]+ calc. for C ₁₀ H ₁₀ O ₂ , 163; found, 163.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and the above 6-vinyl-2,3-dihydrobenzo[b][1,4]dioxin (162 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (71 mg, 23% yield).

1H NMR (499 MHz, chloroform-d) δ 11.07 (s, 1H), 9.94 (s, 1H), 7.26-7.22 (m, 2H), 7.03 (d, J= 2.1 Hz, 1H), 6.99 (dd, J=8.3, 2.1 Hz, 1H), 6.89 (s, 2H), 6.86 (d, J=8.3 Hz, 1H), 4.28 (s, 4H), 3.98 (s, 3H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₈ H ₁₆ O ₅ , 313; found, 313.

Example 39 (E)-5-(2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)vinyl)-3-fluoro-2-hydroxybenzaldehyde (compound 72)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 6-vinyl-2,3-dihydrobenzo[b][1,4]dioxin (162 mg, 1 .0 mmol) as described in Example 25 to give the title compound as a yellow solid (62 mg, 21% yield).

1H NMR (499 MHz, chloroform-d) δ 10.91 (s, 1H), 9.95 (d, J=1.9 Hz, 1H), 7.51 (dd, J=11.8, 2, 1 Hz, 1H), 7.42 (t, J=1.4 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.3, 2.1 Hz, 1H), 6.90 (d, J=16.3 Hz, 1H), 6.86 (d, J=6.5 Hz, 1H), 6.84 (d, J=14, 3 Hz, 1H), 4.28 (s, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₇ H ₁₃ FO ₄ , 301; found, 301.

Example 40 (E)-2-Hydroxy-3-methoxy-5-(4-morpholinostyryl)benzaldehyde (compound 73)

Stage 1. Synthesis of 4-(4-vinylphenyl)morpholine

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The title compound was prepared from 4-morpholinobenzaldehyde (1.912 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure as in Example 38 step 1 to give the product as a white solid ( 1.32 g, 70% yield.

LC-MS m/z [M+H]+ calc. for C ₁₂ H ₁₅ NO, 190; found, 190.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 4-(4-vinylphenyl)morpholine (189 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (92 mg, 27% yield).

1H NMR (500 MHz, chloroform-d) δ 11.05 (s, 1H), 9.94 (s, 1H), 7.49-7.40 (m, 2H), 7.28-7.21 ( m, 2H), 6.96 (d, J=16.3 Hz, 1H), 6.93-6.86 (m, 3H), 3.98 (s, 3H), 3.92-3.73 (m, 4H), 3.32-3.06 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₀ H ₂₁ NO ₄ , 340; found, 340.

Example 41 (2)-2-Hydroxy-3-methoxy-5-(4-morpholinostyryl)benzaldehyde (compound 74)

Mixture of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (693 mg, 3.0 mmol), 4-(4-vinylphenyl)morpholine (567 mg, 3.0 mmol), 1,3-bis-(diphenylphosphino)propane (dppp) (247 mg, 0.6 mmol), K ₂ CO ₃ powder (1.24 g, 9.0 mmol) and palladium acetate (67 mg, 0.3 mmol) in DMF-water (3:1) (12 ml) was heated overnight at 85°C. The mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (2x50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1-10:1) to give the title product as a yellow solid (27 mg, 3% yield).

1H NMR (CDCl ₃ , 400 MHz) δ 11.16 (s, 1H), 9.87 (s, 1H), 7.29 (s, 2H), 7.12-7.15 (m, 2H), 6.95 (m, 2H), 5.40 (s, 1H), 5.31 (s, 1H), 3.90 (m, 7H), 3.23 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C20H21NO4, 340; found, 340.

Example 42 (E)-3-Fluoro-2-hydroxy-5-(4-morpholinostyryl)benzaldehyde (compound 75)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 4-(4-vinylphenyl)morpholine (189 mg, 1.0 mmol) as described in Example 25 , to give the title compound as a yellow solid (63 mg, 19% yield).

1H NMR (500 MHz, chloroform-d) δ 10.89 (s, 1H), 9.95 (d, J=1.9 Hz, 1H), 7.52 (dd, J=11.9, 2, 1 Hz, 1H), 7.45 - 7.39 (m, 3H), 6.95 (d, J=16.3 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H) , 6.86 (d, J=16.2 Hz, 1H), 3.96-3.74 (m, 4H), 3.21 (dd, J=5.7, 3.9 Hz, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₉ H ₁₈ FNO ₃ , 328; found, 328.

Example 43 (2)-3-Fluoro-2-hydroxy-5-(4-morpholinostyryl)benzaldehyde (compound 76)

A mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1.73 g, 7.95 mmol), 4-(4-vinylphenyl)morpholine (500 mg, 2.65 mmol), 1,3-bis-(diphenylphosphino ) propane (dppp) (218 mg, 0.53 mmol), K ₂ CO ₃ powder (1.1 g, 7.95 mmol) and palladium acetate (59 mg, 0.27 mmol) in DMF-water (10 ml :3 ml) was heated overnight at 90°C. The mixture was cooled to RT, diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The organic extracts were combined, washed with brine (2x50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1-30:1) and preparative HPLC to give the title product as a yellow solid (15 mg, 2% yield).

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1H NMR (CDCl3, 400 MHz) δ 10.97 (s, 1H), 9.88 (s, 1H), 7.29-7.37 (m, 2H), 7.24 (m, 2H), 6 .93 (m, 2H), 5.41 (s, 1H), 5.34 (s, 1H), 3.90 (m, 4H), 3.23 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₉ H ₁₈ FNO ₃ , 328; found, 328.

Example 44 (E)-2-Hydroxy-3-methoxy-5-(3-morpholinostyryl)benzaldehyde (compound 77)

Stage 1. Synthesis of 4-(3-vinylphenyl)morpholine

The title compound was prepared from 3-morpholinobenzaldehyde (1.912 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure as in step 1 of Example 38 to give the product as a colorless oil (1. 26 g, 67% yield.

LC-MS m/z [M+H] ⁺ calc. for C12H15NO, 190; found, 190.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 4-(3-vinylphenyl)morpholine (189 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (98 mg, 29% yield).

¹ H NMR (500 MHz, chloroform-d) δ 11.09 (s, 1H), 9.95 (s, 1H), 7.32-7.23 (m, 3H), 7.09-7.02 (m, 3H), 6.98 (d, J=16.3 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 3.99 (s, 3H), 3.89 (t, J=4.7 Hz, 4H), 3.28-3.08 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C20H21NO4, 340; found, 340.

Example 45 (E)-3-Fluoro-2-hydroxy-5-(3-morpholinostyryl)benzaldehyde (compound 78)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 4-(3-vinylphenyl)morpholine (189 mg, 1.0 mmol) as described in Example 25 , to give the title compound as a yellow solid (56 mg, 17% yield).

1H NMR (500 MHz, chloroform-d) δ 10.94 (s, 1H), 9.96 (d, J=1.9 Hz, 1H), 7.55 (dd, J=11.7, 2, 1 Hz, 1H), 7.46 (t, J=1.5 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.05 (t, J=8.4 Hz , 2H), 6.99 (s, 2H), 6.88 (d, J=8.2 Hz, 1H), 4.083.76 (m, 4H), 3.30-3.05 (m, 4H) ;

LC-MS m/z [M+H] ⁺ calc. for C19H18FNO3, 328; found, 328.

Example 46 (E)-2-Hydroxy-3-methoxy-5-(3-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 79)

Stage 1. Synthesis of 1-(3-vinylphenyl)pyrrolidine

The title compound was prepared from 3-(pyrrolidin-1-yl)benzaldehyde (1.75 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure as mentioned in step 1 of Example 38, with obtaining the product as a colorless oil (1.25 g, 72% yield).

LC-MS m/z [M+H]+ calc. for C ₁₂ H ₁₅ N, 174; found, 174.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(3-vinylphenyl)pyrrolidine (173 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (62 mg, 29% yield).

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1H NMR (500 MHz, chloroform-d) δ 11.08 (s, 1H), 9.94 (s, 1H), 7.33-7.27 (m, 2H), 7.23 (t, J= 7.8 Hz, 1H), 7.04 (d, J=16.3 Hz, 1H), 6.99 (d, J=16.0 Hz, 1H), 6.84 (d, J=7, 6 Hz, 1H), 6.67 (t, J=1.9 Hz, 1H), 6.52 (dd, J=8.2, 2.3 Hz, 1H), 4.00 (s, 3H) , 3.41-3.20 (m, 4H), 2.09-1.90 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₂₀ H ₂₁ NO ₃ , 324; found, 324.

Example 47 (E)-3-Fluoro-2-hydroxy-5-(3-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 80)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(3-vinylphenyl)pyrrolidine (173 mg, 1.0 mmol) as described in Example 25 , to give the title compound as a yellow solid (48 mg, 15% yield).

1H NMR (500 MHz, chloroform-d) δ 10.92 (s, 1H), 9.95 (d, J=1.9 Hz, 1H), 7.55 (dd, J=11.9, 2, 1 Hz, 1H), 7.48-7.42 (m, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.99 (s, 2H), 6.83 (d, J=7.5Hz, 1H), 6.65(t, J=2.0Hz, 1H), 6.53(dd, J=8.2, 2.4Hz, 1H), 3.53- 3.12 (m, 4H), 2.18-1.85 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₁₉ H ₁₈ FNO ₂ , 312; found, 312.

Example 48 (E)-2-Hydroxy-3-methoxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 81)

Step 1. Synthesis of 1-(4-vinylphenyl)pyrrolidine

The title compound was prepared from 4-(pyrrolidin-1-yl)benzaldehyde (1.75 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using a similar procedure as described in step 1 of Example 38, with obtaining the product as a colorless oil (1.38 g, 80% yield).

LC-MS m/z [M+H] ⁺ calc. for C ₁₂ H ₁₅ N, 174; found, 174.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(4-vinylphenyl)pyrrolidine (173 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (42 mg, 13% yield).

1H NMR (500 MHz, chloroform-d) δ 11.02 (s, 1H), 9.93 (s, 1H), 7.46-7.30 (m, 2H), 7.27 (d, J= 2.1 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.95 (d, J=16.2 Hz, 1H), 6.83 (d, J=16, 2 Hz, 1H), 6.64-6.48 (m, 2H), 3.98 (s, 3H), 3.38-3.23 (m, 4H), 2.12-1.88 (m , 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₀ H ₂₁ NO ₃ , 324; found, 324.

Example 49 (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 82)

Example 49a. Synthesis route (a).

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(4-vinylphenyl)pyrrolidine (173 mg, 1.0 mmol) as described in Example 25 , to give the title compound as a pinkish yellow solid (38 mg, 12% yield).

1H NMR (500 MHz, chloroform-d) δ 10.84 (s, 1H), 9.94 (d, J=1.9 Hz, 1H), 7.50 (dd, J=12.0, 2, 1 Hz, 1H), 7.41-7.35 (m, 3H), 6.94 (d, J=16.2 Hz, 1H), 6.77 (d, J=16.2 Hz, 1H) , 6.59-6.52 (m, 2H), 3.35-3.29 (m, 4H), 2.052.00 (m, 4H);

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LC-MS m/z [M+H]+ calc. for C ₁₉ H ₁₈ FNO ₂ , 312; found, 312.

Example 49b. Synthesis route (b).

A mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (4.36 g, 20.0 mmol), 1-(4-vinylphenyl)pyrrolidine (3.46 g, 20.0 mmol), 1,3-bis- (diphenylphosphino)propane (dppp) (1.65 g, 4.0 mmol), K ₂ CO ₃ powder (8.28 g, 60.0 mmol) and palladium acetate (448 mg, 2.0 mmol) in DMF- water (50 ml:17 ml) was heated overnight at 90°C. The mixture was cooled to RT, diluted with water (300 ml) and extracted with ethyl acetate (3x200 ml). The organic extracts were combined, washed with brine (2x100 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=200:1-100:1) and preparative HPLC to give the title product as a yellow solid (816 mg, 13% yield).

1H NMR (CDCl3, 400 MHz) δ 10.87 (s, 1H), 9.94 (s, 1H), 7.51 (d, J=12.0 Hz, 1H), 7.41 (m, 3H ), 6.94 (d, J=16.4 Hz, 1H), 6.80 (d, J=16.4 Hz, 1H), 6.68 (m, 2H), 3.37 (m, 4H ), 2.06 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C19H18FNO2, 312; found, 312.

Example 49c. Synthesis of (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde hydrochloride (hydrochloride salt of compound 82)

The title compound was obtained by treating (E)-2-hydroxy-3-methoxy-5-(4(pyrrolidin-1-yl)styryl)benzaldehyde (623 mg, 2.0 mmol) (from Example 49b above) with 4N. HCl with dioxane (1.0 ml) after dissolving in dichloromethane (25 ml) at room temperature. The yellow solution turned into a light pink precipitate. The reaction mixture was stirred for an additional 5 minutes, then filtered and the precipitate was collected to give the desired product as a light pink solid (yield 100%).

Example 50 (2)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 83)

The crude top spot on TLC (from Example 49b above) was collected and repurified by preparative TLC to give the title product as a yellow solid (74 mg, 1% yield).

1H NMR (CDCl3, 400 MHz) δ 10.97 (s, 1H), 9.88 (s, 1H), 7.38 (m, 2H), 7.22 (m, 2H), 6.70 (br , 2H), 5.37 (s, 1H), 5.26 (s, 1H), 3.38 (m, 4H), 2.07 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C19H18FNO2, 312; found, 312.

Example 51 (2)-2-Hydroxy-3-methoxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 84)

A mixture of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1.44 g, 6.24 mmol), 1-(4-vinylphenyl)pyrrolidine (900 mg, 5.20 mmol), 1,3-bis-(diphenylphosphino ) propane (dppp) (429 mg, 1.04 mmol), K ₂ CO ₃ powder (2.15 g, 15.6 mmol) and palladium acetate (117 mg, 0.52 mmol) in DMF-water (3: 1) (12 ml) heated overnight at 90°C. The mixture was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The organic extracts were combined, washed with brine (2x50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=200:1-150:1) and preparative TLC to give the title product as a yellow solid (25 mg, 1% yield).

1H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 9.87 (s, 1H), 7.08-7.25 (m, 4H), 6.69 (m, 2H), 5 .37 (s, 1H), 5.24 (s, 1H), 3.89 (s, 3H), 3.38 (m, 4H), 2.07 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₀ H ₂₁ NO ₃ , 324; found, 324.

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Example 52 (E)-2-Hydroxy-6-methoxy-4-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 85)

Step 1. 4-Bromo-2-hydroxy-6-methoxybenzaldehyde

A solution of 4-bromo-2,6-dimethoxybenzaldehyde (10 g, 40.8 mmol) and sodium iodide (12.2 g, 81.6 mmol) in MeCN/DCM (50 ml, 1:1) was cooled to 0°C . AlCl ₃ (10.8 g, 81.6 mmol) was added slowly. The reaction mixture was stirred at RT for 5 h, and TLC showed that the reaction was complete. The mixture was poured into sat. ammonium chloride and extracted with ethyl acetate (3x100 ml). The organic extracts were combined, washed with brine (2x50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=300:1-200:1) to obtain the desired product and its iodo-substituted compound (6.3 g, 67% yield).

LC-MS m/z [M+H] ⁺ calc. for C ₈ H ₇ BrO ₃ and C ₈ H ₇ O ₃ , 232 and 278; found, 232 and 278.

Step 2: Mixture of 4-bromo-2-hydroxy-6-methoxybenzaldehyde (300 mg, 0.93 mmol), 1-(4-vinylphenyl)pyrrolidine (254 mg, 0.93 mmol), Pd ₂ (dba) prepared above ₃ (8 mg, 0.009 mmol), 1,3-bis(diphenylphosphino)propane (dppp) (15.3 mg, 0.037 mmol) in dioxane (8 mL) was stirred for 10 min at RT under nitrogen protection. Then formic acid (0.08 ml) was added. The reaction mixture was heated overnight at 80° C. under a protective nitrogen atmosphere. The mixture was cooled to RT, diluted with water (10 ml) and extracted with ethyl acetate (3x10 ml). The organic extracts were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1-10:1) to give the title product as an orange solid (145 mg, 48% yield).

¹ H NMR (CDCl3, 400 MHz) δ 12.07 (s, 1H), 10.26 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.19 (m, 3H), 6.92 (m, 1H), 6.65 (s, 1H), 6.49 (s, 1H), 3.96 (s, 3H), 3.54 (m, 4H), 2, 21 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C20H21NO3, 324; found, 324.

Example 53 (E)-2-Fluoro-6-hydroxy-4-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (compound 86)

A mixture of 4-bromo-2-fluoro-6-hydroxybenzaldehyde (200 mg, 0.91 mmol), 1-(4-vinylphenyl)pyrrolidine (249 mg, 0.91 mmol), Pd ₂ (dba) ₃ (6 mg, 0.007 mmol), 1,3-bis-(diphenylphosphino)propane (dppp) (10.7 mg, 0.026 mmol) in dioxane (5 mL) was stirred for 10 min at RT under nitrogen protection. Then formic acid (0.05 ml) was added. The reaction mixture was heated overnight at 80° C. under a protective nitrogen atmosphere. The mixture was cooled to RT, diluted with water (10 ml) and extracted with ethyl acetate (3x10 ml). The organic extracts were combined, washed with brine (2x10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1-10:1) to give the title product as a brown solid (77 mg, 38% yield).

1H NMR (CDCl ₃ , 400 MHz) δ 11.57 (s, 1H), 10.18 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.12-7, 20 (m, 3H), 6.766.90 (m, 3H), 3.53 (m, 4H), 2.20 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₁₉ H ₁₈ FNO ₂ , 312; found, 312.

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Example 54 (E)-2-Hydroxy-3-methoxy-5-(4-(2-methoxyethoxy)styryl)benzaldehyde (compound 87)

Step 1. 1-(2-Methoxyethoxy)-4-vinylbenzene

The title compound was prepared from 4-(2-methoxyethoxy)benzaldehyde (1.80 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure as mentioned in step 1 of Example 38 to give the product as a colorless oil (0.93 g, 22% yield).

LC-MS m/z [M+H] ⁺ calc. for C11H14O2, 179; found, 179.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(2-methoxyethoxy)-4-vinylbenzene (178 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (72 mg, 22% yield).

1H NMR (500 MHz, chloroform-d) δ 11.06 (s, 1H), 9.94 (s, 1H), 7.46-7.40 (m, 2H), 7.29-7.23 ( m, 2H), 6.96 (d, J=16.9 Hz, 2H), 6.93 (s, 2H), 4.15 (dd, J=5.6, 3.8 Hz, 2H), 3.98 (s, 3H), 3.84-3.68 (m, 2H), 3.46 (s, 3H);

LC-MS m/z [M+H] ⁺ calc. for C19H20O5, 329; found, 329.

Example 55 (E)-3-Fluoro-2-hydroxy-5-(4-(2-methoxyethoxy)styryl)benzαaldehyde (compound 88)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(2-methoxyethoxy)-4-vinylbenzene (178 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (68 mg, 22% yield).

1H NMR (500 MHz, chloroform-d) δ 10.90 (s, 1H), 9.95 (d, J=1.8 Hz, 1H), 7.52 (dd, J=11.8, 2, 1 Hz, 1H), 7.45-7.40 (m, 3H), 6.96 (d, J=14.0 Hz, 1H), 6.93 (d, 2H), 6.87 (d, J=16.2 Hz, 1H), 4.23-4.07 (m, 2H), 3.81-3.69 (m, 2H), 3.47 (s, 3H);

LC-MS m/z [M+H]+ calc. for C18H17FO4, 317; found, 317.

Example 56 (E)-5-(4-(1H-Pyrazol-1-yl)styryl)-2-hydroxy-3-methoxybenzaldehyde (compound 89)

Step 1. 1-(4-Vinylphenyl)-1H-pyrazole

The title compound was prepared from 4-(1H-pyrazol-1-yl)benzaldehyde (1.72 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure as mentioned in step 1 of Example 38 , to give the product as a white solid (1.08 g, 63% yield).

LC-MS m/z [M+H] ⁺ calc. for C _n H _w N2, 171; found, 171.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(4-vinylphenyl)-1H-pyrazole (170 mg, 1.0 mmol) , as described in example 25, with

- 117 042453 to give the title compound as a yellow solid (108 mg, 34% yield).

1H NMR (500 MHz, chloroform-d) δ 11.11 (s, 1H), 9.96 (s, 1H), 7.95 (d, J=2.5 Hz, 1H), 7.74 (d , J=1.8 Hz, 1H), 7.73-7.69 (m, 2H), 7.62-7.55 (m, 2H), 7.30 (s, 2H), 7.07 ( d, J=16.3 Hz, 1H), 7.02 (d, J=16.3 Hz, 1H), 6.49 (t, J=2.2 Hz, 1H), 4.00 (s, 3H);

LC-MS m/z [M+H]+ calc. for C19H16N2O3, 321; found, 321.

Example 57 (E)-5-(4-(1H-Pyrazol-1-yl)styryl)-3-fluoro-2-hydroxybenzaldehyde (compound 90)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(4-vinylphenyl)-1H-pyrazole (170 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (78 mg, 25% yield).

1H NMR (500 MHz, chloroform-d) δ 10.96 (s, 1H), 9.97 (d, J=1.8 Hz, 1H), 7.95 (d, J=2.5 Hz, 1H ), 7.75 (d, J=1.8 Hz, 1H), 7.73-7.69 (m, 2H), 7.61-7.53 (m, 3H), 7.50-7, 45 (m, 1H), 7.02 (s, 2H), 6.49 (t, J=2.2 Hz, 1H);

LC-MS m/z [M+H]+ calc. for C ₁₈ H ₁₃ FN ₂ O ₂ , 309; found, 309.

Example 58 (E)-2-Hydroxy-3-methoxy-5-(2-(quinolin-6-yl)vinyl)benzaldehyde (compound 91)

Stage 1. 6-Vinylquinoline

The title compound was prepared from quinoline-6-carbaldehyde (1.57 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using a similar procedure as described in step 1 of Example 38 to give the product as a colorless liquid (1.28 g, 82% yield).

LC-MS m/z [M+H]+ calc. for C11H9N, 156; found, 156.

Step 2 The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 6-vinylquinoline (155 mg, 1.0 mmol) as described in Example 25, with affording the title compound as a brown solid (18 mg, 6% yield).

1H NMR (500 MHz, chloroform-d) δ 11.14 (s, 1H), 9.98 (s, 1H), 8.88 (dd, J=4.3, 1.7 Hz, 1H), 8 .15 (dd, J=20.9, 8.6 Hz, 2H), 7.97 (dd, J=8.9, 2.0 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.43 (dd, J=8.3, 4.3 Hz, 1H), 7.35 (d, J=1.5 Hz, 2H), 7.22 (d, J=16 .3 Hz, 1H), 7.18 (d, J=16.3 Hz, 1H), 4.02 (s, 3H);

LC-MS m/z [M+H]+ calc. for C ₁₉ H ₁₅ NO ₃ , 306; found, 306.

Example 59 (E)-3-Fluoro-2-hydroxy-5-(2-(quinolin-6-yl)vinyl)benzaldehyde (compound 92)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 6-vinylquinoline (155 mg, 1.0 mmol) as described in Example 25 to give title compound as a yellow solid (52 mg, 18% yield).

1H NMR (500 MHz, chloroform-d) δ 10.99 (s, 1H), 9.99 (d, J=1.8 Hz, 1H), 8.90 (dd, J=4.3, 1, 7 Hz, 1H), 8.19 (dd, J=8.4, 1.6 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.96 (dd, J= 8.9, 2.0 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.61 (dd, J=11.6, 2.1 Hz, 1H), 7, 56-7.49 (m, 1H), 7.45 (dd, J=8.3, 4.3 Hz, 1H), 7.18 (s, 2H);

LC-MS m/z [M+H]+ calc. for C ₁₈ H ₁₂ FNO ₂ , 294; found, 294.

- 118 042453

Example 60 tert-Butyl (E)-6-(3-formyl-4-hydroxy-5-methoxystyryl)-3,4-dihydroquinoline-1(2H)carboxylate (compound 93) he

Step 1. tert-Butyl 6-vinyl-3,4-dihydroquinoline-1(2H)-carboxylate

The title compound was prepared from t-butyl 6-formyl-3,4-dihydroquinoline-1(2H)carboxylate (0.91 g, 3.5 mmol) and methyltriphenylphosphonium bromide (2.5 g, 7 mmol) using a similar the procedure described in step 1 of Example 38 to give the product as a white solid (0.68 g, 75% yield).

LC-MS m/z [M+H]+ calc. for C ₁₆ H ₂₁ NO ₂ , 260; found, 260.

Step 2. The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and tert-butyl 6-vinyl-3,4-dihydroquinoline-1(2H)-carboxylate ( 259 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (148 mg, 36% yield).

1H NMR (500 MHz, chloroform-d) δ 11.07 (s, 1H), 9.94 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.29 (dd , J=8.7, 2.3 Hz, 1H), 7.28-7.26 (m, 2H), 7.22 (d, J=2.0 Hz, 1H), 6.96 (d, J=16Hz, 1H), 6.95(d, J=16Hz, 1H), 3.99(s, 3H), 3.81-3.65(m, 2H), 2.79(t, J=6.6 Hz, 2H), 1.94 (p, J=6.4 Hz, 2H), 1.54 (s, 9H);

LC-MS m/z [M+H] ⁺ calc. for C24H27NO5, 410; found, 410.

Example 61 tert-Butyl (E)-6-(3-Fluoro-5-Formyl-4-hydroxystyryl)-3,4-dihydroquinoline-1(2H)carboxylate (compound 94) he

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 6-vinyl-3,4-dihydroquinoline-1(2H)-carboxylate (259 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (28 mg, 7% yield).

1H NMR (500 MHz, chloroform-d) δ 10.91 (s, 1H), 9.95 (d, J=1.9 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H ), 7.53 (dd, J=11.8, 2.1 Hz, 1H), 7.45-7.41 (m, 1H), 7.28 (dd, J=8.7, 2.2 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 6.93 (m, 2H), 3.81-3.57 (m, 2H), 2.79 (t, J =6.5 Hz, 2H), 1.94 (p, J=6.4 Hz, 2H), 1.54 (s, 9H);

LC-MS m/z [M+H] ⁺ calc. for C23H24FNO4, 398; found, 398.

Example 62 (E)-3-Fluoro-2-hydroxy-5-(2-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)vinyl)benzaldehyde (compound 95) he

Step 1. 1-Methyl-6-vinyl-1,2,3,4-tetrahydroquinoline

The title compound was prepared from 1-methyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (1.75 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using a similar procedure.

- 119 042453

DURU described in step 1 of Example 38 to give the product as a brown liquid (1.01 g, 58% yield). LC-MS m/z [M+H]+ calc. for C12H15N, 174; found, 174.

Step 2. The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-methyl-6-vinyl-1,2,3,4-tetrahydroquinoline (173 mg , 1.0 mmol) as described in Example 25 to give the title compound as a red solid (25 mg, 8% yield).

1H NMR (500 MHz, chloroform-d) δ 10.84 (s, 1H), 9.93 (d, J=1.8 Hz, 1H), 7.49 (dd, J=12.0, 2, 1 Hz, 1H), 7.39 (t, J=1.5 Hz, 1H), 7.21 (dd, J=8.3, 2.2 Hz, 1H), 7.13 (d, J= 2.0 Hz, 1H), 6.89 (d, J=16.1 Hz, 1H), 6.77 (d, J=16.1 Hz, 1H), 6.57 (d, J=8, 5 Hz, 1H), 3.35-3.17 (m, 2H), 2.93 (s, 3H), 2.79 (t, J=6.4 Hz, 2H), 2.08-1, 82 (m, 2H);

LC-MS m/z [M+H]+ calc. for C19H18FNO2, 312; found, 312.

Example 63 (E)-5-(4-(Diethylamino)styryl)-2-hydroxy-3-methoxybenzaldehyde (compound 96) he

MeO^A^CHO

THAT

A

Stage 1. N,N-Diethyl-4-vinylaniline

A

The title compound was prepared from 4-(diethylamino)benzaldehyde (1.77 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using a similar procedure as described in step 1 of Example 38 to give the product as colorless liquid (1.72 g, 98% yield).

LC-MS m/z [M+H]+ calc. for C12H17N, 176; found, 176.

Step 2 The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and N,N-diethyl-4-vinylaniline (176 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (48 mg, 15% yield).

1H NMR (500 MHz, chloroform-d) δ 11.02 (s, 1H), 9.93 (s, 1H), 7.42-7.34 (m, 2H), 7.26 (s, 1H) , 7.23 (d, J=1.9 Hz, 1H), 6.93 (d, J=16.2 Hz, 1H), 6.82 (d, J=16.2 Hz, 1H), 6 .71-6.49 (m, 2H), 3.98 (s, 3H), 3.39 (k, J=7.1 Hz, 4H), 1.19 (t, J=7.0 Hz, 6H);

LC-MS m/z [M+H]+ calc. for C ₂₀ H ₂₃ NO ₃ , 326; found, 326.

Example 64 (E)-5-(4-(Diethylamino)styryl)-3-fluoro-2-hydroxybenzaldehyde (compound 97)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and N,N-diethyl-4-vinylaniline (176 mg, 1.0 mmol) as described in Example 25 to give the title compound as an orange solid (38 mg, 12% yield).

1H NMR (500 MHz, chloroform-d) δ 10.84 (s, 1H), 9.94 (d, J=1.9 Hz, 1H), 7.50 (dd, J=12.1, 2, 0 Hz, 1H), 7.39 (t, J=1.4 Hz, 1H), 7.38-7.33 (m, 2H), 6.92 (d, J=16.1 Hz, 1H) , 6.77 (d, J=16.2 Hz, 1H), 6.70-6.64 (m, 2H), 3.39 (q, J=7.1 Hz, 4H), 1.19 ( t, J=7.0 Hz, 6H);

LC-MS m/z [M+H]+ calc. for C19H20FNO2, 314; found, 314.

Example 65 (E)-5-(4-(Cyclopropylmethoxy)styryl)-2-hydroxy-3-methoxybenzaldehyde (compound 98)

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Step 1. 1-(Cyclopropylmethoxy)-4-vinylbenzene

The title compound was prepared from 4-(cyclopropylmethoxy)benzaldehyde (1.76 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using a similar procedure as described in step 1 of Example 38 to give the product as white solid (1.67 g, 96% yield).

LC-MS m/z [M+H]+ calc. for C ₁₂ H ₁₄ O, 175; found, 175.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(cyclopropylmethoxy)-4-vinylbenzene (175 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (58 mg, 18% yield).

1H NMR (500 MHz, chloroform-d) δ 11.06 (s, 1H), 9.94 (s, 1H), 7.47-7.40 (m, 2H), 7.29-7.23 ( m, 2H), 6.96 (d, J=16.3 Hz, 1H), 6.93-6.88 (m, 3H), 3.99 (s, 3H), 3.83 (d, J =6.9 Hz, 2H), 1.37-1.12 (m, 1H), 0.73-0.56 (m, 2H), 0.36 (dt, J=6.2, 4.7 Hz, 2H);

LC-MS m/z [M+H]+ calc. for C ₂₀ H ₂₀ O ₄ , 325; found, 325.

Example 66 (E)-5-(4-(Cyclopropylmethoxy)styryl)-3-fluoro-2-hydroxybenzaldehyde (compound 99)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(cyclopropylmethoxy)-4-vinylbenzene (175 mg, 1.0 mmol) as described in Example 25 to give the title compound as an off-white solid (43 mg, 14% yield).

1H NMR (500 MHz, chloroform-d) δ 10.90 (s, 1H), 9.95 (d, J=1.9 Hz, 1H), 7.52 (dd, J=11.8, 2, 1 Hz, 1H), 7.45-7.39 (m, 3H), 6.96 (d, J=16.3 Hz, 1H), 6.92-6.89 (m, 2H), 6, 86 (d, J=16.2 Hz, 1H), 3.83 (d, J=6.9 Hz, 2H), 1.29 (dddd, J=15.1, 6.9, 5.1, 2.8 Hz, 1H), 0.78-0.57 (m, 2H), 0.37 (dt, J=6.1, 4.6 Hz, 2H);

LC-MS m/z [M+H]+ calc. for C ₁₉ H ₁₇ FO ₃ , 313; found, 313.

Example 67 (E)-5-(2-(Chroman-6-yl)vinyl)-2-hydroxy-3-methoxybenzaldehyde (compound 100)

Stage 1. 6-Vinylchroman

The title compound was prepared from chroman-6-carbaldehyde (1.62 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure as in step 1 of Example 38 to give the product as a colorless oil (1.6 g, 100% yield).

LC-MS m/z [M+H]+ calc. for C11H ₁₂ O, 161; found, 161.

Step 2 The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 6-vinylchroman (160 mg, 1.0 mmol) as described in Example 25, with affording the title compound as a yellow solid (56 mg, 18% yield).

1H NMR (500 MHz, chloroform-d) δ 11.05 (s, 1H), 9.94 (s, 1H), 7.26 (s, 1H), 7.24 (d, J=1.9 Hz , 2H), 7.19 (d, J=2.1 Hz, 1H), 6.93 (d, J=16.2 Hz, 1H), 6.88 (d, J=16.2 Hz, 1H ), 6.79 (d, J=8.5 Hz, 1H), 4.39-4.14 (m, 2H), 3.98 (s, 3H), 2.82 (t, J=6, 4 Hz, 2H), 2.13-1.91 (m, 2H);

LC-MS m/z [M+H]+ calc. for C ₁₉ H ₁₈ O ₄ , 311; found, 311.

- 121 042453

Example 68 (E)-5-(2-(Chroman-6-yl)vinyl)-3-fluoro-2-hydroxybenzaldehyde (compound 101)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 6-vinylchroman (160 mg, 1.0 mmol) as described in Example 25 to give title compound as an off-white solid (58 mg, 19% yield).

1H NMR (500 MHz, chloroform-d) δ 10.89 (s, 1H), 9.95 (d, J=1.7 Hz, 1H), 7.51 (dd, J=11.8, 2, 1 Hz, 1H), 7.43-7.39 (m, 1H), 7.24 (dd, J=9.3, 3.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 6.92 (d, J=16.3 Hz, 1H), 6.84 (d, J=16.3 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 4.36-4.07 (m, 2H), 2.82 (t, J=6.5 Hz, 2H), 2.19-1.85 (m, 2H);

LC-MS m/z [M+H]+ calc. for C ₁₈ H ₁₅ FO ₃ , 299; found, 299.

Example 69 (E)-2-Hydroxy-3-methoxy-5-(4-(piperidin-1-yl)styryl)benzaldehyde (compound 102)

Step 1. 1-(4-Vinylphenyl)piperidine

The title compound was prepared from 4-(piperidin-1-yl)benzaldehyde (1.89 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using a similar procedure as described in step 1 of Example 38, with obtaining the product as a colorless oil (1.62 g, 87% yield).

LC-MS m/z [M+H] ⁺ calc. for C13H17N, 188; found, 188.

Step 2: The title compound was prepared from 5-bromo-2-hydroxy-3-methoxybenzaldehyde (231 mg, 1.0 mmol) and 1-(4-vinylphenyl)piperidine (188 mg, 1.0 mmol) as described in Example 25 to give the title compound as a yellow solid (58 mg, 17% yield).

1H NMR (500 MHz, chloroform-d) δ 11.04 (s, 1H), 9.94 (s, 1H), 7.47-7.33 (m, 2H), 7.29-7.22 ( m, 2H), 6.95 (d, J=16.3 Hz, 1H), 6.91 (s, 2H), 6.88 (d, J=16.2 Hz, 1H), 3.98 ( s, 3H), 3.32-3.13 (m, 4H), 1.71 (p, J=5.6 Hz, 4H), 1.61 (k, J=8.6, 7.3 Hz , 2H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₁ H ₂₃ NO ₃ , 338; found, 338.

Example 70 (E)-3-Fluoro-2-hydroxy-5-(4-(piperidin-1-yl)styryl)benzaldehyde (compound 103)

The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(4-vinylphenyl)piperidine (188 mg, 1.0 mmol) as described in Example 25 , to give the title compound as a yellow solid (42 mg, 13% yield).

1H NMR (500 MHz, chloroform-d) δ 10.87 (s, 1H), 9.94 (d, J=1.9 Hz, 1H), 7.51 (dd, J=11.8, 2, 1 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.40-7.37 (m, 2H), 6.94 (d, J=16.2 Hz, 1H) , 6.91 (s, 2H), 6.83 (d, J=16.3 Hz, 1H), 3.23 (t, J=5.5 Hz, 4H), 1.72 (t, J= 8.2 Hz, 4H), 1.61 (k, J=5.7 Hz, 2H);

LC-MS m/z [M+H] ⁺ calc. for C20H20FNO2, 326; found, 326.

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Example 71 (E)-2-Fluoro-6-hydroxy-4-(4-(piperidin-1-yl)styryl)benzaldehyde (compound 104)

The title compound was prepared from 4-bromo-2-fluoro-6-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-(4-vinylphenyl)piperidine (188 mg, 1.0 mmol) as described in Example 25 , to give the title compound as an orange solid (140 mg, 43% yield).

1H NMR (500 MHz, chloroform-d) δ 11.56 (s, 1H), 10.15 (s, 1H), 7.46-7.39 (m, 2H), 7.16 (d, J= 16.2 Hz, 1H), 6.90 (d, J=8.3 Hz, 2H), 6.85-6.70 (m, 3H), 3.33-3.14 (m, 4H), 1.70 (h, J=5.0 Hz, 4H), 1.62 (k, J=5.6 Hz, 2H);

LC-MS m/z [M+H]+ calc. for C ₂ oH ₂ oFN0 ₂ , 326; found, 326.

Example 72 (E)-4-(4-(4-Ethylpiperazin-1-yl)styryl)-2-fluoro-6-hydroxybenzaldehyde (compound 105)

Step 1. 1-Ethyl-4-(4-vinylphenyl)piperazine

The title compound was prepared from 4-(4-ethylpiperazin-1-yl)benzaldehyde (2.18 g, 10 mmol) and methyltriphenylphosphonium bromide (7.14 g, 20 mmol) using the same procedure described in step 1 of Example 38 , to give the product as a white solid (1.58 g, 73% yield).

LC-MS m/z [M+H]+ calc. for C14H20N2, 217; found, 217.

Step 2. The title compound was prepared from 5-bromo-3-fluoro-2-hydroxybenzaldehyde (219 mg, 1.0 mmol) and 1-ethyl-4-(4-vinylphenyl)piperazine (217 mg, 1.0 mmol ) as described in Example 25 to give the title compound as a brown solid (198 mg, 56% yield).

1H NMR (500 MHz, chloroform-d) δ 11.55 (s, 1H), 10.16 (s, 1H), 7.46-7.39 (m, 2H), 7.16 (d, J= 16.1 Hz, 1H), 6.94-6.88 (m, 2H), 6.82 (d, J=16.3 Hz, 1H), 6.80 (s, 1H), 6.76 ( dd, J=11.7, 1.5 Hz, 1H), 3.35 (t, J=5.1 Hz, 4H), 2.70 (t, J=5.0 Hz, 4H), 2, 56 (k, J=7.3 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H);

LC-MS m/z [M+H]+ calc. for C ₂ iH ₂ 3FN ₂ O ₂ , 355; found, 355.

Example 73 (E)-3-(5-(5-(Cyclopropanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)-1 -phenylprop-2-en-1-one (compound 106)

added to mixture

KOH (403 mg, 7.2 mmol)

5-(5-(cyclopropanecarbonyl)-4,5,6,7 tetrahydrothieno[3,2-c]pyridin-2-yl)-2-hydroxy-3-methoxybenzaldehyde (650 mg, 1.8 mmol) and acetophenone ( 216 mg, 1.8 mmol) in EtOH/water (20 ml/7 ml). The reaction mixture was heated overnight at 95°C. Ethanol was removed under vacuum and the residue was diluted with water (20 ml). The mixture was then extracted with ethyl acetate (3x20 ml). The organic extracts were combined, dried over anhydrous sulfate

- 123 042453 sodium and concentrated. The crude product was purified by preparative HPLC to give the desired product as a brown solid (73 mg, 9% yield).

1H NMR (DMSO-H6, 400 MHz) δ 9.75 (br, 1H), 8.14 (m, 2H), 8.07 (s, 1H), 7.92 (m, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.33 (s, 1H), 7.19 (s, 1H), 4.82 (br, 1H), 4.57 (s, 1H) , 4.01(m, 1H), 3.91(s, 3H), 3.82(m, 1H), 2.92(m, 1H), 2.78(m, 1H), 1.98- 2.15 (m, 1H), 0.77 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₂₇ H ₂₅ NO ₄ S, 460; found, 460.

Example 74 (E)-1-(5-(5-(Cyclopropanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)-3 -phenylprop-2-en-1-one (compound 107)

Step 1. 1-(5-(5-(Cyclopropanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-hydroxy-3methoxyphenyl)ethan-1-one O

Mixture of 1-(2-hydroxy-3-methoxy-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)ethanone (300 mg, 1.0 mmol), (2 -bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(cyclopropyl)methanone (342 mg, 1.2 mmol), K ₂ CO ₃ (284 mg, 2.1 mmol ) and Pd(dppf) ₂ Cl ₂ (84 mg, 0.1 mmol) in dioxane (20 ml)/water (6 ml) was stirred overnight at 110° C. under N ₂ atmosphere. The mixture was cooled to RT, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1-10:1) to give the desired intermediate (213 mg, 56% yield).

Step 2. KOH (120 mg, 2.16 mmol) was added to a mixture of the desired intermediate from Step 1 above (200 mg, 0.54 mmol) and benzaldehyde (57 mg, 0.54 mmol) in EtOH/water (10 ml /3 ml). The reaction mixture was heated overnight at 95°C. Ethanol was removed under vacuum and the residue was diluted with water (20 ml). The mixture was then extracted with ethyl acetate (3x20 ml). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC to give the desired end product as a brown solid (93 mg, 38% yield).

1H NMR (CDCl ₃ , 400 MHz) δ 13.21 (br, 1H), 7.95 (d, J=15.2 Hz, 1H), 7.58-7.69 (m, 4H), 7, 46 (m, 3H), 7.20 (m, 1H), 6.96 (s, 1H), 4.82 (m, 1H), 4.71 (m, 1H), 3.97-4.02 (m, 5H), 2.99 (m, 1H), 2.88 (m, 1H), 1.86 (m, 1H), 1.08 (m, 2H), 0.87 (m, 2H) ;

LC-MS m/z [M+H] ⁺ calc. for C ₂₇ H ₂₅ NO ₄ S, 460; found, 460.

Example 75 (B)-2-(1,3-Dioxan-2-yl)-6-fluoro-4-(4-(pyrrolidin-1-yl)styryl)phenol (compound 108)

A suspension of (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (200 mg, 0.64 mmol), triethyl orthoformate (105 mg, 0.71 mmol) and Bu ₄ NBr (2 mg, 0.005 mmol) in propane-1,3-diol (5 ml) was stirred for 3 hours at RT. The solvent was removed in vacuo and the residue was purified by preparative TLC to give the title product as a yellow solid (90 mg, 38% yield).

1H NMR (DMSO-d6, 400 MHz) δ 9.62 (s, 1H), 7.29-7.39 (m, 4H), 6.81-6.94 (m, 2H), 6.52 ( d, J=8.4 Hz, 2H), 5.76 (s, 1H), 4.13 (m, 2H), 3.93 (m, 2H), 3.25 (m, 4H), 2, 00 (m, 1H), 1.95 (m, 4H), 1.43 (m, 1H);

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LC-MS m/z [M+H] ⁺ calc. for C ₂₂ H ₂₄ FNO ₃ , 370; found, 370.

Example 76 2-Fluoro-6-((E)-((4-methylpiperazin-1-yl)imino)methyl)-4-((E)-4-(pyrrolidin-1yl)styryl)phenol (compound 109)

Compound 109 was generally prepared as described in Scheme 6a. (E)-3-Fluoro-2-hydroxy-5-(4(pyrrolidin-1-yl)styryl)benzaldehyde (200 mg, 0.64 mmol) and 4-methylpiperazin-1-amine (74 mg, 0.64 mmol) was dissolved in ethanol. The reaction mixture was refluxed for 2 hours. The solvent was removed and the residue was filtered. The precipitate was washed with ethanol and dried under vacuum to give the title compound as a pale yellow solid (210 mg, 80% yield).

1H NMR (CDCl3, 400 MHz) δ 11.65 (br, 1H), 7.67 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.18 (m, 1H ), 7.00 (s, 1H), 6.87 (d, J=16.0 Hz, 1H), 6.74 (d, J=16.0 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 3.32 (m, 4H), 3.27 (m, 4H), 2.71 (m, 4H), 2.42 (s, 3H), 2.01 (m , 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₄ H ₂₉ FN ₄ O, 409; found, 409.

Example 77 N'-((E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)acetohydrazide (compound 110)

The title compound was prepared in an analogous manner as described in Example 76 and generally as described in Scheme 6a using (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl) benzaldehyde (200 mg, 0.64 mmol) and acetohydrazide (48 mg, 0.64 mmol) to give the title compound as a pale yellow solid (210 mg, 89% yield).

1H NMR (DMSO-66, 400 MHz) δ 11.79 (s, 0.6H), 11.47 (s, 0.6H), 11.37 (s, 0.4H), 10.30 (s, 0.4H), 8.35 (s, 0.6H), 8.28 (s, 0.4H), 7.46-7.53 (m, 2H), 7.38 (m, 2H), 7 .04 (m, 1H), 6.89 (m, 1H), 6.85 (m, 2H), 3.25 (m, 4H), 2.23 (s, 1H), 1.95-2, 00 (m, 6H);

LC-MS m/z [M+H]+ calc. for C ₂₁ H ₂₂ FN ₃ O ₂ , 368; found, 368.

Example 78 2-Fluoro-6-((E)-(phenylimino)methyl)-4-((E)-4-(pyrrolidin-1-yl)styryl)phenol (compound 111)

The title compound was prepared in an analogous manner as described in Example 76 and generally as described in Scheme 6a using (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol) and aniline (60 mg, 0.64 mmol) to give the title compound as a pale yellow solid (200 mg, 81% yield).

1H NMR (CDCl ₃ , 400 MHz) δ 13.63 (br, 1H), 8.66 (s, 1H), 7.30-7.47 (m, 9H), 6.71-6.95 (m , 4H), 3.41 (m, 4H), 2.10 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₅ H ₂₃ FN ₂ O, 387; found, 387.

Example 79 2-Fluoro-6-((E)-(2-phenylhydrazono)methyl)-4-((E)-4-(pyrrolidin-1-yl)styryl)phenol (compound 112)

- 125 042453

The title compound was prepared in an analogous manner as described in Example 76 and generally as described in Scheme 6a using (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol) and phenylhydrazine (70 mg, 0.64 mmol) to give the title compound as a pale yellow solid (180 mg, 70% yield).

¹ H NMR (DMSO-06, 400 MHz) δ 10.67 (s, 1H), 10.59 (s, 1H), 8.15 (s, 1H), 7.49 (s, 1H), 7, 38 (m, 3H), 7.28 (m, 2H), 7.03 (m, 3H), 6.90 (m, 1H), 6.54 (d, J=8.4 Hz, 2H), 3.26 (m, 4H), 1.96 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₅ H ₂₄ FN ₃ O, 402; found, 402.

Example 80 N'-((E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)benzohydrazide (compound 113)

The title compound was prepared in an analogous manner as described in Example 76 and generally as described in Scheme 6a using (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol) and benzohydrazide (88 mg, 0.64 mmol) to give the title compound as a yellow solid (240 mg, 87% yield).

1H NMR (DMSO-66, 400 MHz) δ 12.29 (s, 1H), 11.58 (s, 1H), 8.67 (s, 1H), 7.96 (d, J=7.2 Hz , 2H), 7.517.64 (m, 5H), 7.39 (d, J=8.0 Hz, 2H), 7.06 (d, J=16.4 Hz, 1H), 6.90 (d , J=16.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 2H), 3.26 (m, 4H), 1.96 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₆ H ₂₄ FN ₃ O ₂ , 430; found, 430.

Example 81 N'-((E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)benzenesulfonohydrazide (compound 114)

The title compound was prepared in an analogous manner as described in Example 76 and generally as described in Scheme 6a from (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde ( 200 mg, 0.64 mmol) and benzenesulfonohydrazide (111 mg, 0.64 mmol) to give the title compound as a yellow solid (230 mg, 77% yield).

1H NMR (DMSO-06, 400 MHz) δ 11.74 (s, 1H), 10.36 (s, 1H), 8.19 (s, 1H), 7.90 (d, J=7.2 Hz , 2H), 7.65 (m, 3H), 7.48 (d, J=12.4 Hz, 1H), 7.39 (m, 3H), 6.97 (d, J=16.0 Hz , 1H), 6.85 (d, J=16.0 Hz, 1H), 6.53 (d, J=8.0 Hz, 2H), 3.25 (m, 4H), 1.96 (m , 4H);

LC-MS m/z [M+H]+ calc. for C ₂₅ H ₂₄ FN ₃ O ₃ S, 466; found, 466.

Example 82 (E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzaldehyde O-phenyloxime (compound 115)

The title compound was prepared in an analogous manner as described in Example 76 and generally as described in Scheme 6a from (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl) benzaldehyde (400 mg, 1.28 mmol) and O-phenylhydroxylamine (140 mg, 1.28 mmol) to give the title compound as an orange solid (200 mg, 39% yield).

'I NMR (DMSO-dg, 400 MHz) δ 10.37 (br, 1H), 8.81 (s, 1H), 7.67 (s, 1H), 7.58 (d, J=12.0 Hz, 1H), 7.39 (m, 4H), 7.28 (d, J=8.0 Hz, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6, 54 (d, J=8.4 Hz, 2H), 3.25 (m, 4H), 1.96 (m, 4H);

LC-MS m/z [M+H]+ calc. for C25H23FN2O2, 403; found, 403.

Example 83 2-((E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)hydrazine-1carboximidamide (compound 116) he _n

NNH2

ΪΎ ^Ν T MD ΝΗ r

A mixture of (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (200 mg, 0.64 mmol), hydrazinecarboximidamide hydrochloride (70 mg, 0.64 mmol) and sodium acetate (53 mg, 0.64 mmol) in ethanol (5 ml) was refluxed for 5 h. The mixture was cooled to room temperature and filtered. The precipitate was washed with ethanol (5 ml), water (1 ml) and dried under vacuum to give the title product as a green solid (130 mg, 55% yield).

1H NMR (DMSO-d ₆ , 400 MHz) δ 11.39 (br, 1H), 8.29 (s, 1H), 7.53 (s, 1H), 7.36 (m, 3H), 7, 01 (m, 1H), 6.84 (m, 1H), 6.54 (d, J=8.4 Hz, 2H), 6.43 (br, 2H), 3.25 (m, 4H), 1.96 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₂₀ H ₂₂ FN ₅ O, 368; found, 368.

Example 84 (E)-3-(3-Cinnamoyl-4-hydroxy-5-methoxyphenyl)-1-phenylprop-2-en-1-one (compound 117) he o

T 1 J

Step 1. N-Methoxy-N-methylbenzamide

CDI (7.13 g, 44.0 mmol) was added to a solution of benzoic acid (4.88 g, 44.0 mmol) in DCM (100 ml). The reaction mixture was stirred for 2 hours at room temperature. N,O-dimethylhydroxylamine.HCl (4.66 g, 48.0 mmol) was added. The reaction was stirred overnight at room temperature. The mixture was diluted with sat. sodium bicarbonate (100 ml). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (2x100 ml). The organic extracts were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated to give the title product as a colorless oil (4.9 g, 74% yield) which was used in the next reaction without further purification.

Step 2. 1-Phenylprop-2-in-1-one

Ethynylmagnesium bromide (109 ml, 54.54 mmol, 0.5 M in THF) was added dropwise to a solution of a mixture of N-methoxy-N-methylbenzamide (3 g, 18.18 mmol) in THF (20 ml) at 0°C . The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with water (50 ml) and the pH of the system was adjusted to 7-8 with 5% KHSO4. THF was removed in vacuo and the aqueous phase was extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give the crude desired product (7.4 g, 97% yield) which was used in the next reaction without further purification.

Step 3. 3-Iodine-1-phenylprop-2-en-1-one

NaI (534 mg, 3.54 mmol) was added to a solution of 1-phenylprop-2-yn-1-one (460 mg, 3.54 mmol) in TFA (3 ml). The reaction mixture was stirred for 2 hours at room temperature. The solution was added dropwise to a sat. sodium bicarbonate (20 ml) and then extracted with ethyl acetate

- 127 042453 (3x20 ml). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 200:1-100:1) to obtain the desired product (900 mg, ~60% purity, 59% yield).

Step 4. (E)-1-(5-Bromo-3-methoxy-2-(4-methoxybenzyloxy)phenyl)-3-phenylprop-2-en-1-one

A mixture of 1-(5-bromo-2-hydroxy-3-methoxyphenyl)ethanone (2 g, 8.7 mmol), PMBCl (2.7 g, 17.4 mmol) and K ₂ CO ₃ (3.6 g, 26.1 mmol) in DMF (10 ml) was stirred for 1 h at 90°C. The mixture was cooled to room temperature, diluted with water (50 ml). The resulting precipitate was collected by filtration and dried to give the PMB-protected ketone (3.2 g, quant.) which was used in the next reaction without further purification. PMB-ketone (1.2 g, 3.3 mmol) was dissolved in EtOH/water (20 ml/7 ml). KOH (739 mg, 13.2 mmol) and benzaldehyde (350 mg, 0.54 mmol) were added. The reaction mixture was heated overnight at 95°C. Ethanol was removed under vacuum and the residue was diluted with water (20 ml). The mixture was then extracted with ethyl acetate (3x20 ml). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give crude compound 4 (1.2 g, 81% yield), which was used in the next reaction without further purification. LC-MS m/z [M+Na]+ calc. for C ₂₄ H ₂₁ BrO ₄ , 476; found, 476.

Step 5. (E)-1-(3-Methoxy-2-(4-methoxybenzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-3 - phenylprop-2-en-1-one

Mixture of the product of the above step 4 (1.2 g, 2.7 mmol), bis-(pinacolato)diborone (686 mg, 2.7 mmol), KOAc (778 mg, 8.1 mmol) and Pd(dppf) ₂ Cl ₂ (221 mg, 0.27 mmol) in dioxane (30 ml) was stirred at 110°C for 2 h under N ₂ atmosphere. The mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic extracts were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1-10:1) to give the title product (710 mg, 53% yield).

LC-MS m/z [M+Na] ⁺ calc. for C30H33BO6, 523; found, 523.

Step 6. Mixture of the product of the above step 5 (500 mg, 1.0 mmol), 3-iodo-1-phenylprop-2-en-1-one (358 mg, 1.0 mmol), K ₂ CO ₃ (414 mg , 3.0 mmol) and Pd(dppf) ₂ Cl ₂ (41 mg, 0.1 mmol) in dioxane (20 ml) and H ₂ O (7 ml) were stirred at 110°C for 3 h under N ₂ . The mixture was cooled to room temperature, diluted with water (50 ml) and ethyl acetate (100 ml). The resulting precipitate was filtered. The organic layer of the filtrate was collected, combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:110:1) to give a crude PMB-protected product (307 mg, 61% yield). The PMB-protected product (300 mg, 0.60 mmol) was dissolved in dichloromethane (5 ml) and TEA (3 ml) was added. The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed and the residue was purified by preparative TLC to give the desired title end product as a yellow solid (51 mg, 22% yield).

1H NMR (CDCl ₃ , 400 MHz) δ 13.63 (s, 1H), 7.98-8.05 (m, 3H), 7.34-7.84 (m, 13H), 4.02 (s , 3H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₅ H ₂₀ O ₄ , 385; found, 385.

Example 85 4-(((E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)amino)-1 methylpiperazine 1-oxide (Compound 118 )

In a 20 ml glass vial, the compound 2-fluoro-6-((E)-((4-methylpiperazin-1yl)imino)methyl)-4-((E)-4-(pyrrolidin-1-yl)styryl)phenol (from example 110 above) (102 mg, 0.25 mmol)

- 128 042453 was dissolved in chloroform (5.0 ml) and mCPBA (67 mg, 0.3 mmol) was added to the vial. The vial was then closed and stirred at room temperature for 10 min. Without any workup, the reaction solution was loaded directly onto a wet alumina column and eluted with dichloromethane-methanol (0-15%). Purified product fractions were combined and evaporated to give the desired product as a light yellow solid (35 mg, 33% yield).

1H NMR (500 MHz, chloroform-d) δ 11.36 (s, 1H), 7.77 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.21 (d , J=12.0 Hz, 1H), 7.02 (s, 1H), 6.88 (d, J=16.2 Hz, 1H), 6.74 (d, J=16.2 Hz, 1H ), 6.54 (d, J=8.3 Hz, 2H), 3.80 (t, J=12.5 Hz, 2H), 3.53 (d, J=11.4 Hz, 4H), 3.40 (d, J=11.2 Hz, 2H), 3.32 (dd, J=14.7, 8.1 Hz, 4H), 2.30-1.86 (m, 7H);

LC-MS m/z [M+H]+ calc. for C ₂₄ H ₂₉ FN ₄ O ₂ , 425; found, 425.

Example 86 (E)-3-Fluoro-2-hydroxy-5-(2-(6-(pyrrolidin-1-yl)pyridin-3-yl)vinyl)benzaldehyde (compound 119)

Step 1. 6-(Pyrrolidin-1-yl)nicotinaldehyde

A mixture of 6-chloronicotinaldehyde (141 mg, 1.0 mmol), pyrrolidine (142 mg, 2.0 mmol) and potassium phosphate (848 mg, 4.0 mmol) in dioxane (10 mg) was heated overnight at 95°C . The reaction mixture was cooled to room temperature, diluted with water (20 ml) and was extracted with EtOAc (3x20 ml). The organic layers were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50:1-15:1) to obtain the desired product (130 mg, 74% yield).

1H NMR (DMSO-d6, 400 MHz) δ 9.71 (s, 1H), 8.57 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 6.57 (d , J=9.6 Hz, 1H), 3.49 (m, 4H), 1.97 (m, 4H).

Step 2. 2-(Pyrrolidin-1-yl)-5-vinylpyridine

Methyltriphenylphosphonium bromide (405 mg, 1.14 mmol) was suspended in THF (5 ml) and cooled to 0° C. in an ice bath under nitrogen. Then n-BuLi (0.46 ml, 1.14 mmol, 2.5 M in THF) was added dropwise. The reaction mixture was stirred for 1 hour at 0°C. Then a solution of 6-(pyrrolidin-1-yl)nicotinaldehyde (100 mg, 0.57 mmol) in THF (5 ml) was added dropwise. The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with saturated ammonium chloride solution (20 ml) and extracted with EtOAc (3x20 ml). The organic layers were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was used in the next reaction without further purification.

LC-MS m/z [M+H]+ calc. for CnH ₁₄ N ₂ , 175; found, 175.

Step 3: 5-bromo-3-fluoro-2-hydroxybenzaldehyde mixture (124.3 mg, 0.57 mmol), 2-(pyrrolidin-1-yl)-5-vinylpyridine (crude, 0.57 mmol), 1, 3-bis-(diphenylphosphino)propane (dppp) (47.0 mg, 0.11 mmol), K ₂ CO ₃ powder (236.0 mg, 1.71 mmol) and palladium acetate (12.8 mg, 0.11 mmol) 06 mmol) in DMF water (2 ml/0.6 ml) was heated overnight at 90°C. The mixture was cooled to room temperature, diluted with water (10 ml) and extracted with ethyl acetate (3x10 ml). The organic extracts were combined, washed with brine (3x10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1-3:1) to give the desired product as an orange solid (26 mg, 15% yield, overall yield over two steps).

1H NMR (CDClj, 400 MHz) δ 9.97 (s, 1H), 8.24 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.52 (d, J =11.6 Hz, 1H), 7.44 (s, 1H), 6.91 (d, J=16.0 Hz, 1H), 6.78 (d, J=16.4 Hz, 1H), 6.44 (d, J=9.2 Hz, 1H), 3.54 (m, 4H), 2.06 (m,

- 129 042453

4H);

LC-MS m/z [M+H]+ calc. for C ₁₈ H ₁₇ FN ₂ O ₂ , 313; found, 313.

Example 87 (E)-3-Fluoro-2-hydroxy-5-(2-(5-(pyrrolidin-1-yl)pyridin-2-yl)vinyl)benzaldehyde (compound 120) he

Step 1. 5-(Pyrrolidin-1-yl)picolinaldehyde

A mixture of 5-fluoropicolinaldehyde (141 mg, 1.0 mmol), pyrrolidine (142 mg, 2.0 mmol) and potassium phosphate (848 mg, 4.0 mmol) in dioxane (10 mg) was heated overnight at 95°C . The reaction mixture was cooled to room temperature, diluted with water (20 ml) and was extracted with EtOAc (3x20 ml). The organic layers were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50:1-15:1) to obtain the desired product (120 mg, 68% yield).

Step 2. 5-(pyrrolidin-1-yl)-2-vinylpyridine

Methyltriphenylphosphonium bromide (1.21 g, 3.42 mmol) was suspended in THF (10 mL) and cooled to 0° C. in an ice bath under nitrogen. Then n-BuLi (1.38 ml, 3.42 mmol, 2.5 M in THF) was added dropwise. The reaction mixture was stirred for 1 hour at 0°C. Then a solution of 5-(pyrrolidin-1-yl)picolinaldehyde (300 mg, 1.71 mmol) in THF (5 ml) was added dropwise. The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with saturated ammonium chloride solution (30 ml) and extracted with EtOAc (3x30 ml). The organic layers were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated.

The residue was used in the next reaction without further purification.

Step 3: 5-bromo-3-fluoro-2-hydroxybenzaldehyde mixture (373 mg, 1.71 mmol), 5-(pyrrolidin-1-yl)2-vinylpyridine (crude, 1.71 mmol), 1,3- bis-(diphenylphosphino)propane (dppp) (141 mg, 0.33 mmol), K ₂ CO ₃ powder (708 mg, 5.13 mmol) and palladium acetate (38.4 mg, 0.18 mmol) in DMF- water (6 ml/1.8 ml) was heated overnight at 90°C. The mixture was cooled to RT, diluted with water (10 ml) and extracted with ethyl acetate (3x10 ml). The organic extracts were combined, washed with brine (3x10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1-3:1) and washed with a combination of petroleum ether/dichloromethane to give the desired product as a pale yellow solid (45 mg, 8% yield over two steps) .

1H NMR (DMSO-d ₆ , 400 MHz) δ 10.99 (br, 1H), 10.29 (s, 1H), 7.96 (s, 1H), 7.84 (d, J=12.4 Hz, 1H), 7.64 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.28 (d, J=16.4 Hz, 1H), 7.14 ( d, J=16.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 3.30 (m, 4H), 1.97 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₁₈ H ₁₇ FN ₂ O ₂ , 313; found, 313.

Example 88 1-(((B)-3-fluoro-2-hydroxy-5-((B)-4-(pyrrolidin-1-yl)styryl)benzylidene)amino)imidazolidine-2,4-dione (compound 121)

- 130 042453

The title compound was obtained generally as (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (200 described in Scheme 6b. mg, 0.64 mmol) ,

1-aminoimidazolidine-2,4-dione hydrochloride (195 mg, 1.28 mmol) and TEA (195 mg, 1.92 mmol) were dissolved in ethanol. The reaction mixture was refluxed for 2 hours. The solvent was removed and the residue was filtered. The precipitate was washed with ethanol and dried under vacuum to give the title compound as an orange solid (200 mg, 76% yield).

¹ H NMR (DMSO-06, 400 MHz) δ 11.42 (br, 1H), 10.78 (br, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 7, 40 (d, J=8.8 Hz, 2H), 7.02 (d, J=16.4 Hz, 1H), 6.89 (d, J=16.4 Hz, 1H), 6.54 ( e, J=8.8 Hz, 2H), 4.41 (s, 2H), 3.26 (m, 4H), 1.95 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₂₂ H ₂₁ FN ₄ O ₃ , 409; found, 409.

Example 89 (E)-3-Fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzaldehyde O-ethyloxime (compound 122)

The title compound was prepared in a similar manner as described in Example 88 and generally as described in Scheme 6b using (B)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol), O-ethylhydroxyamine hydrochloride (75 mg, 0.77 mmol) and TEA (129 mg, 1.28 mmol) to give the title compound as a pale yellow solid ( 140 mg, 61% yield.

1H NMR (CDCl ₃ , 400 MHz) δ 10.08 (br, 1H), 8.19 (s, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 7.03 (s, 1H), 6.91 (d, J=16.0 Hz, 1H), 6.78 (d, J=16.0 Hz, 1H), 6.61 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.36 (m, 4H), 2.07 (m, 4H), 1.38 (t, J=7.0 Hz, 3H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₁ H ₂₃ FN ₂ O ₂ , 355; found, 355.

Example 90 (E)-2-Fluoro-6-(hydroxymethyl)-4-(4-(pyrrolidin-1-yl)styryl)phenol (compound 123)

In a 25 ml round bottom flask, LiAlH ₄ (26 mg, 0.64 mmol) was added to a solution of (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (100 mg , 0.32 mmol) in THF (5 ml) at 0°C. The reaction mixture was stirred for 30 minutes. at room temperature and quenched with ice water. The mixture was extracted with ethyl acetate three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was stirred in a combination of petroleum ether/dichloromethane and filtered. The precipitate was dried under vacuum to give the title product as a green solid (50 mg, 50% yield).

1H NMR (DMSO-a ₆ , 400 MHz) δ 9.48 (br, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.24 (m, 2H), 6.95 ( d, J=16.4 Hz, 1H), 6.84 (d, J=16.4 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 4.52 (s, 2H), 3.25 (m, 4H), 1.98 (m, 4H);

LC-MS m/z [M+H] ⁺ calc. for C19H20FNO2, 314; found, 314.

Example 91 (E)-2-((Cyclopropylamino)methyl)-6-fluoro-4-(4-(pyrrolidin-1-yl)styryl)phenol (compound 124)

- 131 042453

Solution of (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1-yl)styryl)benzaldehyde (120 mg, 0.39 mmol) and cyclopropanamine (27 mg, 0.47 mmol) in methanol (5 ml) was stirred for 2 h at room temperature. Sodium cyanoborohydride (121 mg, 1.93 mmol) was added and the reaction mixture was heated overnight at 50°C. The solvent was removed under vacuum and the residue was diluted with water. The system was acidified to pH 5-6 and extracted twice with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the title product as a white solid (55 mg, 38% yield).

1H NMR (CDCl3, 400 MHz) δ 7.38 (d, J=8.8 Hz, 2H), 7.15 (d, J=12.0 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J=16.0 Hz, 1H), 6.75 (d, J=16.4 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 4, 13 (s, 2H), 3.34 (m, 4H), 2.27 (m, 1H), 2.03 (m, 4H), 0.58 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₂₂ H ₂₅ FN ₂ O, 353; found, 353.

Example 92 2-((E)-((4-Cyclopropylpiperazin-1-yl)imino)methyl)-6-fluoro-4-((E)-4-(pyrrolidin-1yl)styryl)phenol (compound 125)

The title compound was prepared in an analogous manner as described in Example 88 and generally as described in Scheme 6b using (E)-3-fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol), 4-cyclopropylpiperazin-1-amine dihydrochloride (165 mg, 0.77 mmol) and TEA (195 mg, 1.93 mmol) to give the title compound as a pale solid -yellow color (240 mg, 86% yield).

1H NMR (DMSO-a ₆ , 400 MHz) δ 11.56 (br, 1H), 7.92 (s, 1H), 7.34 (m, 4H), 6.99 (d, J=16.4 Hz, 1H), 6.83 (d, J=16.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 2H), 3.25 (m, 4H), 3.11 ( m, 4H), 2.74 (m, 4H), 1.96 (m, 4H), 1.70 (m, 1H), 0.45 (m, 2H), 0.36 (m, 2H);

LC-MS m/z [MH] ^- calc. for C26H31FN4O, 433; found, 433.

Example 93 2-((E)-((4-Ethylpiperazin-1-yl)imino)methyl)-6-fluoro-4-((E)-4-(pyrrolidin-1-yl)styryl)phenol (compound 126 )

The title compound was prepared in a similar manner as described in Example 88 and generally as described in Scheme 6b using (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (100 mg, 0.32 mmol), 4-ethylpiperazin-1-amine dihydrochloride (78 mg, 0.38 mmol) and TEA (97 mg, 0.96 mmol) to give the title compound as a pale solid -yellow color (100 mg, 74% yield).

1H NMR (DMSO-66, 400 MHz) δ 11.57 (br, 1H), 7.92 (s, 1H), 7.36 (m, 4H), 6.99 (d, J=16.4 Hz , 1H), 6.83 (d, J=16.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 2H), 3.25 (m, 4H), 3.16 (m , 4H), 2.56 (m, 4H), 2.39 (k, J=7.2 Hz, 2H), 1.96 (m, 4H), 1.04 (t, J=7.2 Hz , 3H);

LC-MS m/z [MH] ^- calc. for C ₂₅ H ₃₁ FN ₄ O, 421; found, 421.

Example 94 2-Fluoro-6-((E)-(morpholinoimino)methyl)-4-((E)-4-(pyrrolidin-1-yl)styryl)phenol (compound 127)

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The title compound was prepared in a similar manner as described in Example 88 and generally as described in Scheme 6b using (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol) and morpholine-4-amine (130 mg, 1.28 mmol) to give the title compound as a pale yellow solid (220 mg, 87% yield).

1H NMR (DMSO-d6, 400 MHz) δ 11.44 (br, 1H), 7.99 (s, 1H), 7.36 (m, 4H), 6.99 (d, J=16.4 Hz , 1H), 6.83 (d, J=16.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 2H), 3.79 (m, 4H), 3.25 (m , 4H), 3.15 (m, 4H), 1.96 (m, 4H);

LC-MS m/z [M+H]+ calc. for C ₂₃ H ₂₆ FN ₃ O ₂ , 396; found, 396.

Example 95 tert-Butyl 4-(((E)-3-fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)amino)piperazine-1-carboxylate ( connection 128)

The title compound was prepared in a similar manner as described in Example 88 and generally as described in Scheme 6b using (E)-3-Fluoro-2-hydroxy-5-(4-(pyrrolidin-1yl)styryl)benzaldehyde (200 mg, 0.64 mmol) and tert-butyl 4-aminopiperazine-1-carboxylate (259 mg, 1.28 mmol) to give the title compound as a white solid (155 mg, 49% yield) .

1H NMR (DMSO-d ₆ , 400 MHz) δ 11.42 (br, 1H), 7.98 (s, 1H), 7.36 (m, 4H), 6.99 (d, J=16.0 Hz, 1H), 6.84 (d, J=16.8 Hz, 1H), 6.54 (d, J=8.8 Hz, 2H), 3.53 (m, 4H), 3.25 ( m, 4H), 3.14 (m, 4H), 1.96 (m, 4H), 1.43 (s, 9H);

LC-MS m/z [M+H] ⁺ calc. for C ₂₈ H ₃₅ FN4O ₃ , 495; found, 495.

Example 96 2-Fluoro-6-((E)-(piperazin-1-ylimino)methyl)-4-((E)-4-(pyrrolidin-1-yl)styryl)phenol hydrochloride (compound 129 hydrochloride salt)

The above tert-butyl 4-(((E)-3-fluoro-2-hydroxy-5-((E)-4-(pyrrolidin-1-yl)styryl)benzylidene)amino)piperazine-1-carboxylate (90 mg, 0.18 mmol) (see Example 96 above) was treated with 6N. HCl/dioxane (5 ml), filtered and washed with a small amount of dichloromethane to give the Boc-unprotected hydrochloride salt as a white solid (55 mg, 70% yield).

1H NMR (DMSO-a ₆ , 400 MHz) δ 11.13 (br, 2H), 9.97 (br, 1H), 9.20 (br, 2H), 8.04 (s, 1H), 7, 41 (m, 4H), 7.00 (d, J=16.4 Hz, 1H), 6.84 (d, J=16.8 Hz, 1H), 6.58 (d, J=8.4 Hz, 2H), 3.41 (m, 4H), 3.28 (m, 8H), 1.97 (m, 4H);

LC-MS m/z [MH] ^- calc. for C ₂₃ H ₂₇ FN ₄ O, 393; found, 393.

Biological example 1. In vitro assay.

Synthetic diacyl lipoprotein (Pam2CSK4, TLR2/6 agonist) and synthetic triacyl lipoprotein (Pam3CSK4, TLR1/2 agonist) were obtained from InvivoGen and dissolved in endotoxin-free water to a concentration of 1 mg/mL, vortexed until completely solubilized, and stored in aliquots at -20°C. Before adding to the cells, an aliquot of the dissolved ligand was briefly vortexed and then diluted in the medium to 25 ng/ml Pam2CSK4 or

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1000 ng/ml Pam3CSK4. The EC ₅₀ agonists for each assay were determined using 3-fold dilutions of each agonist from the following initial concentrations: 5 ng/ml for Pam2CSK4 and 200 ng/ml for Pam3CSK4.

Test compounds were freshly dissolved to stock solutions of 10-20 mM in DMSO and sonicated for 5-10 min in an ultrasonic disperser in a water bath. Serial dilutions were made in DMSO and then diluted in medium. The final concentration of DMSO that was used in the assay was 1%.

HEK-Blue hTLR2 reporter cells (InvivoGen) are HEK-293 cells that stably express the human TLR2 gene and secreted embryonic alkaline phosphatase (SEAP) reporter construct downstream of NFkB promoter sites. HEK-Blue hTLR2 reporter cells were cultured according to the manufacturer's protocol using Dulbecco's Modified Eagle's Medium (DMEM; Gibco) containing 1X GlutaMax (Gibco), 10% heat-inactivated fetal bovine serum (Gibco), Pen-Strep (50 U/ ml penicillin, 50 µg/ml streptomycin, Gibco), 100 µg/ml Normocin (InvivoGen) and selective antibiotics, 1x HEK-Blue Selection (InvivoGen). Quanti-Blue reagent (InvivoGen) for detecting and quantifying secreted alkaline phosphatase was dissolved in 100 ml of endotoxin-free water, heated to 37° C. for 30 min, and then filtered using a 0.2 μm membrane.

Biological Example 2 HEK-Blue hTLR2 Antagonism Assay.

On day 1, 50 µl of each test compound's duplicate dilution or control solution was added to each well of a 96-well plate, followed by the addition of 150 µl of HEK-Blue hTLR2 cell suspension (1 x 10 ⁵ cells/well) and incubated at 37°C/ 5% CO ₂ for 2 hours. Then 50 μl of each agonist (Pam2CSK4 or Pam3CSK4) at a concentration of approximately 3xEC ₅₀ was added to the wells containing test compounds or control solution. The plates were then incubated at 37° C./5% CO2 for 18 hours. For each assay, untreated HEK-Blue hTLR2 cells were treated with serial dilutions of the agonists to determine the EC50 values for the respective assay.

On day 2, secreted alkaline phosphatase (SEAP) activity was detected in cell culture supernatants. Briefly, 20 μl was collected from each well and transferred to a 96-well plate. Then 200 µl of Quanti-Blue detection reagent was added to each well. The plates were incubated at room temperature for 15 min and SEAP activity was assessed using the OD value of the spectrophotometer at 655 nm. In table. A shows activity values of compounds tested in HEK cells using Pam2CSK4 and Pam3CSK4 as agonists. The activity of the compounds against Pam2CSK4 and Pam3CSK4 is presented as IC ₅₀ values for response from cells treated with background subtracted agonists.

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Table A

Compound from Example No. IC50 (µM) s Pam2CSK4 ICso (µM) with Pam3CSK4 1 3.2 1.7 2 5.3 1.4 3 4.8 3.1 4 5.5 4 5 4 3.2 6 2.5 2.3 7 7.9 6.2 8 6.3 5.5 9 >100 >100 10 4.6 3.8 AND 1.1 1 12 1.4 1.3 13 4.5 3.8 14 5.7 4.2 15 14.7 12.6 16 5.9 6.9 17 2.0 2.1 18 10.4 12.2 19 26.7 38.1 20 AND 2 10.0 21 40 57.3 22 17.8 6.3 23 I,8 11.5 24 >100 >100 25 15.2 16.4 26 7.4 9.3 27 4.4 7.7 28 19.5 29.4 29 9.1 10 thirty 20.6 18.8 31 3.8 6 32 1.1 1 33 6.2 6.4 34 9.7 7.5 35 68.5 62.6 36 0.6 0.4 37 1 oh, s 38 4.4 5 39 12.8 15.4 40 2.3 2.5 41 35.1 29.8 42 3.4 4.5 43 32.8 40.7 44 3 3.2 45 5 6.7

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Claims (10)

46 1.4 1 47 1.3 0.9 48 1 0.6 49a 0.5 0.6 49b 0.8 0.8 50 10 6.7 51 71.3 70.1 52 >100 >100 53 1.3 1.5 54 4 4.6 55 3.6 4.1 56 1.8 1.7 57 1.7 1.9 58 4.9 5 59 4.1 2.6 60 2.3 0.9 61 1 0.4 62 1.5 0.8 63 1.5 0.6 64 1.1 0.5 65 1.7 0.5 66 0.9 oh, s 67 1.7 1.2 68 1.6 1.3 69 0.7 0.6 70 0.9 0.4 71 13.7 2.5 72 8.2 AND 2 73 4.5 4.8 74 6.3 7 75 1.2 1.3 76 0.4 0.5 77 1.4 1.1 78 1 0.9 79 4.4 6 80 28.4 14.8 81 16.4 13.2 82 2.1 2.1 83 36.7 88.9 84 3.4 3.1 85 4.5 1.9 86 3.8 4.1 87 3.9 h, h 88 AND 2 7.9 89 29.5 29.6 90 5.4 8.5 91 30.6 82.1 92 26.6 32.3 93 24.5 3.2 94 2.9 1.4 95 4.4 3.6 96 3.2 1.3 CLAIM 1. Compound of formula (A) or a tautomer, or a pharmaceutically acceptable salt of any of the foregoing, G' where ' ^-z indicates that the ring is saturated, partially unsaturated, or completely unsaturated; - 136 042453 G4 *'^θβ indicates that ' ^G = attached in E- or Z-configuration; Gi and G2 are each independently CR ^x or N; R ^x is hydrogen or halogen; one of R ¹ and R ² is -OH and the other is selected from the group consisting of: (a) -C(O)R ^a , (b) -CH=NR ^j , (c) -S(O)R ^b , (d) -S(O)2R ^c , (e) -NHC(O) R ^d , (f) -NHS(O)2R ^e , (g) -C ₁ -C ₆ -alkyl-R ^f , (h) -C ₂ -C ₆ -alkenyl-R ^g , (i) C ₃ - C ₈ -cycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of =O, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C6-alkyl, -OC ₁ -C6-alkyl and C ₃ -C ₈ -cycloalkyl, (j) C ₃ -C ₈ -cycloalkenyl, unsubstituted or substituted with 1 -5 substituents selected from the group consisting of C ₁ -C6 alkyl, C ₁ -C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C6-alkyl, -OC ₁ -C6-alkyl and C3-C8-cycloalkyl, and (k) heterocycloalkyl unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ - C ₆ -haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl; R ^a , R ^b , R ^c and R ^e are each independently: (a) H, (b) C ₁ -C ₆ alkyl, (c) C ₂ -C ₆ alkenyl, (d) C ₂ -C6 alkynyl, (e) C ₁ -C 6 haloalkyl, (f) 3-10 membered heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C6 alkyl, C ₃ -C ₈ -cycloalkyl, =O and -C(O)O-(C ₁ - C6-alkyl), (g) 5-18 membered heteroaryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C6 alkyl, C ₃ -C ₈ -cycloalkyl and -C(O)O -(C ₁ -C6 alkyl), (h) benzoyl or (i) styryl; Rd is: (a) H, (b) C ₁ -C ₆ alkyl, (c) C ₂ -C ₆ alkenyl, (d) C ₂ -C6 alkynyl, (e) C ₁ -C 6 haloalkyl, (f) heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C6 alkyl, C ₁ -C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, - C(O)O-(C ₁ -C6 alkyl), -OC ₁ -C6 alkyl) and C ₃ -C ₈ cycloalkyl, (g) heteroaryl unsubstituted or substituted with 1-5 substituents selected from the group consisting of from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, halogen, -OH, -C (O) H, -C (O) OH, -C (O) O - (C ₁ -C ₆ - alkyl), -O-(C ₁ -C ₆ -alkyl) and C ₃ -C ₈ -cycloalkyl, or (h) benzoyl; R ^f and R ^g are each independently -OH, unsubstituted heteroaryl, -NR ^m R ⁿ , benzoyl or styryl; R ^m and R ⁿ are each independently H, C ₁ -C 6 alkyl, C ₂ -C 6 alkenyl, C ₂ -C 6 alkynyl, or C ₃ -C ₈ cycloalkyl, unsubstituted or substituted with 1-5 substituents, selected from the group consisting of C ₁ -C6 alkyl, C ₁ -C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C6 alkyl , -OC ₁ -C6-alkyl and C ₃ -C ₈ -cycloalkyl; ^Rj is: (a) 5-6 membered heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, =O and -C(O)O- (C ₁ -C ₆ -alkyl), (b) C ₆ -C ₁₂ -aryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and -C(O)O-(C ₁ -C ₆ -alkyl), (c) -OR ^k , - 137 042453 (d) ^-NHRk , (e) -NHC(O) ^Rk , (f) -NHS(O) ^2Rk or (g) -NHC(NH)NH2; R ^k is Q^-alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, or C6-C1 ₈ aryl; R ³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or halo, where C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy of R ³ are each independently unsubstituted or substituted with 1-5 halogens; Where: when R ¹ or R ² is -(C1-C6 alkyl)-OH or -(C1-C6 alkyl)-NR ^m R ⁿ where R ^m and R ⁿ are each C1-C ₆ alkyl , R ³ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C6 -alkoxy and halogen; when R ¹ or R ² is unsubstituted or substituted C3-C8 cycloalkyl, -NHC(O)CH3 or -S(O)2-R ^c , where R ^c is unsubstituted or substituted heterocyclyl, R ³ is selected from the group, consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy and halogen; when R ¹ or R ² represents -CHO, R ³ is selected from the group consisting of hydrogen, C ₂ -C ₆ -alkoxy and halogen; when R ¹ or R ² is -C(O)CH3, R ³ is selected from the group consisting of C2-C ₆ -alkoxy and halogen; when R ¹ or R ² is -C(O)CH(Br)CH ₃ or -C(O)CH(Br)CH ₂ CH ₃ , G7 is C or CH; when R ³ is hydrogen, not more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CF3, not more than one of R ^6a , R ^6b , R ^6c and R ^6d is -CH3 and not more than one of R ^6a , R ^6b , R ^6c and R ^6d is -OH; Y is -C(O)- or absent, and R ⁴ and R ⁵ are each H or Y is absent, and R ⁴ and R ⁵ combine to form -S-; G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S or O; G ₄ is CH(X ₂ -R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O; G ₅ is CH(X ₃ -R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O; G ₆ is CH(X ₄ -R ^6d ), C(X4-R ^6d ), N,N(X4-R ^6d ), S, O, or absent; G7 is N, C or CH; where, when G5 is N, at least one of (i), (ii) and (iii) applies: (i) at least one of G3, G4 and G6 is not CH; (ii) R ⁴ and R ⁵ combine to form -S-; (iii) R ³ is -OCH3 or halo; X1, X ₂ , X ₃ and X ₄ , each independently absent, are m equal to 1-6; R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, -NRpR ^q , C6-C ₁₈ -aryl, heterocyclyl, heteroaryl , -(C ₁ -C ₆ -alkyl)heterocyclyl, -OC(O)-heterocyclyl, -C(O)R ^h , -S(O)2NR ^w1 R ^w2 , -S(O)2R ^y or -NR ^z1 S(O)2R ^z2 , where C1-C6 alkyl and C1-C6 alkoxy of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with 1-5 groups selected from the group consisting of C3-C ₁ o-cycloalkyl and halogen; C ₆ -C ₁₈ aryl and heteroaryl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with 1-5 groups selected from the group consisting of C1-C6 alkyl, C1-C6- alkoxy, -OH and -(C1-C6 alkyl)-OH; and heterocyclyl, -(C1-C6-alkyl)heterocyclyl and -OC(O)-heterocyclyl of R ^6a , R ^6b , R ^6c and R ^6d are each independently unsubstituted or substituted with 1-5 groups selected from the group consisting of from C1- _C6 alkyl, _C1 - _C6 alkoxy, -OH, -( _C1 - _C6 alkyl)-OH, ═O and ═S; R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl and -NR ^r R ^s ; R ^p represents H or C ₁ -C ₆ -alkyl; R ^q is C ₂ -C ₃ alkyl, -C(O)R'' -C(O)OR ^u , -C(O)NR ^v ; R ^r , R ^s , R ^w1 and R ^z1 are each independently selected from H and C ₁ -C ₆ alkyl and Rt, R ^u , R ^v , R ^w2 , R ^y and R ^z2 are each independently selected from: (a) H, (b) C ₁ -C ₆ -alkyl, (c) C ₃ -C ₈ -cycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of halogen, hydroxyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl and C ₃ -C ₈ -cycloalkyl, and (d) heterocyclyl unsubstituted or substituted with 1-5 substituents selected from the group consisting of halogen, hydroxyl , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₈ cycloalkyl; or G5 is CH(X ₃ -R ^6c ) or C(X3-R ^6c ), G6 is CH(X ₄ -R ^6d ) or C(X ₄ -R ^6d ), a - 138 042453 R ^6c and R ^6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring; where the 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl rings are each independently unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C ₆ -alkyl and -C(O)O- (C ₁ -C ₆ -alkyl); where, except where otherwise indicated, each heteroaryl independently has up to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and from 3 to 12 ring atoms; where, except where indicated otherwise, each heterocyclyl or heterocycloalkyl independently has 1 to 10 heteroatoms selected from nitrogen, oxygen and sulfur, and has 3 to 20 ring atoms; where no more than one of R ^6a , R ^6b , R ^6c and R ^6d is C ₁ -C ₆ -alkoxy or -OH; and where the connection is not a connection from the table below. XI OH A^CHO T 9 Vg X2 OH A^CHO t 9 OMe xs C3 ^- av ^\u003d v'9 ° Hc * O z X4 dream,Τ,ΟΗ T J^OMe t p-Rg X5 ω About PA /=\o X O - 139 042453 X6 OH A^clear T 0 X7 he A^ ^clear t t X8 He T Q CI X9 he A. ^sn ° t 9 F HYU HE t A γΧΗΟ OH chi he xi ^sno - 140 042453 (e) -NHS(O)2R ^e , (f) -СрС6-alkyl-KU (g) -C ₂ -C ₆ -alkenyl-R ^g , (h) С ₃ -С ₈ -cycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of =O, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH , -C(O)OC ₁ -C ₆ -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl, (i) C ₃ -C ₈ -cycloalkenyl, unsubstituted or substituted with 1-5 substituents, selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)OC ₁ -C6 -alkyl, -OC ₁ -C ₆ -alkyl and C ₃ -C ₈ -cycloalkyl, and (j) heterocycloalkyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C6 -alkyl, C ₁ - C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)O-C ₁ -C6 alkyl, -OC ₁ -C6 alkyl and C ₃ -C ₈ -cycloalkyl; R ^a , R ^b , R ^c and R ^e are each independently: (a) H, (b) C1- _C6 alkyl, (c) _C2 - _C6 alkenyl, (d) _C2 - _C6 alkynyl, (e) C1- _C6 haloalkyl, (f) 3-10 membered heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C1- _C6 alkyl, _C3 - _C8 cycloalkyl, =O and -C(O)O-( _C1- C ₆ -alkyl), (g) 5-18 membered heteroaryl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C6 -alkyl, C ₃ -C ₈ -cycloalkyl and -C(O) O-(C ₁ -C6 alkyl), (h) benzoyl or (i) styryl; ^Rd is: (a) H, (b) C1- _C6 alkyl, (c) _C2 - _C6 alkenyl, (d) _C2 - _C6 alkynyl, (e) C1- _C6 haloalkyl, (f) heterocyclyl, unsubstituted or substituted with 1-5 substituents selected from the group consisting of C ₁ -C6 alkyl, C ₁ -C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, - C(O)O-(C ₁ -C6 alkyl), -O-(C ₁ -C6 alkyl) and C ₃ -C ₈ -cycloalkyl, (g) heteroaryl, unsubstituted or substituted with 1-5 substituents selected from a group consisting of C ₁ -C6 alkyl, C ₁ -C6 haloalkyl, halogen, -OH, -C(O)H, -C(O)OH, -C(O)O-(C ₁ -C6- alkyl), -O-(C ₁ -C6 alkyl) and C ₃ -C ₈ -cycloalkyl, or (h) benzoyl; R ^f and R ^g are each independently unsubstituted heteroaryl, benzoyl or styryl; R ³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen; R ⁴ and R ⁵ are each H or R ⁴ and R ⁵ combine to form -S-; G ₃ is CH(X1-R ^6a ), C(X1-R ^6a ), N,N(X1-R ^6a ), S or O; G ₄ is CH(X2-R ^6b ), C(X2-R ^6b ), N,N(X2-R ^6b ), S or O; G ₅ is CH(X ₃ -R ^6c ), C(X3-R ^6c ), N,N(X3-R ^6c ), S or O; G ₆ is CH(X4-R ^6d ), C(X ₄ -R ^6d ), N,N(X4-R ^6d ), S, O, or absent; where when G5 is N, or (i) at least one of G ₃ , G ₄ and G ₆ is not CH; or (ii) R ⁴ and R ⁵ combine to form -S-; X1, X ₂ , X ₃ and X ₄ , each independently absent, are m equal to 1-6; R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen or -C(O)R ^h where C1-C6 alkyl from R ^6a , R ^6b , R ^6c and R ^6d are independently unsubstituted or substituted with C3-C8 cycloalkyl or halogen; R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C1-C ₆ alkoxy and C ₃ -C ₈ cycloalkyl; where, except where otherwise indicated, each heteroaryl independently has up to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and from 3 to 12 ring atoms; where, except where indicated otherwise, each heterocyclyl or heterocycloalkyl independently has 1 to 10 heteroatoms selected from nitrogen, oxygen and sulfur, and has 3 to 20 ring atoms; and where the connection is not a connection from the table below. - 141 042453 XI OH A^CHO 1 ΎBr X2 OH Ay ^but OMe xs 0 a _nh ±^oh 1 0 X4 CHO i° ^h 1 ^L^OMe y n-Pr X5 OH A^ ^CH0 T j0 FaC^ ⁵ ^ - 142 042453 X6 OH X^CHO T ABOUT X7 he H.CHO T T X8 he D^ ⁰ CI x9 he /^.no T q F HYU HE t A u'hno he chi He 3. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein Y is -C(O)-. 4. The compound according to claim 1, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where Y is absent. 5. A compound according to any one of claims 1-4, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G1 and G2 are each CR ^x . 6. A compound according to any one of claims 1 to 5, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G1 is CF, CCl or CBr. 7. A compound according to any one of claims 1 to 5, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G2 is CF, CCl or CBr. 8. A compound according to any one of claims 1 to 5, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G1 and G2 are each CH. 9. A compound according to any one of claims 1-4, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G1 is CH and G2 is N. 10. A compound according to any one of claims 1-4, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G1 is N and G2 is CH. 11. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ¹ is -OH and R ² is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C ₆ -alkenyl- R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl. 12. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ¹ is -OH and R ² is selected from the group consisting of - 143 042453 from -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C ₂ -C ₆ -alkenyl-R ^g and unsubstituted or substituted cycloalkenyl. 13. The compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, where R ¹ is -OH and R ² is -CH=NR ^j ', where R ^j is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, -OR ^k , -NHR ^k , -NHC(O)R ^k , -NHS(O)2R ^k or -NHC(NH)NH2. 14. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ¹ is -OH and R ² is selected from the group consisting of -CHO, -C(O) CH3, -C(O)CH2F, -C(O)CH=CH2, -S(O^CH=CH2, -C(O)C CH, -C(O)C CCH3, -NHS(O)2CH=CH2, -NHC(O)CH=CH2, -C(O)C(=CH2)CH3, 15. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ¹ is -OH and R ² is selected from the group consisting of: 16. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ² is -OH and R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)R ^b , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C1-C6-alkyl-R ^f , -C2-C ₆ -alkenyl- R ^g , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl. 17. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ² is -OH and R ¹ is selected from the group consisting of -C(O)R ^a , -S(O)2R ^c , -NHC(O)R ^d , -NHS(O)2R ^e , -C ₂ -C ₆ -alkenyl-R ^g and unsubstituted or substituted cycloalkenyl. 18. The compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, where R ² is -OH and R ¹ is -CH=NR ^j , where R ^j is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, -OR ^k , -NHR ^k , -NHC(O)R ^k , -NHS(O) 2 R ^k , or -NHC(NH)NH 2 . 19. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, where R ² is -OH and R ¹ is selected -CHO, -C(O)CH3, -C(O)CH2F, -C(O)CH=CH2, -S(O) ₂ CH=CH2, -NHS(O)2CH=CH2, -NHC(O)CH=CH2, -C(O)C(=CH2)CH3, from the group consisting of -C(O)C CH, -C(O)C CH 20. A compound according to any one of claims 1-10, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ² is -OH and R ¹ is selected from the group consisting of - 144 042453 CHON, 21. The compound according to any one of claims 1-20, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, where R ³ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and halogen. 22. A compound according to any one of claims 1-21, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein ^R3 is selected from the group consisting of -OCH3 or F. 23. A compound according to any one of claims 1-20, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ³ is H. 24. A compound according to any one of claims 1-23, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ⁴ and R ⁵ are each H. 25. A compound according to any one of claims 1-23, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ⁴ and R ⁵ combine to form -S-. 26. The compound according to claim 1, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₅ represents CH(X ₃ -R ^6c ) or C(X3-R ^6c ), G6 represents CH(X ₄ - R ^6d ) or C(X4-R ^6d ), and R ^6c and R ^6d are combined with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl or 6-membered heteroaryl ring, where the 6-membered aryl, 6-membered heterocyclyl and 6-membered heteroaryl rings are each independently unsubstituted or substituted. 27. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G ₇ is N. 28. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G ₇ is C or CH. 29. The compound according to any one of paragraphs.1-28, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₃ represents CH(X _r R ^6a ) or C(XrR ^6a ); X1 missing; m is 1-6; R ^6a is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or —C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl. 30. The compound according to any one of paragraphs.1-28, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₃ represents N or N(X1-R ^6a ); X1 missing; m is 1-6; R ^6a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl. 31. The compound according to any one of paragraphs.1-30, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G4 represents CH(X ₂ -R ^6b ) or C(X2-R ^6b ); X2 missing; m is 1-6; R ^6b is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl. 32. The compound according to any one of paragraphs.1-30, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₄ represents N or N(X ₂ -R ^6b ); X2 missing; m is 1-6; R ^6b is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or —C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl. 33. The compound according to any one of paragraphs.1-32, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₅ represents CH(X ₃ -R ^6c ) or C(X3-R ^6c ); X3 missing; m is 1-6; R ^6c is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or -C(O)R ^h , where C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₃ -C ₈ cycloalkyl. 34. The compound according to any one of paragraphs.1-32, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₅ represents N or N(X ₃ -R ^6c ); X3 missing; m is 1-6; R ^6c is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or -C(O)R ^h , where - 145 042453 C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or C ₃ -C ₈ -cycloalkyl. 35. A compound according to any one of claims 1-34, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G ₃ , G ₄ and G ₅ are S or O. 36. A compound according to any one of claims 1 to 35, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein G ₆ is absent. 37. The compound according to any one of paragraphs.1-35, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₆ represents CH(X ₄ -R ^6d ) or C(X4-R ^6d ); X4 missing; m is 1-6; R ^6d is hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or -C(O)R ^h , where C1-C6 -alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy or C ₃ -C ₈ -cycloalkyl. 38. The compound according to any one of paragraphs.1-35, or its tautomer, or a pharmaceutically acceptable salt of any of the above, where G ₆ represents N or N(X ₄ -R ^6d ); X4 missing; m is 1-6; R ^6d is hydrogen, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or —C(O)R ^h , where C1-C6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C1-C ₆ -alkyl, C ₁ -C ₆ -alkoxy or C ₃ -C ₈ -cycloalkyl. 39. A compound according to any one of claims 1-38, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C1-C6 alkyl , C1-C6-alkoxy, halogen or -C(O)R ^h , where C1-C ₆ -αkyl is unsubstituted or substituted with cycloalkyl or halogen; a R ^h is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₃ -C ₈ cycloalkyl. 40. A compound according to any one of claims 1-38, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ^6a , R ^6b , R ^6c and R ^6d are each independently hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or halogen. 41. A compound according to any one of claims 1-38, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein R ^6a , R ^6b , R ^6c and R ^6d are each independently selected from the group consisting of Cl, F, -CH3, -OCH3, -CF3, -CH2CH2F, -CH(CH3)2, -C(O)OC(CH3)3, -C(O)CH3, 42. The compound according to claim 1, selected from the following: No. conn. Chemical structure chemical name 1 3 CD 0 t o (E)-2-hydroxy-3-methoxy-5-(4methoxystyryl)benzaldehyde 2 3 η y Chf ω O I O (E)-2-hydroxy-3-methoxy-5 -(3 - (trifluoromethyl)styryl)benzaldehyde 3 3 f o I o 5-(4-chlorostyryl)-2-hydroxy-3 methoxybenzaldehyde 4 he MeO^U^CHO y ABOUT (E)-2-hydroxy-3-methoxy-5 styrylbenzaldehyde - 146 042453 5 OH MeO^X_CHO O' Y (E)-5-(3,5-d iftorstyryl)-2-hydroxy-3 methoxybenzaldehyde 6 he MeO^xL.CHO Y V F (E)-5-(2,4-difluorostyryl)-2-hydroxy-3methoxybenzaldehyde 7 OH MeO^X.CHO IJ ΎF (E)-5-(4-fluorostyryl)-2-hydroxy-3methoxybenzaldehyde 8 S f ” Mpg o t ABOUT (E)-2-hydroxy-3-methoxy-5 -(4- (trifluoromethyl)styryl)benzaldehyde - 147 042453 9 It (E)-1-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)ethan-1-one 9 OMe 10 OH kX^sno XX 9 OME (E)-3-fluoro-2-hydroxy-5-(4methoxystyryl)benzaldehyde AND X ) \u003d / -C d © ί ^ x ¹ ω O TO (E) -3 -fluoro-2-hydroxy-5 - (3 - (trifluoromethyl) styryl) benzal dehyde 12 OH MeO^X^CHO XY \ ^s N--/ Boc tert-butyl 2-(3-formyl-4-hydroxy-5methoxyphenyl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-carboxylate 13 OH MeO.1,CHO XX \ ^s HN-X - 148 042453 14 OH MeO^D,CHO XT \ ^s Ν-Λ 5-(5-(cyclopropanecarbonyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxybenzaldehyde 15 He MeO^D_CHO XT As N—/ Me 5-(5-acetyl-4,5,6,7-tetrahydrothieno[3,2c]pyridin-2-yl)-2-hydroxy-3 - methoxybenzaldehyde 16 OH MeO^X,CHO XT \ ^s N—Z F -methoxybenzaldehyde 17 OH MeO^D^CHO XT \ ^s N—/ V - 149 042453 18 O X o / ^x f S 19 he kAxNO TU \^ ^s N—/°h Me 20 OH MeO^X.CHO XY As N-U Me^ Me 2-hydroxy-5-(5-isopropyl-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-3methoxybenzaldehyde 21 O X o / \u003d ". \—/ \_/ \ S al ⁵ (E)-2-hydroxy-5-(2-(6-methylpyridin-3yl)vinyl)benzaldehyde 22 LA / ^0Me MeO-C /=\ \=/ M^Hon / ° (E)-1 - (2-hydroxy-3-methoxy-5 - (4-methoxystyryl) phenyl) prop-2-en-1 -one - 150 042453 23 ΖΑ / ^0Μβ MeO—CS—, /=/ ⁴⁼⁷ M_/ ^he k° V ⁰ (E)-2-methoxy-4-(4-methoxystyryl)-6-(vinylsulfonyl)phenol 24 MesPM /=G \=/ VQ-u / ⁰ (E)-1-(2-hydroxy-3-methoxy-5-(4-methoxystyryl)phenyl)prop-2-in-1-one 25 LA / ^OMe MeO—/ /=( \=/ m^ _on /° / (E)-1-(2-hydroxy-3-methoxy-5-(4-methoxystyryl)phenyl)but-2-yn-1 -He 26 LA / ^OMe MeO—/ U-l /=< \=/ o. , ^NH zS °? (E)^-(2-hydroxy-3-methoxy-5-(4-methoxystyryl)phenyl)ethensulfonamide 27 _Μβ0Η ρρ " \=/ MP-one /° (E)-1-(2-hydroxy-3-methoxy-5-(4-methoxystyryl)phenyl)-2-methylprop-2en-1-one 28 ΛΑ / ^OMe / ° O (E) - (2-hydroxy-3 -methoxy-5 - (4 methoxystyryl) phenyl) (2-methyloxiran2-yl) methanone - 151 042453 29 OH O I Ν Ν^Ο 1 n V OME (E)-6-(2-hydroxy-3-methoxy-5-(4methoxystyryl)benzoyl)-3-isopentyl3,4-dihydropyrido[2,3-<1]pyrimidin2(1Н)-one 30 γγ / ^OMe MeO—/ γ^ /=< \=/ ^ΛοΗ /° AL (E)-1-(2-hydroxy-3-methoxy-5-((E)-4methoxystyryl)phenyl)-3-phenylprop -2en-1-he 31 LA / ^0Me MeO—/ Αγ /=< \=/ A-£A _OH /° Al(E)-3-(2-hydroxy-3-methoxy-5-((E)-4methoxystyryl)phenyl)-1 -phenylprop-2en-1-one 32 LA / ^0Me MeO—/ /=( \=/ νχ ^{Lon ν} Α O. , ^ΝΗ zS °? (E)-M-(3-hydroxy-4-methoxy-6-(4methoxystyryl)pyridin-2yl)ethensulfonamide 33 _ΜβΟ γγ^ Υ ⁶ \=/ ΥΥ-one /° 'O' (E)-(2-hydroxy-3-methoxy-5-(4-methoxystyryl)phenyl)(6-methylpyridin3-yl)methanone - 152 042453 34 GA / ^OMe MeO—C /=(NH (E)-X-(2-hydroxy-3-methoxy-5-(4methoxystyryl)phenyl)acrylamide 35 OMe <LN> ^he / ⁰ y 2-en-1 - he 36 OME V 4-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2methoxy-6-(vinylsulfonyl)phenol 37 _ _ OMe K A _S V<C ^OH / ° / 1-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3 -methoxyphenyl)prop-2-yn-1-one 38 _ OMe ^H'nH AL< ^Aon / ⁰ / 1-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3 -methoxyphenyl)but-2-yn-1-one 39 OMe \X ^h M^y-l /=/ A _s >Af ^OH o. , ^NH zS °? X-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3methoxyphenyl)ethensulfonamide - 153 042453 40 OH O I NN^O 1 n N—/ 6-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxybenzoyl)-3 isopentyl-3,4-d ihydropyride o [2,3 - d] pyrimidin-2( 1 H)-one 41 ULs^Cr™ /° 1-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)-2-methylprop2-en-1-one 42 OMe /=/ CSHX ^he /° o (5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)(2- methyloxiran-2-yl) methanone 43 OME uhlx /° Ά W (E)-1-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)-3 phenylprop-2-ene -1 -on 44 _ OMe / /°w (E)-3-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)-1 phenylprop-2-ene -1 -on - 154 042453 45? X °A ^z a Al o'o Z—/ L L -2yl)ethensulfonamide 46 OMe u/iy / ⁰ o -3 -yl) methanone 47 Anu° ⁿ ΝΗ 9 N-(5-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-3-methoxyphenyl)acrylamide 48 LA / ^OMe \=/ ν—Leno OH (E)-2-hydroxy-6-methoxy-4-(4methoxystyryl)benzaldehyde 49 ^OMe ξΛ /=(OH 4-(5-(cyclopropylmethyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridin-2-yl)-2hydroxy-6-methoxybenzaldehyde 50 OME LCH \=/ OME Mu™ sno (2)-2-hydroxy-3-methoxy-5-(4methoxystyryl)benzaldehyde - 155 042453 51 LA / ^0Me MeO—C E-^h /=< / ° F 52 LA / ^0Me MeO-C E-l /=( \=/ \MC- ^{one 0} \ / (E)-2'-hydroxy-3'-methoxy-5'-(4methoxystyryl)-4,5-dihydro- [ 1, Hbiphenyl]-2(3H)-one 53 LA / ^0Me MeO—/ Y^h /=( \=/ A^ ^on ° \ / (E)-2'-hydroxy-3'-methoxy-5'-(4methoxystyryl)-5,6-dihydro- [ 1, Gbiphenyl]-2(1H)-one 54 LA / ^0Me MeO—/ y^h /=< \=/ VQ-oh ° \ / ° (E)-2'-hydroxy-3'-methoxy-5'-(4-methoxystyryl)- [ 1.1 '-biphenyl]-2,5-dione 55 OH A _; ^Cl Jf JF^^p 9 OMe (E)-4-fluoro-2-hydroxy-5-(4methoxystyryl)benzaldehyde 56 OH MeO^T^XHO y r^N and (E)-2-hydroxy-3-methoxy-5-(2-(pyridine- 2-yl)vinyl)benzaldehyde - 156 042453 57 OH A^ ^ch ° t and (E)-2-hydroxy-5-(2-(pyridin-2yl)vinyl)benzaldehyde 58 he is MeO ^ A, CHO XY o N (E)-2-hydroxy-3-methoxy-5-(2-(pyridine- 4-yl)vinyl)benzaldehyde 59 S f ^z=7 AZp o X o (E)-2-hydroxy-3-methoxy-5-(2-(6-methylpyridin-3-yl)vinyl)benzaldehyde 60 3 f /—\ ° D0-Z)—l /=/ ⁸ o X o tert-butyl (E)-4-(3-formyl-4-hydroxy5-methoxystyryl)piperide in-1 carboxylate 61 he p^A^eno A uA and (E)-3-fluoro-2-hydroxy-5-(2-(pyridin-2yl)vinyl)benzaldehyde - 157 042453 62 o I o (E)-3-fluoro-2-hydroxy-5-(2-(6- methylpyridin-3-yl)vinyl)benzaldehyde 63 he kDhno (E)-3-fluoro-2-hydroxy-5-(2-(pyridin-4yl)vinyl)benzaldehyde 64 00-Z)--l /=/ ⁸ o Z o tert-butyl (E)-4-(3-fluoro-5-formyl-4hydroxystyryl)piperidine-1 carboxylate 65 OH MeO^X, SNO TU Q and (E)-2-hydroxy-3-methoxy-5 -(2- (naphthalene-2-yl)vinyl)benzaldehyde 66 ABOUT V p oh oh f S (E)-2-hydroxy-3-methoxy-5-(3-oxo-3-phenylprop-1-eu-1-yl)benzaldehyde 67 He MeO^U.CHO tu OL p^OMe HE (E) -2-hydroxy-5 - (4-hydroxy-3 - methoxystyryl)-3-methoxybenzaldehyde 68 OH MeO^A.CHO 7 Ο^Ν^ l^^o (E)-2-hydroxy-3-methoxy-5-(3-morpholino-3-oxoprop-1-en-1 yl)benzaldehyde 69 OH MeO^X^CHO THAT I O (E)-5-(2-([1,1'-biphenyl]-4-yl)vinyl)-2hydroxy-3-methoxybenzaldehyde - 158 042453 70 o I o (E)-5-(2-([1,G-biphenyl]-4-yl)vinyl)-3fluoro-2-hydroxybenzaldehyde 71 OH MeO^D,CHO T T 5-(2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)vinyl)-2-hydroxy-3- Λ O^J methoxybenzaldehyde 72 Oh (E)-5-(2-(2,3- κΛ,οηο TH dihydrobenzo[b] [1,4]dioxin-6-yl)vinyl)-3-fluoro-2- A η^^ο o^/J hydroxybenzaldehyde 73 Oh (E)-2-hydroxy-3-methoxy-5 -(4- MeO^^L/CHO u Q0 morpholinostyryl)benzaldehyde - 159 042453 74 HE MeO. 4h CNO xu ii (2)-2-hydroxy-3-methoxy-5-(4morpholinostyryl)benzaldehyde 75 Z—-l /=/ O I o (E)-3-fluoro-2-hydroxy-5-(4- morpholinostyryl)benzaldehyde 76 o X o o (2)-3-fluoro-2-hydroxy-5-(4- morpholinostyryl)benzaldehyde 77 he MeO^X.CHO XY 0x l^o (E)-2-hydroxy-3-methoxy-5-(3 morpholinostyryl)benzaldehyde 78 M>§ About s ABOUT (E)-3-fluoro-2-hydroxy-5-(3 morpholinostyryl)benzaldehyde - 160 042453 79 HE MeO^X^CHO tt A (E)-2-hydroxy-3-methoxy-5 -(3 - (pyrrolidin-1 -yl)styryl)benzaldehyde 80 _G U M>s 0 s o (E) -3 -fluoro-2-hydroxy-5 - (3 - (pyrrolidin-1 -yl) styryl) benzaldehyde 81 He MeO^J^CHO TU 9 (E)-2-hydroxy-3-methoxy-5 -(4- (pyrrolidin-1 -yl)styryl)benzaldehyde 82 OH R±XHO tu R (E)-3-fluoro-2-hydroxy-5-(4- (pyrrolidin-1 -yl)styryl)benzaldehyde - 161 042453 83 HE _ R JxOHO a^V υυ (2)-3-fluoro-2-hydroxy-5-(4- (pyrrolidin-1 -yl)styryl)benzaldehyde 84 HE MeO.H.CHO Ον,^^ΧΧ XXX (2)-2-hydroxy-3-methoxy-5-(4- (pyrrolidin-1 -yl)styryl)benzaldehyde 85 CHO MeO^XzOH XY ρ O (E)-2-hydroxy-6-methoxy-4-(4- (pyrrolidin-1 -yl)styryl)benzaldehyde 86 CHO f.1 he XY p (E)-2-fluoro-6-hydroxy-4-(4- (pyrrolidin-1 -yl)styryl)benzaldehyde 87 / Oh w Η,ρ O X about (E)-2-hydroxy-3-methoxy-5-(4-(2- methoxyethoxy)styryl)benzaldehyde - 162 042453 88 Oh x oh O / (E)-3-fluoro-2-hydroxy-5-(4-(2- methoxyethoxy)styryl)benzaldehyde 89 He MeO^X^CHO xm Q Ό (E)-5-(4-(1H-pyrazol-1-yl)styryl)-2hydroxy-3-methoxybenzaldehyde 90 o X o (E)-5-(4-( 1 H-pyrazol-1 -yl)styryl)-3 fluoro-2-hydroxybenzaldehyde 91 one MeO^X,CHO XT Q ⁿ 0 (E)-2-hydroxy-3-methoxy-5-(2-(quinolin-6-yl)vinyl)benzaldehyde - 163 042453 92 ζ-θ-^ /=( o z O (E)-3-fluoro-2-hydroxy-5-(2-(quinolin-6yl)vinyl)benzaldehyde 93 OH MeO^X.CHO XT ψι Vos tert-butyl (E)-b-(3-formyl-4-hydroxy5-methoxystyryl)-3,4-dihydroquinoline 1 (2H)-carboxylate 94 00 o HW 0 \u003d ⁷ o X o tert-butyl (E) -6- (3-fluoro-5-formyl-4-hydroxystyryl) -3,4-dihydroquinoline-1 (2H) -carboxylate 95 o X o yoHul /=O G (E)-3-fluoro-2-hydroxy-5-(2-(1-methyl1,2,3,4-tetrahydroquinolin-6yl)vinyl)benzaldehyde - 164 042453 96 S φ -4χ o X about (E)-5-(4-(diethylamino)styryl)-2hydroxy-3-methoxybenzaldehyde 97 Z ^z SE o X o (E)-5-(4-(diethylamino)styryl)-3-fluoro-2hydroxybenzaldehyde 98 He ΜεΟ,Χ,ΟΗΟ THAT 9 (E)-5-(4-(cyclopropylmethoxy)styryl)- 2-hydroxy-3-methoxybenzaldehyde 99 ° - / = ( GU ^! X O (E) -5- (4- (cyclopropylmethoxy) styryl) - 3-fluoro-2-hydroxybenzaldehyde - 165 042453 100 3 φ IKA Su o t o (E)-5-(2-(chroman-6-yl)vinyl)-2- hydroxy-3-methoxybenzaldehyde 101 He F,1.CHO TU a (E)-5-(2-(chroman-6-yl)vinyl)-3-fluoro-2hydroxybenzaldehyde 102 He MeO.D.SNO TU 9 (E)-2-hydroxy-3-methoxy-5 -(4- (piperidin-1 -yl)styryl)benzaldehyde 103 SUSMuH. MD? O I o (E)-3-fluoro-2-hydroxy-5-(4-(piperidine- 1 -yl)styryl)benzaldehyde - 166 042453 104 S-Ochf o X (E)-2-fluoro-6-hydroxy-4-(4-(piperidine- 1 -yl)styryl)benzaldehyde 105 ^{4ζ -} 77 - / = ( chl - \ ° o x (E) -4- (4- (4-ethylpiperazin-1 -yl) styryl) 2-fluoro-6-hydroxybenzaldehyde 106 J V—Y ¹ / / ° ML (E) -3 - (5 - (5 - (cyclopropanecarbonyl) 4,5D7-tetrahydrothieno[3,2-c] pyridin2-yl) -2-hydroxy-3-methoxyphenyl) - 1 phenylprop-2-en-1-one 107 OH 0 (E) -1 - (5 - (5 - (cyclopropanecarbonyl) - LA /“'-ML MV 3 O S 4,5,6,7-Tetrahydrothieno[3,2-c]pyridin2-yl)-2-hydroxy-3-methoxyphenyl)-3-phenylprop-2-en-1-one - 167 042453 108 (E)-2-(1,3-d ioxan-2-yl)-6-fluoro-4-(4(pyrrolidin-1-yl)styryl)phenol 109 HE 9 2-fluoro-6-((E)-((4-methylpiperazin-1 yl)imino)methyl)-4-((E)-4-(pyrrolidin1-yl)styryl)phenol PO he _n ^f yV-v AL O 9 X'-((E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1yl)styryl)benzylidene)acetohydrazide 111 HE R 2-fluoro-6-((E)-(phenylimino)methyl)-4- ((E)-4-(pyrrolidin-1 -yl)styryl)phenol - 168042453 112 OH _n'M'O 9 2-φτορ-6-((Ε)-(2-phenylhydrazono)methyl)-4-((E)-4(pyrrolidin-1-yl)styryl)phenol FROM O )=° IZ 2 // /=\ d V/ ^Z J M'-((E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1yl)styryl)benzylidene) benzo-hydrazide 114 Chl 2 O _x )(0 b M'-((E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1yl)styryl)benzylidene)benzenesulfonohydrazide 115 He MM 9 (E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1-yl)styryl)benzaldehyde O-phenyloxime - 169 042453 116 OH _n ^f vVn^ ⁿ _¥ ^NH2 XA NH Αιΐ 2-((E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1-yl)styryl)benzylidene)hydrazine-1 carboximidamide T 117 IT XT XJ (E)-3-(3-cinnamoyl-4-hydroxy-5methoxyphenyl)-1-phenylprop-2-en-1-one o ABOUT 118 \,° Q Z // d ^X X 4-(((E)-3-fluoro-2-hydroxy-5- ⁽ (E)-4(pyrrolidin-1-yl)styryl)benzylidene)amino) -1 methylpiperazine 1-oxide 119 OH ^F \ A. y ⁰ (E) -3-fluoro-2-hydroxy-5- (2- (6 (pyrrolide in-1 -yl) pyride in-3 yl) vinyl) benzaldehyde A - 170042453 120 OH k ⁰ An t ^N^ (E) -3 -fluoro-2-hydroxy-5 - (2- (5 (pyrrolidin-1 -yl) pyridin-2yl) vinyl) benzaldehyde 121 ABOUT OH gChn ’A-h 9 about 1-(((E)-3-fluoro-2-hydroxy-5-((E)-4(pyrrolidin-1yl)styryl)benzylidene)amino)imidazolidine-2,4-dione 122 Oh oh AND (E)-3-fluoro-2-hydroxy-5-((E)-4- (pyrrolidin-1 -yl)styryl)benzaldehyde O-ethyloxime 123 he ίγΑ” ¹ 9 ^Ν^ (E)-2-fluoro-6-(hydroxymethyl)-4-(4(pyrrolidin-1-yl)styryl)phenol - 171 042453 124 OH * YrC O ⁿ Q (E) -2- ((cyclopropylamino) methyl) -6fluoro-4- (4- (pyrrolidin-1 yl) styryl) phenol 125 C ² ~Ol/Ch_ 2-k A _z yl)styryl)phenol 126 Member Q ) 2-((E)-((4-ethylpiperazin-1 yl)imino)methyl)-6-fluoro-4-((E)-4(pyrrolidin-1-yl)styryl)phenol 127 OH ^0 ^G LA ? 2-fluoro-6-((E)-(morpholinoimino)methyl)- 4-((E)-4-(pyrrolidin-1-yl)styryl)phenol - 172 042453 128 OH I ^x 9 o 1 -lL tert-butyl 4-(((E)-3-fluoro-2-hydroxy-5((E)-4-(pyrrolidin-1 - yl)styryl)benzylidene)amino)piperazine1 -carboxylate 129 HE ^ΝΗ 2-fluoro-6-((E)-(piperazine-1 - U. imino)methyl)-4-((E)-4-(pyrrolidin-1 yl)styryl)phenol hydrochloride 130 HE V /SNO (E)-2-hydroxy-5 -(4-(3 - hydroxypyrrolidin-1 -yl)styryl)-3 methoxybenzaldehyde 9 7 he - 173 042453 131 OH\1xno XT 9 9 He (E)-3-fluoro-2-hydroxy-5-(4-(3 hydroxypyrrolidin-1 yl)styryl)benzaldehyde 132 O (E)-2-hydroxy-5-(4-(2- (hydroxymethyl) pyrrolide in-1 - yl)styryl)-3-methoxybenzaldehyde 133 he FX,CHO TJ Q < ^N r ^s 4yl)styryl)benzaldehyde 134 OH FXCHO Y 9 i ^N r° N-NH (E)-3 -fluoro-2-hydroxy-5 - (4- (5 -oxo-1,5dihydro-4H-1,2,4-triazol-4yl) styryl)benzaldehyde - 174042453 135 OH / odsno HU Q Cr° (E)-2-hydroxy-3-methoxy-5-(4-(2oxopyrrolidin-1 yl)styryl)benzaldehyde 136 o chl X o E)-5-(4-(6,7-dihydropyrano[4,3c]pyrazol-1 (4H)-yl)styryl)-3-fluoro-2 hydroxybenzaldehyde 137 ON D/SNO HU 9 θΎ° Xnh (E)-3-fluoro-2-hydroxy-5-(4-(2oxotetrahydropyrimidin-1 (2H)yl)styryl)benzaldehyde 138 o ⁵ D>a;x (E)-5-(4-(2,2-dimethyltetrahydro-5H[1,3] dioxolo[4,5-c]pyrrol-5yl)styryl)-2-hydroxy -3 methoxybenzaldehyde 139 5, O HOOKIE s mule O X about (E)-5-(4-(3,4-dihydroxypyrrolidin-1 yl)styryl)-2-hydroxy-3 methoxybenzaldehyde 140 he ^o^X^cno XY 9 9 °Υ ^ΝΗ o (E)-2-hydroxy-3-methoxy-5-(4-(2oxohexahydro-5H-pyrrolo[3,4d]oxazol-5-yl)styryl )benzaldehyde - 175 042453 141 OH /O^X/NO HU 9 ύ (E)-2-hydroxy-3-methoxy-5-(4(tetrahydro-1H-furo[3,4-c]pyrrole5(3H)-yl)styryl)benzaldehyde 142 M \ =/° ο X ο (E)-5-(4-(2-oxa-7-azaspiro[4.4]nonan-7yl)styryl)-2-hydroxy-3-methoxybenzaldehyde 143 he/O^CHO XY φ 0 (E)-2-hydroxy-3-methoxy-5-(4-(8-oxo-2oxa-7-azaspiro[4.4]nonan-7yl)styryl)benzaldehyde 144 ο\ Ή ο X ο (E)-2-hydroxy-3-methoxy-5-(4-(3,4,4trimethyl-2,5-dioxoimid azolide in-1 yl)styryl)benzaldehyde 145 ο \ /° Ο1 ⁴⁼⁷ ^<4 ο X ο (E)-5-(4-(2,4-dioxo-1,3-d iazaspiro[4.4]nonan-3-yl)styryl)-2hydroxy -3-methoxybenzaldehyde 146 he arguably XY 9 Q ΗΝ^Υθ A ^nh 0 (E)-5-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)styryl)-2hydroxy -3-methoxybenzaldehyde - 176 042453 147 \ O I o (E)-4-(3-formyl-4-hydroxy-5 methoxystyryl)phenyl pyrrolidine-1 - carboxylate 148 0/¾ / ° L _Z - _O W o X o (E) -2-hydroxy-3 -methoxy-5 - (4-( 1 oxido-4,5 -dihydro-3H-116-isothiazol-1 yl) styryl)benzaldehyde 149 \ O /—< o y / A-l * ^w NC o X o (E) -4- (3-formyl-4-hydroxy-5 methoxystyryl) benzamide 150 OH ^o^Xhno TU about O^JNI-^ (E)-4-(3-formyl-4-hydroxy-5-methoxystyryl)-X-isopropylbenzamide - 177 042453 151 OH _x o.1.clearly 9 (E)-X-(4-(3-formyl-4-hydroxy-5-methoxystyryl)phenyl)isobutyramide 152 o I o (E)-5-(4-(1H-imidazol-1-yl)styryl)-2hydroxy-3-methoxybenzaldehyde 153 = about I O (E)-5-(4-(1H-1,2,4-triazol-1-yl)styryl)- 2-hydroxy-3-methoxybenzaldehyde 154 he/x1.cno y ά (E)-2-hydroxy-3-methoxy-5-(4-(oxazole- 4-yl)styryl)benzaldehyde - 178042453 155 OH ^o^Lxho XT I N 7 C-s (E)-2-hydroxy-3-methoxy-5-(4-(thiazol-4yl)styryl)benzaldehyde 156 Oh ^O^/LxHO XT 0 (E)-2-hydroxy-3-methoxy-5-(4-((4methylpiperazin-1 yl)methyl)styryl)benzaldehyde 157 iXWo o z o (E)-3-fluoro-2-hydroxy-5-(4-(1-methyl-1Hpyrazol-4-yl)styryl)benzaldehyde 158 OH F.X.CHO XT I Cr \ (E)-3-fluoro-2-hydroxy-5-(4-(1-methyl-1Hpyrazol-3-yl)styryl)benzaldehyde 159 o Z O ^s ~0'X_/ ⁼ W'? (E)-5-(4-(2H-tetrazol-5-yl)styryl)-3fluoro-2-hydroxybenzaldehyde 160 o z o °(Wv ethyl (E) - (4- (3-fluoro-5-formyl-4- hydroxystyryl)phenyl)carbamate - 179 042453 161 o X o (E)-1-(4-(3-fluoro-5-formyl-4hydroxystyryl)phenyl)-3 isopropylurea 162 HE (E)^-cyclopropyl-4-(3-fluoro-5-formyl- εX,οηο THAT 4-hydroxystyryl)benzenesulfonamide ω—(/h—O O '—' 163 He (E)-X-(4-(3-fluoro-5-formyl-4-cHcHO XY hydroxystyryl)phenyl)methanesulfonamide o gt 164 OH FUCK HU (E) -3 -fluoro-2-hydroxy-5 - (4- (( 1 - methylpiperidine-4- yl)sulfonyl)styryl)benzaldehyde o χν% or its tautomer, or a pharmaceutically acceptable salt of any of the above. 43. A pharmaceutical composition containing at least one compound according to any one of claims 1 to 42, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above. 44. A pharmaceutical composition according to claim 43, further comprising a pharmaceutically acceptable excipient. 45. A method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 42, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above. . 46. The method of claim 45, wherein the disease or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy , amyotrophic lateral sclerosis, Huntington's disease, progressive supranuclear palsy (PNP), Niemann-Pick type C disease, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, irritable bowel syndrome, tuberculosis, rheumatoid arthritis, osteoarthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy ), stroke, coronary heart disease, atopic dermis atitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, corneal trauma, corneal disorders, corneal HSV, Stargardt's disease (juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus and fungal, bacterial, viral and neoplastic diseases or conditions. - 180 042453 47. A method of interfering with TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound according to any one of claims 1 to 42, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the above and/or at least with one pharmaceutical composition according to claim 43, wherein the contacting takes place in vitro, ex vivo or in vivo. 48. The method of π.47, wherein interfering with TLR2 heterodimerization in the cell comprises modulating, preventing, slowing down, reversing or inhibiting TLR2 heterodimerization in the cell. About the Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 181 -