Substituted bicyclic heteroaryl compounds

Abstract

Disclosed are compounds of formula (I), N-oxides or salts thereof, wherein X, Y, A, G, R1 and R5 are defined herein. Also disclosed are methods of using such compounds as inhibitors of signal transduction via Toll-like receptors 7, 8 or 9, and pharmaceutical compositions comprising such compounds. These compounds can be used to treat inflammatory and autoimmune diseases.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 908,840, filed October 1, 2019, which is incorporated herein in its entirety. Background Technology

[0003] This invention generally relates to substituted bicyclic heteroaryl compounds that can be used as inhibitors of signal transduction via Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Substituted bicyclic heteroaryl compounds, compositions comprising such compounds, and methods of using them are provided herein. The invention further relates to pharmaceutical compositions containing at least one compound according to the invention, which can be used to treat conditions related to TLR regulation, such as inflammatory and autoimmune diseases; and methods for inhibiting TLR activity in mammals.

[0004] Members of the Toll / IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor family recognizes molecular patterns derived from infectious organisms, including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to the receptor induces dimerization of the adaptor molecule and recruitment to a conserved cytoplasmic motif called the Toll / IL-1 receptor (TIR) ​​domain within the receptor. Except for TLR3, all TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, JE et al., Nature Rev. Immunol., 10:89-102 (2010)).

[0005] Toll-like receptors (TLRs) are an evolutionarily conserved family of transmembrane innate immune receptors involved in the first line of defense. As pattern recognition receptors, TLRs protect against foreign molecules, activated via pathogen-associated molecular patterns (PAMPs); or protect against tissue damage, activated via damage-associated molecular patterns (DAMPs). A total of 13 TLR family members have been identified, 10 of which are found in humans; these family members span either the cell surface or endosome compartments. TLR7 / 8 / 9 belong to a set of endosome-localized, responsive single-stranded RNAs (TLR7 and TLR8) or unmethylated single-stranded DNAs containing a cytosine-phosphate-guanine (CpG) motif (TLR9).

[0006] Activation of TLR7 / 8 / 9 can trigger various inflammatory responses (cytokine production, B cell activation and IgG production, type I interferon response). In autoimmune disorders, persistent abnormal activation of TLR7 / 8 / 9 exacerbates the disease state. Although overexpression of TLR7 in mice has been shown to exacerbate autoimmune diseases, knockout of TLR7 in mice was found to protect against disease in lupus-prone MRL / lpr mice. Dual knockout of TLR7 and TLR9 showed further enhanced protection.

[0007] Since many conditions can benefit from treatments involving the regulation of cytokines, IFN production, and B cell activity, it is immediately apparent that novel compounds capable of regulating TLR7 and / or TLR8 and / or TLR9, and methods of using these compounds, could provide substantial therapeutic benefits to a wide variety of patients. Summary of the Invention

[0008] This invention relates to a new class of substituted bicyclic heteroaryl compounds, which have been found to be effective inhibitors of TLR7 / 8 / 9 signaling. These compounds are intended for use as pharmaceuticals with desired stability, bioavailability, therapeutic index, and toxicity values ​​important for their druggability.

[0009] The present invention provides compounds of formula (I), or stereoisomers thereof, N-oxides, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, which can be used as inhibitors of signal transduction via Toll-like receptors 7, 8 or 9 and can be used to treat proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases.

[0010] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs.

[0011] The present invention also provides a method for inhibiting Toll-like receptors 7, 8, or 9, the method comprising administering to a host requiring such treatment a therapeutically effective amount of at least one of the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs.

[0012] The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune, and inflammatory diseases, the method comprising administering to a host requiring such treatment a therapeutically effective amount of at least one of the following: a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug.

[0013] The present invention also provides a method for treating diseases or disorders associated with Toll-like receptor 7, 8 or 9 activity, the method comprising administering to a mammal in need at least one of a compound of formula (I) or a salt thereof, a solvate or a prodrug.

[0014] The present invention also provides methods and intermediates for preparing compounds of formula (I), including their salts, solvates and prodrugs.

[0015] The present invention also provides at least one of a compound of formula (I) or a salt thereof, a solvate thereof, and a prodrug for use in a therapy.

[0016] The present invention also provides the use of at least one of the compounds of formula (I) or salts thereof, solvates and prodrugs thereof for the manufacture of medicaments for the treatment or prevention of conditions related to Toll-like receptors 7, 8 or 9 (such as allergic diseases, autoimmune diseases, inflammatory diseases and proliferative diseases).

[0017] Compounds of formula (I) and compositions comprising compounds of formula (I) can be used to treat, prevent, or cure various Toll-like receptor 7, 8, or 9-related conditions. Pharmaceutical compositions comprising these compounds can be used to treat, prevent, or slow the progression of diseases or disorders in multiple therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.

[0018] As this disclosure continues, these and other features of the invention will be set forth in an expanded form. Detailed Implementation

[0019] The first aspect of the present invention provides at least one compound of formula (I):

[0020]

[0021] Its N-oxide or salt, wherein:

[0022] X is N and Y is S; or X is S and Y is N or CH;

[0023] R1 is H, F, Cl, -CN, C 1-4 Alkyl, C 1-3 Fluoroalkyl, -OCH3 or -S(O)2(C 1-3 alkyl);

[0024] G is:

[0025] (i)

[0026] (ii)

[0027] (iii)

[0028] (iv) Selected from the following 9-membered heterocycles:

[0029]

[0030]

[0031]

[0032] or

[0033] (v) Selected from the following 10-membered heterocycles:

[0034]

[0035] Each R2 group is independently a halogen, -CN, -OH, -NO2, or C group. 1-4 Alkyl, C 1-2 fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 Alkyl), C 1-3 Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 Alkyl group), -O(CH2) 1-2 OC(O)(C 1-3 Alkyl group), -O(CH2) 1-2 NR x R x -C(O)O(C 1-3 Alkyl group), -(CH2) 0-2 C(O)NR y R y -C(O)NR x (C 1-5 hydroxyalkyl), -C(O)NR x (C 2-6 alkoxyalkyl), -C(O)NR x (C 3-6 cycloalkyl), -NR y R y -NR y (C 1-3 fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR xS(O)2(C 3-6 cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x CH2(C 3-6 cycloalkyl), -(CH2) 0-2 S(O)2(C 1-3 Alkyl group), -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholino, dioxothiomorpholino, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, pyrimidinyl, triazolyl or -C(O)(thiazolyl);

[0036] R 2a It is C 1-6 Alkyl, C 1-3 fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR y R y -CH2(C 3-6 Cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;

[0037] Each R 2b Independently, it is H, halogen, -CN, -NR x R x C 1-6 Alkyl, C 1-3 fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 Alkyl group), -(CH2) 0-3 C(O)NR x R x -(CH2) 1-3 (C 3-6 cycloalkyl), -C(O)O(C 1-3 Alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CR x R x or -CR x =CH(C 3-6 cycloalkyl);

[0038] R 2c It is R 2a or R 2b ;

[0039] R 2d It is R 2a or R 2b The condition is R. 2c and R 2d One of them is R 2a And R 2c The other one in R2 is R 2b ;

[0040] A is:

[0041] (i)H、-NR y R y or -CH2NHCH2C(O)NR x R x ;

[0042] (ii)-CR x R x R3, -CR x R x NR x R3, -CR x R x NR x CH2R3、-C(O)NR x R3、-C(O)NR x R4、-C(O)R 3 or -NR x C(O)R 3 ;or

[0043] (iii)R3;

[0044] R3 is:

[0045] (i)C 3-5 Cycloalkyl, aziridine, oxaziridine, pyrrolidine, pyrrolidone, piperidinyl, piperazinyl, piperazinone, morpholinyl, thiomorpholinyl, oxazaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, thioazaspiro[3.3]heptyl, or oxazaspiro[3.5]nonyl, each marked with 0 to 2 R 3a and 0 to 2 R 3b replace;

[0046] (ii) Cyclohexyl groups substituted with the following: -NR y R y -NR x (C 1-6 hydroxyalkyl), -NRx (CR x R x ) 1-2 O(C 1-3 alkyl), -NR x (C 1-6 hydroxy-fluoroalkyl), -NR x CH2C(O)NR x R x -NR x (CH2) 1-2 S(O)2(C 1-3 alkyl), -NR x C(O)(C 1-3 alkyl), -NR x C(O)CH2NR x R x -NR x C(O)CH2NR x R y -NR x (CH2) 1-2 C(O)NR x R x -NR x (CH2) 1-2 NR x R x -NR x S(O)2(C 1-3 Alkyl), -S(O)2(C 1-3 alkyl), -NR x (cyanocyclopropyl), -NR x (azacyclobutane), -NR x (oxetane), -NR x (methyloxetane), -NR x (ethyloxetane), -NR x (isopropyloxetane), -NR x (tetrahydropyranyl), -NR x (bicyclo[1.1.1]pentyl), -NR x (CH2(methyloxetane)), -NR x (tetrahydrophenylthio) -NR x CH2 (hydroxymethylcyclopropyl), -NR x CH2 (methylsulfonylcyclopropyl), -NR x CH2 (methylcyclobutyl), -NR xHCH2C(O) (morpholinyl), aziridine, fluoroaziridine, hydroxyaziridine, methoxyaziridine, hydroxy(trifluoromethyl)aziridine, bis(hydroxymethyl)aziridine, pyrrolidine, piperazinone, morpholinyl, dioxothiomorpholinyl, oxazaspiroheptanyl, bicyclo[1.1.1]pentyl, azirspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, sulfazaspiro[3.3]heptyl, oxazabicyclo[3.2.1]octyl, oxazaspiro[3.5]nonyl or diazaspiro[4.4]nonyl; or

[0047] (iii) The following substituted diazaspiro[3.3]heptyl group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) 1-3 S(O)2(C 1-6 Alkyl), oxetane butyl, or -CH2 (tetrahydropyranyl);

[0048] Each R 3a Independently, they are F, Cl, and C. 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 fluoroalkyl, C 1-6 Hydroxyalkyl, -(CH2) 1- 3O(C 1-3 Alkyl), -C(O)(C 1-6 Alkyl group), -CH2C(O)NR y R y -NR y R y -NR x (C 1-4 Hydroxyalkyl), -C(O)(CH2) 1- 3NR y R y -C(O)(C 1-6 Alkyl group), -(CH2) 0-2 S(O)2(C 1-3 Alkyl group), -(CH2) 1-2 NR x S(O)2(C 1-3 alkyl), -NR x CH2C(O)NR y R y -NR x (CH2) 1-3 S(O)2(C 1-3 alkyl), -NR x (C 3-6 cycloalkyl), -NR x(oxetanebutyl), -CH2(methyltriazolyl), C 3-6 Cycloalkyl, oxetyl, oxetyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, -CH2(C 3-6 cycloalkyl), -CH2 (oxetane), -CH2 (methyloxetane), -CH2 (tetrahydropyranyl), -NR x (C 3-6 cycloalkyl), -NR x (oxetane), -NR x (methyloxetane), -NR x CH2 (methyloxetane butyl) or -C(O) (tetrahydrothiopyranyl);

[0049] Each R 3b It is -CH3;

[0050] R4 is H, C 1-2 fluoroalkyl, -(CR) x R x ) 1-2 NR y R y or -(CR) x R x ) 1-3 R3;

[0051] R5 is H, C 1-3 Alkyl or C 1-3 fluoroalkyl;

[0052] Each R x It is either H or -CH3 independently;

[0053] Each R y Independently, it is H or C 1-6 Alkyl; and

[0054] p is 0, 1, or 2.

[0055] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein X is N and Y is S. The compound of this embodiment has the structure of formula (II):

[0056]

[0057] One embodiment provides a compound of formula (I), its N-oxide, or salt, wherein X is S and Y is N. The compound of this embodiment has the structure of formula (III):

[0058]

[0059] One embodiment provides a compound of formula (I), its N-oxide, or salt, wherein X is S and Y is CH. The compound of this embodiment has the structure of formula (IV):

[0060]

[0061] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein:

[0062] R1 is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3, or -S(O)2(C 1-2 alkyl);

[0063] G is:

[0064] (i)

[0065] (ii)

[0066] (iii)

[0067] (iv) Selected from the following 9-membered heterocycles:

[0068]

[0069]

[0070] or

[0071] (v) Selected from the following 10-membered heterocycles:

[0072]

[0073] Each R2 is independently F, Cl, -CN, -OH, C 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-2 Aminoalkyl, -(CH2) 0-2 O(C 1-3 Alkyl), C 3-6 cycloalkyl, -NR x R x -(CH2) 0-2 C(O)NR x R x -(CH2) 0-2 S(O)2(C 1-3 alkyl), -CH2(C3-6 Cycloalkyl), -CH2(phenyl), phenyl, pyrimidinyl or triazolyl;

[0074] R 2a It is C 1-4 Alkyl, C 1-2 fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 Cycloalkyl, -CH2C(O)NR x R x -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl or phenyl;

[0075] Each R 2b Independently, they are H, F, Cl, -CN, -NR x R x C 1-6 Alkyl, C 1-2 fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 0- 2O(C 1-2 Alkyl group), -(CH2) 0-2 C(O)NR x R x -(CH2) 1-3 (Cyclopropyl), -C(O)O(C) 1-2 alkyl) or -C(O)NR x (C 1-3 alkyl);

[0076] A is:

[0077] (i)-CH2NHCH2C(O)NR x R x ;

[0078] (ii)-CR x R x R3、-CH2NR x R3、-CH2NR x CH2R3、-C(O)NR x R3、-C(O)NR x R4、-C(O)R 3 or -NR x C(O)R 3 ;or

[0079] (iii)R3; and

[0080] R3 is:

[0081] (i) aziridine, oxaziridine, cyclopropyl, pyrrolidine, pyrrolidone, piperidinyl, piperazinyl, piperazinone, morpholinyl, thiomorpholinyl, oxaziridine, diazaspiro[3.3]heptyl, thioazaspiro[3.3]heptyl, oxaziridine[3.3]heptyl or oxaziridine[3.5]nonyl, each marked with 0 to 1 R 3a and 0 to 2 R 3b replace;

[0082] (ii) Cyclohexyl groups substituted with the following: -NR y R y -NR x (C 1-4 hydroxyalkyl), -NR x (CR x R x ) 1-2 O(C 1-2 alkyl), -NR x (C 1-6 hydroxy-fluoroalkyl), -NR x CH2C(O)NR x R x -NR x (CH2) 1-2 S(O)2(C 1-2 alkyl), -NR x C(O)(C 1-2 alkyl), -NR x C(O)CH2NR x R x -NR x C(O)CH2NR x R y -NR x (CH2) 1-2 C(O)NR x R x -NR x (CH2) 1-2 NR x R x -NR x S(O)2(C 1-2 Alkyl), -S(O)2(C 1-2 alkyl), -NR x (cyanocyclopropyl), -NR x (azacyclobutane), -NR x (oxetane), -NR x (methyloxetane), -NR x (ethyloxetane), -NR x(isopropyloxetane), -NR x (tetrahydropyranyl), -NR x (bicyclo[1.1.1]pentyl), -NR x (CH2(methyloxetane)), -NR x (tetrahydrophenylthio) -NR x CH2 (hydroxymethylcyclopropyl), -NR x CH2 (methylsulfonylcyclopropyl), -NR x CH2 (methylcyclobutyl), -NR x HCH2C(O) (morpholinyl), aziridine, fluoroaziridine, hydroxyaziridine, methoxyaziridine, hydroxy(trifluoromethyl)aziridine, bis(hydroxymethyl)aziridine, pyrrolidine, piperazinone, morpholinyl, dioxothiomorpholinyl, oxazaspiroheptanyl, bicyclo[1.1.1]pentyl, azirspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, sulfazaspiro[3.3]heptyl, oxazabicyclo[3.2.1]octyl, oxazaspiro[3.5]nonyl or diazaspiro[4.4]nonyl; or

[0083] (iii) The following substituted diazaspiro[3.3]heptyl group: C 1-4 Alkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-2 S(O)2(C 1-3 Alkyl), oxetane butyl, or -CH2 (tetrahydropyranyl);

[0084] Each R 3a Independently, they are F, Cl, and C. 1-5 Alkyl, C 1-3 Cyanoalkyl, C 1-3 fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1- 2O(C 1-2 Alkyl), -C(O)(C 1-3 Alkyl group), -CH2C(O)NR x R x -NR y R y -NH(C 1-4 Hydroxyalkyl), -C(O)(CH2) 1- 3NR x R x -C(O)(C 1-3 Alkyl group), -(CH2) 0-2 S(O)2(C 1-2 Alkyl group), -(CH2)1-2 NR x S(O)2(C 1-2 alkyl), -NR x CH2C(O)NR y R y -NR x CH2CH2S(O)2(C 1-2 alkyl), -NR x (C 3-6 cycloalkyl), -NR x (oxetane), -CH2(methyltriazolyl), cyclobutyl, oxetane, pyrrolyl, morpholinyl, tetrahydropyranyl, -CH2(C 3-4 cycloalkyl), -CH2 (oxetane), -CH2 (methyloxetane), -CH2 (tetrahydropyranyl), -NR x (cyclobutyl), -NR x (oxetane), -NR x (methyloxetane), -NR x CH2 (methyloxetane butyl) or -C(O) (tetrahydrothiopyranyl);

[0085] Each R 3b It is -CH3; and

[0086] R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2, or -CH2CF3.

[0087] This embodiment includes a compound in which X is N and Y is S. This embodiment also includes a compound in which X is S and Y is N. Additionally, this embodiment includes a compound in which X is S and Y is CH.

[0088] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein:

[0089] R1 is independently -CH3, -CH2CH3, or -CH(CH3)2;

[0090] G is:

[0091] Each R2 is independently -CN, -CH3, or -OCH3;

[0092] A is:

[0093] (i)-CH2NHCH2C(O)NH2;

[0094] (ii)-CH2R3, -CH2NHR3, -CH2NHCH2R3, -C(O)NHR3, -C(O)NR x R4 or -C(O)R3; or

[0095] (iii) Cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl or diazaspiro[3.3]heptyl, each radicalized by 0 to 1 R 3a replace;

[0096] R3 is aziridine, oxaziridine, cyclopropyl, cyclobutyl, pyrrolidine, pyrrolidone, piperidinyl, piperazinyl, piperazinone, morpholinyl, thiomorpholinyl, oxaziridine, diazaspiro[3.3]heptyl, thioazaspiro[3.3]heptyl, oxaziridine[3.3]heptyl, or oxaziridine[3.5]nonyl, each marked with 0 to 1 R 3a and 0 to 2 R 3b replace;

[0097] R 3a is F-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CF3, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x, -OCH3, -C(O)CH3, -C(O)CH2N(CH3)2, -NH2, -NH(CH3), -NH(CH(CH3)2), -NH(CH2C(CH3)3), -NH(CH2C(CH3)2OH), -NH(CH2CHFC(CH3) 2OH), -NH(CH2C(CH3)2OCH3), -N(CH3)(CH2CH3), -N(CH3)(CH(CH3)2), -N(CH3)CH2CH(CH3)2, -N(CH3)CH2C(O)N(CH3)2, -N(CH3)CH2 CH2S(O)2CH3, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2NH(CH2CH(CH3)2), -NHCH2C(O)NH2, -NHCH2C(O)NH(CH3), -NHCH2C(O)N(CH3)2, -NHCH2CH2NH(CH3), -NHS(O)2CH3, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetyl), -CH2(tetrahydropyranyl), -C(O)(tetrahydrothiocyanate) pyranyl), -NH (cyanocyclopropyl), -NH (cyclobutyl), -NH (methylcyclobutyl), -NH (oxetane), -NH (methyloxetane), -NH (ethyloxetane), -NH (isopropylpiperidinyl), -NH (tetrahydropyranyl), -NH (bicyclo[1.1.1]pentyl), -NHCH2 (methyloxetane), -NH (tetrahydrophenylthio), -NHCH2 (hydroxymethylcyclopropyl), -NHCH2 (methylsulfonylcyclopropyl), -NHCH2 (methylcyclobutyl), -NHCH2C(O) (morpholinyl), cyclobutyl, azacyclobutyl , fluoroazacyclobutane, difluoroazacyclobutane, hydroxyazacyclobutane, methoxyazacyclobutane, hydroxy(trifluoromethyl)azacyclobutane, bis(hydroxymethyl)azacyclobutane, oxazacyclobutane, pyrrolyl, acetamylpyrrolyl, piperazine ketone, tetrahydropyranyl, morpholinyl, dioxothiomorpholinyl, oxazacycloheptyl, bicyclo[1.1.1]pentyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, sulfurazaspiro[3.3]heptyl, oxazabicyclo[3.2.1]octyl, oxazaspiro[3.5]nonyl or diazaspiro[4.4]nonyl;

[0098] Each R 3b It is -CH3;

[0099] R4 is H, -CH2CHF2, -CH2CF3, -CH2CH2N(CH3)2, -CH2R3, -CH2CR x R x R3 is either -(CH2)3R3; R5 is H or -CH2CF3; and

[0100] p is 0, 1, or 2.

[0101] This embodiment includes a compound in which X is N and Y is S. This embodiment also includes a compound in which X is S and Y is N. Additionally, this embodiment includes a compound in which X is S and Y is CH.

[0102] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a Substituted cyclohexyl group. The compound of this embodiment has the following structure:

[0103]

[0104] This embodiment includes a compound in which X is N and Y is S. This embodiment also includes a compound in which X is S and Y is N. Additionally, this embodiment includes a compound in which X is S and Y is CH.

[0105] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a Substituted cyclohexyl group. The compound of this embodiment has the following structure:

[0106]

[0107] This implementation includes a compound in which G is:

[0108] This embodiment also includes compounds in which R 3a is F-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CF3, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x, -OCH3, -C(O)CH3, -C(O)CH2N(CH3)2, -NH2, -NH(CH3), -NH(CH(CH3)2), -NH(CH2C(CH3)3), -NH(CH2C(CH3)2OH), -NH(CH2CHFC(CH3) 2OH), -NH(CH2C(CH3)2OCH3), -N(CH3)(CH2CH3), -N(CH3)(CH(CH3)2), -N(CH3)CH2CH(CH3)2, -N(CH3)CH2C(O)N(CH3)2, -N(CH3)CH2 CH2S(O)2CH3, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2NH(CH2CH(CH3)2), -NHCH2C(O)NH2, -NHCH2C(O)NH(CH3), -NHCH2C(O)N(CH3)2, -NHCH2CH2NH(CH3), -NHS(O)2CH3, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetyl), -CH2(tetrahydropyranyl), -C(O)(tetrahydrothiocyanate) pyranyl), -NH (cyanocyclopropyl), -NH (cyclobutyl), -NH (methylcyclobutyl), -NH (oxetane), -NH (methyloxetane), -NH (ethyloxetane), -NH (isopropylpiperidinyl), -NH (tetrahydropyranyl), -NH (bicyclo[1.1.1]pentyl), -NHCH2 (methyloxetane), -NH (tetrahydrophenylthio), -NHCH2 (hydroxymethylcyclopropyl), -NHCH2 (methylsulfonylcyclopropyl), -NHCH2 (methylcyclobutyl), -NHCH2C(O) (morpholinyl), cyclobutyl, azacyclobutyl , fluoroazines, difluoroazines, hydroxyazines, methoxyazines, hydroxy(trifluoromethyl)azines, bis(hydroxymethyl)azines, oxazines, pyrrolyl, acetamylpyrrolyl, piperazine ketone, tetrahydropyranyl, morpholinyl, dioxothiomorpholinyl, oxazines, bicyclic[1.1.1]pentyl, azines[3.3]heptyl, oxazines[3.3]heptyl, sulfur dioxide azines[3.3]heptyl, oxazines[3.2.1]octyl, oxazines[3.5]nonyl or diazines[4.4]nonyl.

[0109] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a A substituted 1-piperidinyl group. The compound of this embodiment has the following structure:

[0110]

[0111] This embodiment includes a compound in which X is N and Y is S. This embodiment also includes a compound in which X is S and Y is N. Additionally, this embodiment includes a compound in which X is S and Y is CH.

[0112] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a A substituted 1-piperidinyl group. The compound of this embodiment has the following structure:

[0113]

[0114] This implementation includes a compound in which G is: This embodiment also includes compounds in which R 3a is F-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CF3, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x, -OCH3, -C(O)CH3, -C(O)CH2N(CH3)2, -NH2, -NH(CH3), -NH(CH(CH3)2), -NH(CH2C(CH3)3), -NH(CH2C(CH3)2OH), -NH(CH2CHFC(CH3) 2OH), -NH(CH2C(CH3)2OCH3), -N(CH3)(CH2CH3), -N(CH3)(CH(CH3)2), -N(CH3)CH2CH(CH3)2, -N(CH3)CH2C(O)N(CH3)2, -N(CH3)CH2 CH2S(O)2CH3, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2NH(CH2CH(CH3)2), -NHCH2C(O)NH2, -NHCH2C(O)NH(CH3), -NHCH2C(O)N(CH3)2, -NHCH2CH2NH(CH3), -NHS(O)2CH3, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetyl), -CH2(tetrahydropyranyl), -C(O)(tetrahydrothiocyanate) pyranyl), -NH (cyanocyclopropyl), -NH (cyclobutyl), -NH (methylcyclobutyl), -NH (oxetane), -NH (methyloxetane), -NH (ethyloxetane), -NH (isopropylpiperidinyl), -NH (tetrahydropyranyl), -NH (bicyclo[1.1.1]pentyl), -NHCH2 (methyloxetane), -NH (tetrahydrophenylthio), -NHCH2 (hydroxymethylcyclopropyl), -NHCH2 (methylsulfonylcyclopropyl), -NHCH2 (methylcyclobutyl), -NHCH2C(O) (morpholinyl), cyclobutyl, azacyclobutyl , fluoroazines, difluoroazines, hydroxyazines, methoxyazines, hydroxy(trifluoromethyl)azines, bis(hydroxymethyl)azines, oxazines, pyrrolyl, acetamylpyrrolyl, piperazine ketone, tetrahydropyranyl, morpholinyl, dioxothiomorpholinyl, oxazines, bicyclic[1.1.1]pentyl, azines[3.3]heptyl, oxazines[3.3]heptyl, sulfur dioxide azines[3.3]heptyl, oxazines[3.2.1]octyl, oxazines[3.5]nonyl or diazines[4.4]nonyl.

[0115] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a Substituted 4-piperidinyl. The compound of this embodiment has the following structure:

[0116]

[0117] This embodiment includes a compound in which X is N and Y is S. This embodiment also includes a compound in which X is S and Y is N. Additionally, this embodiment includes a compound in which X is S and Y is CH.

[0118] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a Substituted 4-piperidinyl. The compound of this embodiment has the following structure:

[0119]

[0120] This implementation includes a compound in which G is:

[0121]

[0122] This embodiment includes a compound in which R 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CF3, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x -C(O)CH3, -C(O)CH2N(CH3)2, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetane), -CH2(tetrahydropyranyl), -C(O)(tetrahydrothiopyranyl), cyclobutyl, aziridine, fluoroaziridine, difluoroaziridine, hydroxyaziridine, methoxyaziridine, hydroxy(trifluoromethyl)aziridine, bis(hydroxymethyl)aziridine, oxetane, pyrroleyl, acetamylpyrroleyl, tetrahydropyranyl, oxetaneheptyl or bicyclic [1.1.1]pentyl.

[0123] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a and 0 to 2 R 3b The substituted piperazine group. The compound of this embodiment has the following structure:

[0124]

[0125] This embodiment includes a compound in which X is N and Y is S. This embodiment also includes a compound in which X is S and Y is N. Additionally, this embodiment includes a compound in which X is S and Y is CH.

[0126] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a and 0 to 2 R 3b The substituted piperazine group. The compound of this embodiment has the following structure:

[0127]

[0128] This implementation includes a compound in which G is: This embodiment also includes compounds in which R 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CF3, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x -C(O)CH3, -C(O)CH2N(CH3)2, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetane), -CH2(tetrahydropyranyl), -C(O)(tetrahydrothiopyranyl), cyclobutyl, aziridine, fluoroaziridine, difluoroaziridine, hydroxyaziridine, methoxyaziridine, hydroxy(trifluoromethyl)aziridine, bis(hydroxymethyl)aziridine, oxetane, pyrroleyl, acetamylpyrroleyl, tetrahydropyranyl, oxetaneheptyl or bicyclic [1.1.1]pentyl.

[0129] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is reacted with 0 to 1 R 3a Substituted diazaspiro[3.3]heptyl. The compound of this embodiment has the following structure:

[0130]

[0131] This implementation includes a compound in which G is:

[0132] This embodiment also includes compounds in which R 3ais -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CF3, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x -C(O)CH3, -C(O)CH2N(CH3)2, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetane), -CH2(tetrahydropyranyl), -C(O)(tetrahydrothiopyranyl), cyclobutyl, aziridine, fluoroaziridine, difluoroaziridine, hydroxyaziridine, methoxyaziridine, hydroxy(trifluoromethyl)aziridine, bis(hydroxymethyl)aziridine, oxetane, pyrroleyl, acetamylpyrroleyl, tetrahydropyranyl, oxetaneheptyl or bicyclic [1.1.1]pentyl.

[0133] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is H, -NR y R y or -CH2NHCH2C(O)NR x R x This embodiment includes a compound in which A is H. This embodiment also includes a compound in which A is -NR. y R y Furthermore, this embodiment includes a compound wherein A is -CH2NHCH2C(O)NR. x R x .

[0134] One embodiment provides a compound of formula (I), its N-oxide, or salt, wherein A is -CH2R3, -CH2NHR3, or -CH2NHCH2R3. This embodiment includes compounds wherein G is: This embodiment also includes compounds in which R3 is isopropylpiperidinyl, sulfazaspiro[3.3]heptyl, oxazaspiro[3.5]nonyl, methanesulfonylcyclopropyl, piperazinoneyl, morpholinyl, oxazaspiro[3.3]heptyl or diazaspiro[3.3]heptyl.

[0135] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is -C(O)NHR3 or -C(O)NR x R4. This embodiment includes a compound in which G is: This embodiment also includes compounds in which R3 is dimethylaminocyclohexyl, pyrrolyl, pyrrolidone, morpholinyl, methylpiperidinyl, morpholinyl, or methanesulfonylcyclopropyl; and R4 is H, -CH2CHF2, -CH2CF3, -CH2CH2N(CH3)2, -CH2R3, or -CH2CR. x R x R3 or -(CH2)3R3.

[0136] One embodiment provides a compound of formula (I), its N-oxide, or salt, wherein A is -C(O)R3. This embodiment includes compounds wherein G is: This embodiment also includes compounds in which R3 is aziridine, fluoroaziridine, dimethylaminoaziridine, thiomorpholino, morpholino, oxaziridine heptyl, oxaziridine, piperazine ketone, acetylpiperazinyl, isopropylpiperazinyl, methylsulfonylpiperazinyl, dimethylaminopiperidinyl, or pyrrolidinyl.

[0137] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein A is cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl or diazaspiro[3.3]heptyl, each radicalized by 0 to 1 R 3a replace.

[0138] One embodiment provides a compound of formula (I), its N-oxide, or a salt, wherein:

[0139] G is:

[0140] (i)

[0141] (ii)

[0142] (iii)

[0143] (iv) Selected from the following 9-membered heterocycles:

[0144]

[0145]

[0146] or

[0147] (v) Selected from the following 10-membered heterocycles:

[0148] This implementation includes a compound in which G is: This implementation also includes compounds in which G is

[0149] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein each R2 is independently F, Cl, -CN, -OH, C 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-2 Aminoalkyl, -(CH2) 0-2 O(C 1-3 Alkyl), C 3-6 cycloalkyl, -NR x R x -(CH2) 0-2 C(O)NR x R x -(CH2) 0-2 S(O)2(C 1-3 alkyl), -CH2(C 3-6 Cycloalkyl), -CH2(phenyl), phenyl, pyrimidinyl, or triazolyl. This embodiment includes compounds in which each R2 is independently -CN, -CH3, or -OCH3.

[0150] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2 or -CH2CF3. This embodiment includes compounds in which R5 is H or -CH2CF3.

[0151] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein R1 is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3 or -S(O)2(C 1-2 Alkyl group). This embodiment includes compounds in which R1 is independently -CH3, -CH2CH3, or -CH(CH3)2. This embodiment also includes compounds in which R1 is -CH(CH3)2.

[0152] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein R1 is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3 or -S(O)2(C 1-2 Alkyl); each R2 is independently F, Cl, -CN, -OH, C 1-3 Alkyl, C 1-2 fluoroalkyl, C1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-2 Aminoalkyl, -(CH2) 0-2 O(C 1-3 Alkyl), C 3-6 cycloalkyl, -NR x R x -(CH2) 0-2 C(O)NR x R x -(CH2) 0-2 S(O)2(C 1-3 alkyl), -CH2(C 3-6 (cycloalkyl), -CH2(phenyl), phenyl, pyrimidinyl or triazolyl; and R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2 or -CH2CF3.

[0153] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein R1 is independently -CH3, -CH2CH3 or -CH(CH3)2; each R2 is independently -CN, -CH3 or -OCH3; R5 is H or -CH2CF3; and p is 0, 1 or 2.

[0154] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein said compound is: 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (1); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (2); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (3) ; 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (4); 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carboxylonitrile (5); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)acetoone (6); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (7); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N-methylacetamide (8); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2,2-trifluoroethyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl (9); 6-isopropyl-2- (1-Isopropylpiperidin-4-yl)-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (10); 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (11); 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (12);6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-neopentylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (13); 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-((3-methyloxacyclobutane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (14); 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin -1-yl)-2-methylprop-2-ol (15); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16); 2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (17); 1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (17); 1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-1-yl)-N,N-dimethylacetamide 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)piperidin-1-yl)ethyl-1-one (19); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl (20); 6-isopropyl-2-(1-isopropylpiperidin -4-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (21); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (22); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (23);2-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (24); 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl (25); 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl (26); 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-((3-methyloxetane-3- 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)piperidin-1-yl)aceto-1-one (28); 1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)piperidin-1-yl)2-methylprop-2-ol (29); 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl)piperidin-1- 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)piperidin-1-yl)acetamide (31); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)piperidin-1-yl)acetamide (32); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-2-(4-(6-isopropyl-5-(1-methyl-1 ... Pyrrolo[3,2-d]thiazole (33); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (34); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine -3-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (35); 6-isopropyl-2-(1-isopropylpiperidin-4-yl)-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole (36);5-(6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazo-5-yl)quinoline-8-carboxylonitrile (37); 5-(6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazo-5-yl)quinoline-8-carboxylonitrile (38); 5-(2-(1-(dimethylglycyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-5-yl)quinoline-8-carboxylonitrile (39); 2-(4-(5-(8-cyanoquinoline-5-yl)-6-isopropyl-4H-pyrrolo[3,2- d]thiazolyl)piperidin-1-yl)-N,N-dimethylacetamide (40); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl (41); 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl)-1,3,4-trimethylpyridin-2(1H)-one (42); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl)-1,3,4-trimethylpyridin-2(1H)-one 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (44); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(methanesulfonyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (45); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl -2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (46); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (47); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (48);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-methylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (49); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-ethylpiperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-propylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (51); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-propylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole ,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-isobutylpiperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (52); 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (53); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-ethylbutyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (54); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-ethylbutyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole Azo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (55); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N-methylacetamide (56); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (57) ; 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetamide (58); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetamide (59); 5-(6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (60);5-(6-isopropyl-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (61); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (62) ); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)piperidin-1-yl)-N-methylacetamide (63); or 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)piperidin-1-yl)acetamide (64).

[0155] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein the compound is: N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine (65-66); (1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)azacyclobutane-3,3-diyl)diethanol (67); 6-(4-(6-isopropyl-5-( 8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-2-oxa-6-azaspiro[3,3]heptane (68-69); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-3-methyloxacyclobutane-3-amine (70-71); N-ethyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3, 2-d]thiazolyl)-N-methylcyclohexyl-1-amine (72-73); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)-N-methylcyclohexyl-1-amine (74-75); 2-(4-(azacyclobutane-1-yl)cyclohexyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl (76-77); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo) [1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-amine (78-79); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)thiomorpholine 1,1-dioxide (82-83); 1-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)-2-methylprop-2-ol (84-85);4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexyl-1-amine (86-87); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine (88-89); (R)-3-fluoro-4-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl) 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)-2-methylbut-2-ol (90-91); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-amine (92-93); 3-ethyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine (94-95); 6-(4-(6-isopropyl-5-(8-) Methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-thia-6-azaspiro[3,3]heptane 2,2-dioxide (96-97); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(pyrrolidin-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl (98-99); (R)-N-(1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl) ]Thiazol-2-yl)cyclohexyl)pyrrolidine-3-yl)acetamide (100-101); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-1,4-oxazacycloheptane (102-103); (1R,5S)-8-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-3-oxaza-8-azabicyclo[3.2.1]octane (104-105);1-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)cyclopropane-1-carboxylonitrile (106-107); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(1-methylcyclobutyl)cyclohexyl-1-amine (108-109); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo [3,2-d]thiazolyl)cyclohexyl)-7-oxa-2-azaspiro[3.5]nonane (110-111); 7-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-2-oxa-7-azaspiro[3.5]nonane (112-113); 2-(4-(2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl (114- 115); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-azaspiro[3,3]hept-6-amine (116-117); 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-3-(trifluoromethyl)azacyclobutane-3-ol (118-119); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5- [a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)piperazin-2-one (120-121); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(3-methoxyazacyclobutane-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl (122-123); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-N-methyloxacyclobutane-3-amine (124-125);2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide (126); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)methanesulfonamide (127); trans-2-(ethyl(methyl)amino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)methanesulfonamide (127); 2-(isobutylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide (129); N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine (130-131); N-ethyl-4-(6-isopropyl) -5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine (132); 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((3-methyloxacyclobutane-3-yl)methyl)cyclohexyl-1-amine (134-135); 6-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2- [d]thiazolyl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (136-137); N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)bicyclo[1.1.1]pentan-1-amine (138-139); 1-((4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)amino)-2-methylprop-2-ol (140-141);(1-(((4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)methyl)cyclopropyl)methanol (142-143); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-3-methyloxacyclobutane-3-amine (144-145); 4-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-3-methyloxacyclobutane-3-amine (144-145); 4-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)piperazin-2-one (148-149); 6-isopropyl-2-(4-(3-methoxyazacyclobutane-1-yl)cyclohexyl)-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl (150-151); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)- 4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)oxetane-3-amine (152-153); 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(pyrrolidin-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl (154-155); 1-((4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)amino)-2-methylprop-2-ol (156-157); N-isopropyl-4-(6-isopropyl-5-(7-methyl-[1,2,4]... Triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine (158-159); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (160-161); 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide (162-163);4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methyl-N-(2-(methanesulfonyl)ethyl)cyclohexyl-1-amine (164-165); 1-isopropyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)piperidine-4-amine (166-167); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)piperidine-4-amine (166-167); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a) ]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)bicyclo[1.1.1]pentan-1-amine (168-169); N1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-N2-methylethane-1,2-diamine (170-171); 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((3-methyloxacyclobutane-3-yl) )methyl)cyclohexyl-1-amine (172-173); N-ethyl-4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine (174-175); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)bicyclo[1.1.1]pentane-1-amine (176-177); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin- 3-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)oxetane-3-amine (178-179); 6-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (180-181); 1-((4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)amino)-2-methylprop-2-ol (182-183);N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine (184-185); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexyl-1-amine (186-187); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2- (4-(3-methoxyazacyclobutane-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (188-189); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-ethyl-N-methylcyclohexyl-1-amine (190-191); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (192) -193); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-isopropylcyclohexyl-1-amine (194-195); 1-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)-2-methylprop-2-ol (196-197); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl) -4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-neopentylcyclohexyl-1-amine (198-199); N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (200-201); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((1-methylcyclobutyl)methyl)cyclohexyl-1-amine (202-203);2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)amino)-N,N-dimethylacetamide (204-205); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)amino)-1-morpholinoacetyl-1-one (206-207); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin)pyridine -6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)-N-methylacetamide (208-209); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)acetamide (210-211); 4-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)morpholine (212-213); 4 -(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((1-(methanesulfonyl)cyclopropyl)methyl)cyclohexyl-1-amine (214-215); 2-(4-(azacyclobutane-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl (216-217); 2-(4-(3,3-difluoroazacyclobutane-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl (216-217); 2-(4-(3,3-difluoroazacyclobutane-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl) ,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (218-219); 4-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazin-2-one (220-221); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropyl-N-methylcyclohexyl-1-amine (222-223);1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)azacyclobutane-3-ol (224-225); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(3-fluoroazacyclobutane-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl (226-227); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl) -d]thiazolyl-2-yl)-N-isobutyl-N-methylcyclohexyl-1-amine (228-229); 3-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)amino)tetrahydrothiophene 1,1-dioxide (230-232); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (233) -234); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-3-(trifluoromethyl)azacyclobutane-3-ol (235-236); 7-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-oxa-7-azaspiro[3.5]nonane (237-238); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-2-oxa-7-azaspiro[3.5]nonane (237-238); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-2-oxa-7-azaspiro[3.5]nonane -a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-7-oxa-2-azaspiro[3.5]nonane (239-240); 5-(6-isopropyl-2-(4-(oxacyclobutane-3-ylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (241-242); 5-(6-isopropyl-2-(4-((2-methoxy-2-methylpropyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (243-244);5-(2-(4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (245-246); 5-(2-(4-(ethyl(methyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (247-248); 5-(6-isopropyl-2-(4-((tetrahydro-2H-pyran-4-yl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1, 3,4-Trimethylpyridin-2(1H)-one (249-250); 5-(2-(4-((2-hydroxy-2-methylpropyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (251-252); 5-(6-isopropyl-2-(4-(isopropylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (253-254); 5-(2-(4-(azacyclobutane-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2- d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (255-256); 5-(6-isopropyl-2-(4-(((1-(methanesulfonyl)cyclopropyl)methyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (257-258); 4-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)piperazin-2-one (259-260); 5-(6-isopropyl-2-(4-(isopropyl-2-yl)cyclohexyl)piperazin-2-one 5-(2-(4-(3-hydroxyazacyclobutane-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (261-262); 5-(2-(4-(3-hydroxyazacyclobutane-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (263-264); 5-(2-(4-(3-fluoroazacyclobutane-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (265-266);5-(2-(4-(3-hydroxy-3-(trifluoromethyl)azacyclobutane-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (267-268); 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3,3]heptane (269-270); N-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3,3]heptane (269-270); N-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)-2-oxa-6-azaspiro[3,3]heptane -a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)oxetane-3-amine (271-272); N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)oxetane-3-amine (273); or 4-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazolyl)cyclohexyl)piperazin-2-one (275-276).

[0156] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein the compound is: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (278); 5-(6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (279); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl) Piperazin-1-yl)-2-(dimethylamino)ethyl-1-one (280); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)piperazin-1-yl)-2-methylprop-2-ol (281); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(2-(methanesulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazolyl (282); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]) 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)piperazin-1-yl)-N,N-dimethylacetamide (283); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)piperazin-1-yl)-N-methylacetamide (284); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)piperazin-1-yl)acetamide (285); 5-(7,8-dimethyl-[ [1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (286); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (287); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-isopropylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (288);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-((3-methyloxetane-3-yl)methyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (289); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl (308); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-2 (5-Dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (309); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (310); (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (311); (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,2,4]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide (312); (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)acetamide (313); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(2-(methyl) (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (315); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazol (316);(R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (317); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (318); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) (R)-2-(2,4-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (319); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-ethyl-2-methylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (320); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (321); (R)-2-(4-cyclobutyl-2-yl)-2-(2,4-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (321); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (322); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(1-isopropylpiperidin-4-yl)-2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (323); (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole- (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazin-1-yl)-2-(methylamino)ethyl-1-one (326); (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazin-1-yl)-2-(dimethylamino)ethyl-1-one (327);2-((2S,5R)-2,5-dimethyl-4-(oxacyclobutane-3-yl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (328); 2-((2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (329); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole 4] Triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (330); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (331); 2-((2S,5R)-4-(cyclopropylmethyl)-2,5-dimethylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (332); 2-((2S,5R)-4-cyclobutyl-2,5-dimethylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (333); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazin-1-yl)-4H-pyrrolo[3, 2-d]thiazole (334); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazin-1-yl)-N,N-dimethylacetamide (335); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazin-1-yl)-N-methylacetamide (336);2-((2S,5R)-2,5-dimethyl-4-(2-(methanesulfonyl)ethyl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (337); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazin-1-yl)acetamide (338); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazin-1-yl)acetamide (338); [2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-methylprop-2-ol (339); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-(methylamino)ethyl-1-one (340); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrrolo[3,2,4]triazolo[1,5-a]pyrrolo[3,2,4]triazolo[1,5-a]pyrrolo[3,2,4]triazolo[1,5-a]pyrrolo[3,2,4]triazolo[1,5-a]pyrrolo[3,2,4]triazolo[3 ... (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazolo[3,2-d]thiazolyl)-3-methylpiperazolo[1,2,4]thiazolyl)-3-methylpiperazolo[1,2,4]thiazolyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazolo[1,2,4]thiazolyl)-N-methylacetamide (342); (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazolo[3,2-d]thiazolyl)-3-methylpiperazolo[1,2,4]thiazolyl)-3-methylpiperazolo[3,2-d ... (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(2-(methanesulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (344); (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol (345);(S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-(dimethylamino)aceto-1-one (346); (S)-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)(1,1-tetrahydro-2H-thiopyran-4-yl)methyl ketone (347); (S)-5-(7,8-dimethyl-[1,2,4]triazolo ...2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1,2,4]triazolo[1, (S)-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (348); (S)-2-(4-cyclobutyl-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (349); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H -pyrrolo[3,2-d]thiazole (350); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-isopropyl-2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (351); (S)-2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (352); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyrrolo[3,2-d]thiazole) (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (353); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide (354); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)acetamide (355);(R)-6-isopropyl-2-(2-methyl-4-(2-(methanesulfonyl)ethyl)piperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (356); (R)-6-isopropyl-2-(4-(2-methoxyethyl)-2-methylpiperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (357); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin- (6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)acetonitrile (358); (R)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol (359); (R)-2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1- (R)-2-(4-isobutyl-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (361); (R)-2-(4-cyclobutyl-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (362); (R)-6-isopropyl-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-5-(8-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (363); (R)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (364); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (365);(R)-6-isopropyl-2-(4-isopropyl-2-methylpiperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (366); or (R)-2-(2,4-dimethylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (367).

[0157] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein the compound is: 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(3-methyloxetane-3-yl)piperidin-4-amine (290); 1-((1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,2,4]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)piperidin-4-yl)amino)-2-methylprop-2-ol (291); 1-(5-( 7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-isopropyl-N-methylpiperidin-4-amine (292); N-cyclobutyl-1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-4-amine (293); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N -(2-methoxy-2-methylpropyl)piperidin-4-amine (294); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((3-methyloxetane-3-yl)methyl)piperidin-4-amine (295); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(oxetane-3-yl)piperidin-4-amine (296); 1-(5-(7,8-dimethyl-[ [1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-isopropylpiperidine-4-amine (297); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-ethyl-N-methylpiperidine-4-amine (298); or 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidine-4-amine (299).

[0158] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein said compound is: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3.3]hept-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (300); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3] ]Hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (301); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-(oxacyclobutane-3-yl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (302); 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[ 3.3] Hept-2-yl)-2-methylprop-2-ol (303); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-(2-(methanesulfonyl)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (304); 5-(6-isopropyl-2-(6-(2-(methanesulfonyl)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyrrolo ... Pyridine-2(1H)-one (305); 5-(6-isopropyl-2-(6-(oxacyclobutan-3-yl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (306); or 5-(6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (307).

[0159] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein the compound is: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(4-(dimethylamino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carboxamide (368-369); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-(pyrrolidine-1-yl)ethyl)-4H-pyrrolo[3,2-d]thiazolyl-2-carboxamide (370); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6- 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(2-methyl-2-morpholinopropyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (371); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(dimethylamino)ethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (372); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-methyl-2-morpholinopropyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (374); 5-(7,8-dimethyl-[1,2,4]triazolo[1,2,4]pyridin-6-yl)-6-isopropyl-N-(2-methyl-2-morpholinopropyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide ] Triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-(1-methylpiperidin-4-yl)ethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (381); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(dimethylamino)ethyl)-6-isopropyl-N-methyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (382); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(morpholin-2-ylmethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (386); 6 -Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(pyrrolidine-1-yl)ethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (387); N-(2-(dimethylamino)ethyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (388); N-(2,2-difluoroethyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (389);6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2,2,2-trifluoroethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (390); 6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (391); 6-Isopropyl-5-(8- Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-((1-(methanesulfonyl)cyclopropyl)methyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (399); or N-(2-(dimethylamino)ethyl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (400).

[0160] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein the compound is: (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(1,1-thiomorpholino) methyl ketone (373); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carbonyl)piperazin-1-yl) ethyl-1-one (375); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a) ]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(4-(dimethylamino)piperidin-1-yl) ketone (376); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(pyrrolidine-1-yl) ketone (377); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carbonyl)piperazin-2-one (378); (5-(7,8-dimethyl-[1,2,4]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carbonyl)piperazin-2-one Triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(3-fluoroazacyclobutane-1-yl) ketone (379); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(4-isopropylpiperazin-1-yl) ketone (380); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(3-(dimethylamino)azacyclobutane-1-yl) ketone ( 383); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (384); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-carboxamide (385); 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-carbonyl)piperazin-2-one (392);(6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(pyrrolidine-1-yl) ketone (393); (6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(1,4-oxazacycloheptane-4-yl) ketone (394); (4-(dimethylamino)piperidin-1-yl)(6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl) ketone ( 395); (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)(3-methoxyazacyclobutane-1-yl) ketone (396); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(oxacyclobutane-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-carboxamide (397); or (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl)(morpholino) ketone (398).

[0161] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein the compound is: N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)methyl)-1-isopropylpiperidin-4-amine (401); 2-(((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)methyl)amino)acetamide (402); 6-( (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (403); 2-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)methyl)-7-oxa-2-azaspiro[3.5]nonane (404); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,2,4]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)methyl)-7-oxa-2-azaspiro[3.5]nonane (404); ,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((1-(methanesulfonyl)cyclopropyl)methyl)methylamine (405); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)methyl)piperazin-2-one (406); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo [3,2-d]thiazolyl-2-yl)methyl)morpholine (407); 6-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (408); or 2-((2,6-diazaspiro[3.3]hept-2-yl)methyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl (409).

[0162] One embodiment provides a compound of formula (I), its N-oxide, or a salt thereof, wherein said compound is: 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (410); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (410); -a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (411); or 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (412).

[0163] One embodiment provides a compound of formula (I), its N-oxide or salt, wherein the compound is 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-thieno[3,2-b]pyrrole (413).

[0164] The invention may be embodied in other specific forms without departing from the spirit or essential attributes of the invention. The invention encompasses all combinations of the aspects and / or embodiments of the invention mentioned herein. It should be understood that any and all embodiments of the invention can be combined with any one or more other embodiments to describe further embodiments. It should also be understood that each individual element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe further embodiments.

[0165] definition

[0166] After reading the following detailed description, those skilled in the art will more readily understand the features and advantages of the present invention. It should be understood that, for clarity, certain features of the invention described in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be combined to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative rather than restrictive.

[0167] Unless otherwise expressly stated herein, references in the singular may also include the plural form. For example, “a” and “an” can refer to one or more.

[0168] As used herein, the phrase “compound” refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I) as well as two or more compounds of formula (I).

[0169] Unless otherwise indicated, any heteroatom having an unsaturated valence is assumed to have a hydrogen atom sufficient to satisfy the valence.

[0170] The definitions set forth herein take precedence over those set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0171] The following lists definitions of various terms used to describe the invention. These definitions apply to terms as they are used individually throughout the specification or as part of a larger group (unless otherwise limited in specific cases).

[0172] Throughout the specification, those skilled in the art can select groups and their substituents to provide stable moieties and compounds.

[0173] In accordance with the conventions used in this field, the structure described herein uses

[0174]

[0175] To describe the bond as a part or substituent attachment point to the core or skeletal structure.

[0176] As used in this article, the terms “halogen” and “halogen” refer to F, Cl, Br and I.

[0177] The term "cyano" refers to the -CN group.

[0178] The term "amino" refers to the -NH2 group.

[0179] The term "oxo" refers to a group that is equal to O.

[0180] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in a subscript following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C..." 1-6 "Alkyl" refers to straight-chain and branched alkyl groups having one to six carbon atoms.

[0181] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0182] The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and C... 1-4 Cyanoalkyl.

[0183] The term "aminoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C... 1-4 Aminoalkyl.

[0184] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C... 1-4 Hydroxyalkyl.

[0185] The term "hydroxy-fluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy-fluoroalkyl" includes -CHFCH2OH, -CH2CHFC(CH3)2OH, and C... 1-4 Hydroxyfluoroalkyl.

[0186] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in a subscript following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6 cycloalkyl" indicates a cycloalkyl group having three to six carbon atoms.

[0187] As used herein, the term "alkoxy" refers to an alkyl group, such as a methoxy group (-OCH3), which is partially attached to the parent molecule via an oxygen atom. For example, "C 1-3 "Alkoxy" refers to an alkoxy group having one to three carbon atoms.

[0188] As used herein, the term "alkoxyalkyl" refers to an alkoxy group attached to an alkyl group via its oxygen atom, the alkyl group being partially attached to a parent molecule, such as methoxymethyl (-CH2OCH3). For example, "C 2-4"Alkoxyalkyl" refers to alkoxyalkyl groups having two to four carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3 and -CH2CH2OCH2CH3.

[0189] In this document, the phrase “pharmaceutically acceptable” is used to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues within a reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0190] The compound of formula (I) can be provided as an amorphous solid or a crystalline solid. Lyophilization can be used to provide the compound of formula (I) as an amorphous solid.

[0191] It should be further understood that solvates (e.g., hydrates) of compounds of formula (I) are also within the scope of this invention. The term "solvate" refers to the physical association of a compound of formula (I) with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, the solvate will be separable, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0192] Various forms of prodrugs are well known in the art and are described in:

[0193] a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Chapter 31, (Academic Press, 1996);

[0194] b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);

[0195] c) A Textbook of Drug Design and Development, edited by P. Krogsgaard-Larson and H. Bundgaard, Chapter 5, pp. 113–191 (Harwood Academic Publishers, 1991); and

[0196] d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[0197] Alternatively, after the preparation of a compound of formula (I), it can be isolated and purified to obtain a composition containing an amount equal to or greater than 99% by weight of a compound of formula (I) (“substantially pure”), which can then be used or formulated as described herein. Such “substantially pure” compounds of formula (I) are also considered herein as part of the invention.

[0198] The terms "stable compound" and "stable structure" are intended to indicate that a compound is robust enough to withstand separation from the reaction mixture to a useful level of purity and to be formulated into an effective therapeutic agent. This invention aims to include stable compounds.

[0199] "Therapeutic effective amount" is intended to include the amount of a single compound of the present invention, or the amount of a combination of the claimed compounds, or the amount of a compound of the present invention in combination with other active ingredients, said amount being effective as an inhibitor of TLR7 / 8 / 9, or effective in treating or preventing autoimmune and / or inflammatory disease states such as SLE, IBD, multiple sclerosis (MS), Sjögren's syndrome, and rheumatoid arthritis.

[0200] As used herein, “treating” or “treatment” encompasses the treatment of a disease state in mammals, particularly humans, and includes: (a) preventing the occurrence of the disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state; (b) suppressing the disease state, i.e., preventing its development; and / or (c) alleviating the disease state, i.e. causing the remission of the disease state.

[0201] The compounds of this invention are intended to include all isotopes of the atoms present in the compounds of this invention. Isotopes include those atoms with the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of the originally used unlabeled reagents. For example, methyl (-CH3) also includes deuterated methyl groups, such as -CD3.

[0202] utility

[0203] The human immune system has evolved to protect the body from microorganisms, viruses, and parasites that can cause infection, disease, or death. Complex regulatory mechanisms ensure that the various cellular components of the immune system target foreign substances or organisms without causing permanent or significant damage to the individual. While the initiation events are not fully understood at this time, in autoimmune disease states, the immune system directs its inflammatory response toward the target organs of the affected individual. Different autoimmune diseases are typically characterized by the dominant or initial target organ or tissue affected; such as the joints in rheumatoid arthritis, the thyroid gland in Hashimoto's thyroiditis, the central nervous system in multiple sclerosis, the pancreas in type 1 diabetes, and the intestine in inflammatory bowel disease.

[0204] The compounds of the present invention inhibit signal transduction via Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Therefore, the compounds of formula (I) are effective in treating conditions associated with inhibition of signal transduction via one or more of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9 receptor-related diseases, in which cytokine levels are regulated by intracellular signal transduction.

[0205] As used herein, the terms “treating” or “treatment” cover the treatment of a disease state in mammals, particularly humans, and include: (a) preventing or delaying the occurrence of the disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state; (b) suppressing the disease state, i.e., preventing its development; and / or (c) achieving a complete or partial reduction of symptoms or disease state, and / or alleviating, improving, reducing or curing the disease or disorder and / or its symptoms.

[0206] Given their activity as selective inhibitors of TLR7, TLR8, or TLR9, compounds of formula (I) may be used to treat diseases associated with, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic transplant rejection, and chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, and psoriasis; and autoinflammatory diseases including cold pyrrolizine-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), adult-onset Still's disease, and generalized paroxysmal juvenile idiopathic arthritis. Gout and gouty arthritis; metabolic diseases, including type 2 diabetes, atherosclerosis, and myocardial infarction; destructive bone disorders, such as bone resorption diseases, osteoarthritis, osteoporosis, and multiple myeloma-related bone disorders; proliferative disorders, such as acute myeloid leukemia and chronic myeloid leukemia; angiogenesis disorders, such as solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases, such as sepsis, septic shock, and Shigella infection; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and neurodegenerative diseases caused by cerebral ischemia or traumatic injury; tumors and viral diseases, such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, as well as HIV infection and CMV retinitis, and AIDS.

[0207] More specifically, the specific conditions or diseases that can be treated with the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, and inflammation. Enterocolitis, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Leter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allografts. Transplant rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigella infection; Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury; angiogenesis disorders, including solid tumors and ocular neoplasms. Angiogenesis and infantile hemangioma; viral diseases, including acute hepatitis infections (including hepatitis A, hepatitis B, and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignant diseases, and herpes; stroke, myocardial ischemia, ischemia during stroke-cardiac attack, organ hypoxia, angiogenesis, myocardial and renal reperfusion injury, thrombosis, myocardial hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin intraperoxidase synthase-2, and pemphigus vulgaris. This implementation plan includes treatments for conditions selected from lupus nephritis and systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis, allogeneic transplant rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. This also includes treatments for conditions selected from ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction. Another treatment method is one for conditions such as multiple myeloma.

[0208] In one implementation, the compound of formula (I) can be used to treat cancers, including Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B-cell lymphoma, and primary CNS lymphoma.

[0209] Furthermore, the TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin intraperoxidase-2 (PGHS-2) (also known as cyclooxygenase-2 (COX-2)), IL-1, IL-6, IL-18, and chemokines. Therefore, other TLR7 / 8 / 9-related symptoms include edema, analgesia, fever, and pain (such as neuromuscular pain, headache, cancer-related pain, toothache, and arthritis pain). The compounds of the present invention can also be used to treat veterinary viral infections, such as lentiviral infections, including but not limited to equine infectious anemia virus; or retroviral infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.

[0210] Therefore, the present invention provides a method for treating such conditions, the method comprising administering to a subject in need a therapeutically effective amount of at least one compound of formula (I) or a salt thereof. "Therapeutically effective amount" is intended to include an amount of the compounds of the present invention that, when administered alone or in combination, effectively inhibits autoimmune diseases or chronic inflammatory diseases.

[0211] Methods of treating TLR7, TLR8, or TLR9-related conditions may include administering compounds of formula (I) alone or in combination with each other and / or in combination with other suitable therapeutic agents that can be used to treat such conditions. Therefore, "therapeuticly effective amount" is also intended to include the amount by which the combination of the claimed compounds effectively inhibits TLR7, TLR8, or TLR9 and / or treats conditions associated with TLR7, TLR8, or TLR9.

[0212] Other examples of such therapeutic agents include corticosteroids, cyclophosphamide, carvirstatin, cytokine-suppressing anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyguanidine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents, such as abacavir; and antiproliferative agents, such as methotrexate, leflunomide, and FK506 (tacrolimus). Antimalarial drugs, such as hydroxychloroquine; cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or...). ) or its derivatives.

[0213] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by those skilled in the art. In the methods of the present invention, one or more such other therapeutic agents may be administered before, simultaneously with, or after the application of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating TLR7 / 8 / 9 receptor-related conditions, including IL-1 family receptor-mediated diseases as described above.

[0214] The compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, by employing conventional solid or liquid media or diluents and pharmaceutical additives of a type suitable for the desired method of administration (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.) according to techniques such as those well known in the field of pharmaceutical formulation.

[0215] Therefore, the present invention further includes compositions comprising one or more compounds of formula (I) and pharmaceutically acceptable carriers.

[0216] "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of a bioactive agent to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the composition containing the agent will be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may also include many different components and additives in addition to the active agent, such additional components being included in the formulation for a variety of reasons well known to those skilled in the art (e.g., stabilization of the active agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources (e.g., Remington's Pharmaceutical Sciences, 17th edition (1985), which is incorporated herein by reference in its entirety).

[0217] The compound according to formula (I) can be administered by any means suitable for the condition to be treated, depending on the site-specific treatment or the amount of the compound of formula (I) to be delivered.

[0218] This invention also includes a class of pharmaceutical compositions comprising a compound of formula (I) and one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The compound of formula (I) may be administered via any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route, and at a dose effective for the intended treatment. The compounds and compositions of this invention may be administered, for example, orally, via mucosae, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal) in dosage form containing conventional pharmaceutically acceptable carriers, adjuvants, and mediators. For example, the pharmaceutical carrier may contain mannitol or a mixture of lactose and microcrystalline cellulose. The mixture may contain additional components such as lubricants (e.g., magnesium stearate) and disintegrants (e.g., cropovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. For example, the pharmaceutical composition may be administered as an oral dosage form or an infusion.

[0219] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably manufactured in dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose for humans or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0220] Any pharmaceutical composition considered herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, lozenges, sugar lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, pharmaceutical compositions according to the invention may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, modifiers, antioxidants, and preservatives.

[0221] Tablets can be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets. Exemplary excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, and alginate; binders such as starch, gelatin, polyvinylpyrrolidone, and gum arabic; and lubricants such as magnesium stearate, stearic acid, and talc. Additionally, tablets may be uncoated or coated using known techniques to mask unpleasant tastes of the drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effect of the active ingredient for a longer period. Exemplary water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Exemplary delay-release materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0222] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent (such as calcium carbonate, calcium phosphate and kaolin).

[0223] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0224] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) with at least one excipient suitable for making aqueous suspensions. Exemplary excipients suitable for making aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents such as naturally occurring phospholipids, such as lecithin; condensation products of alkyl epoxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols, such as heptadecanethoxycetyl alcohol; condensation products of ethylene oxides and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxides and esters derived from fatty acids and hexitol anhydrides, such as polyvinyl sorbitan monooleate. Aqueous suspensions may also contain at least one preservative, such as ethylparaben and n-propylparaben; at least one colorant; at least one flavoring agent; and / or at least one sweetener, including but not limited to sucrose, saccharin and aspartame.

[0225] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) in vegetable oils (such as peanut oil, olive oil, sesame oil, and coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may also contain at least one thickener, such as beeswax, hard paraffin, and cetyl alcohol. To provide a palatable oily suspension, at least one sweetener and / or at least one flavoring agent described above may be added to the oily suspension. Oily suspensions may further contain at least one preservative, including but not limited to antioxidants such as butylated hydroxyanisole (BHA) and α-tocopherol.

[0226] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including but not limited to, sweeteners, flavoring agents, and coloring agents.

[0227] Emulsions containing at least one compound of formula (I) can be prepared, for example, as oil-in-water emulsions. The oil phase of an emulsion containing a compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. While the phase may contain only an emulsifier, it may contain at least one emulsifier with a fat or oil, or with both fats and oils. Suitable emulsifiers include, but are not limited to, naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of metaesters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both oils and fats. One or more emulsifiers, with or without one or more stabilizers, constitute a so-called emulsified wax, and the wax, together with oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the cream formulation. The emulsion may also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of this invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, distearate alone or with the wax, or other materials well known in the art.

[0228] For example, compounds of formula (I) can also be delivered intravenously, subcutaneously, and / or intramuscularly in any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, sterile aqueous solutions containing acceptable mediators and solvents, such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oil suspensions.

[0229] Formulations intended for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more carriers or diluents mentioned for use in formulations intended for oral administration, or by using other suitable dispersants or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffers. Other adjuvants and methods of administration are well-known and familiar in the pharmaceutical industry. The active ingredient may also be administered by injection as a composition with a suitable carrier (including saline, dextrose, or water) or with cyclodextrin (i.e., Captisol), co-solvent solubilization (i.e., propylene glycol), or micellar solubilization (i.e., Tween 80).

[0230] Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspending media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (such as oleic acid) can be used in the preparation of injectable formulations.

[0231] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) combining the oil phase containing formula (I) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

[0232] Sterile aqueous or oily suspensions can be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions can be prepared with non-toxic, parenteral-acceptable diluents or solvents (e.g., 1,3-butanediol); and sterile oily suspensions can be prepared with sterile, non-toxic, acceptable solvents or suspending media (e.g., sterile non-volatile oils, such as synthetic monoglycerides or diglycerides; and fatty acids, such as oleic acid).

[0233] Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (such as d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (such as Tween, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF) or other similar polymer delivery matrices), serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine), sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-cyclodextrins) or other dissolved derivatives may also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0234] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce medical agents for administration to patients (including humans and other mammals). The pharmaceutical compositions can undergo conventional pharmaceutical processes such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Tablets and pills can be additionally prepared with enteric coating. Such compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents, and aromatizers.

[0235] The amount of compound applied and the dosage regimen for treating symptoms with the compounds and / or compositions of the present invention depend on a variety of factors, including the subject's age, weight, sex, medical condition, disease type, disease severity, route and frequency of administration, and the specific compound used. Therefore, dosage regimens can vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight, and most preferably between about 0.005 and 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing regimens include one dose per week and one dose per two-day cycles.

[0236] For therapeutic purposes, the active compounds of the present invention are typically combined with one or more adjuvants suitable for the indicated route of administration. If administered orally, the compounds may be mixed with lactose, sucrose, starch, cellulose esters of alkyl cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain controlled-release formulations, which may be provided in a dispersion of the active compound in hydroxypropyl methylcellulose.

[0237] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally additional agents selected from any pharmaceutically acceptable carrier, adjuvant, and mediator. Alternative compositions of the present invention comprise a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0238] This invention also covers articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packaging. Articles of manufacture of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a packaging insert indicating that the pharmaceutical composition can be used to treat inflammatory disorders and / or autoimmune diseases (as previously defined). In another embodiment, the packaging insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent for treating inflammatory disorders and / or autoimmune diseases (as previously defined). Articles of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located within or outside the second container. Located within the first and second containers means that the respective containers hold the article within their boundaries.

[0239] The first container is a receiving container for holding a pharmaceutical composition. This container may be used for manufacturing, storing, transporting, and / or selling individually / in bulk. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used for manufacturing, holding, storing, or dispensing pharmaceutical products.

[0240] The second container is used to hold the first container and optional packaging inserts. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and large bags. The packaging insert may be physically attached to the outside of the first container via tape, glue, staples, or another attachment method, or it may remain inside the second container without any physical attachment to the first container. Alternatively, the packaging insert may be located on the outside of the second container. When located on the outside of the second container, it is preferred that the packaging insert be physically attached via tape, glue, staples, or another attachment method. Alternatively, it may be adjacent to or in contact with the outside of the second container, rather than physically attached.

[0241] Packaging inserts are labels, tags, markers, etc., that list information relating to the pharmaceutical composition located within the first container. The listed information will typically be determined by the regulatory authority in the region where the product to be sold is administered (e.g., the U.S. Food and Drug Administration). In one embodiment, the packaging insert specifically lists the indications for which the pharmaceutical composition has been approved. Packaging inserts can be made of any material on which or containing information can be read by a person. For example, packaging inserts are printable materials (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the required information has been formed (e.g., printed or applied).

[0242] Preparation method

[0243] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below in conjunction with synthetic methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated herein by reference in their entirety.

[0244] The compounds of the present invention can be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents suitable for the reagents and materials used, and are adapted to the transformations performed. Furthermore, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and post-treatment procedures) are selected as standard conditions for the reaction, which should be readily apparent to those skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and thus alternative methods must be used. Sometimes, this will require judgment to modify the order of synthetic steps or to select one rather than another specific process scheme in order to obtain the desired compounds of the present invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the prudent selection of protecting groups for protecting the reactive functional groups present in the compounds described in this invention. The authoritative explanation of the many alternatives for trained practitioners is that of Greene and Wuts (Protective Groups in Organic Synthesis, 3rd Edition, Wiley and Sons, 1999).

[0245] Example

[0246] The preparation of compounds of formula (I) and the intermediates used to prepare compounds of formula (I) can be performed using the procedures and related procedures shown in the following examples. The methods and conditions used in these examples and the actual compounds prepared in these examples are not intended to be limiting, but rather to demonstrate how compounds of formula (I) can be prepared. When not prepared by the procedures described herein, the starting materials and reagents used in these examples are generally commercially available or reported in the chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0247] abbreviation

[0248] ACN Acetonitrile

[0249] AcOH (acetic acid)

[0250] DIPEA (diisopropylethylamine)

[0251] Boc tert-butoxycarbonyl

[0252] DCE dichloroethane

[0253] DCM dichloromethane

[0254] TEA Triethylamine

[0255] DMAP dimethylaminopyridine

[0256] DMF (dimethylformamide)

[0257] NaHCO3 (Sodium bicarbonate)

[0258] BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0259] EtOAc (ethyl acetate)

[0260] H or H2 hydrogen

[0261] h, hr or hrs hours

[0262] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate

[0263] HCl hydrochloric acid

[0264] Sodium hydride (NaH)

[0265] CO and carbon monoxide

[0266] HOAc acetic acid

[0267] HPLC (High-Performance Liquid Chromatography)

[0268] MTBE (methyl tert-butyl ether)

[0269] LC liquid chromatography

[0270] M Moore

[0271] M +1 (M+H) +

[0272] NIS n-iodosuccinimide

[0273] MeOH (methanol)

[0274] MHz

[0275] min. minutes

[0276] mM millimole

[0277] MS mass spectrometry

[0278] n or N positive

[0279] NBS n-bromosuccinimide

[0280] nm nanometer

[0281] nM nanomolar

[0282] NMP N-methylpyrrolidine

[0283] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium

[0284] Pd / C Palladium on Carbon

[0285] PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0286] Pet ether (petroleum ether)

[0287] Ret Time

[0288] sat. saturated

[0289] SFC Supercritical Fluid Chromatography

[0290] TFA (trifluoroacetic acid)

[0291] THF Tetrahydrofuran

[0292] Second-generation Xphos precatalyst: (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0293] Analytical and preparative HPLC conditions:

[0294] Method A (SCP): Column: XBridge BEH XP C18 (50x2.1) mm, 2.5 μm; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0-100% B over 3 min; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0295] Method B (SCP): Column: XBridge BEH XP C18 (50x2.1) mm, 2.5 μm: A: 95% water: 5% acetonitrile; 0.1% TFA; B: 5% water: 95% acetonitrile; 0.1% TFA, temperature: 50 °C, gradient: 0-100% B over 3 min, flow rate: 1.11 mL / min; detection: UV at 220 nm.

[0296] (C): Kinetex XB-C18 (75x3mm) 2.6 μm; Solvent A: 10mM ammonium formate aqueous solution: acetonitrile (98:2); Mobile phase B: 10mM ammonium formate aqueous solution: acetonitrile (2:98); Temperature: 50℃; Gradient: 0-100% B over 5 minutes; Flow rate: 1.1 mL / min; Detection: UV at 220 nm.

[0297] (D): Column: Ascentis Express C18 (50x2.1) mm, 2.7 μm; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM NH4OAc); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM NH4OAc); Temperature: 50 °C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min.

[0298] (E) Waters Acquity SDS Mobile phase: A: Water; B: ACN; 5%-95% B over 1 min; Gradient range: 50%-98% B (0-0.5 min); 98% B (0.5 min-1 min); 98%-2% B (1-1.1 min); Run time: 1.2 min; Flow rate: 0.7 mL / min; Analysis time: 1.7 min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ES) + ).

[0299] (F) Acquity UPLC BEH C18 (3.0x50mm) 1.7μm. Buffer: 5mM ammonium acetate

[0300] Mobile phase A: Buffer:ACN (95:5); Mobile phase B: Buffer:ACN (5:95); Method: %B: 0 min - 20% : 1.1 min - 90% : 1.7 min - 90%. Run time: 2.25 min; Flow rate: 0.7 mL / min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ES) + ).

[0301] (G) Column-Luna 3.0 C18(2) LC column (20 x 4.0 mm) Mercury MS™ Mobile phase A: 0.1% TFAMilli-Q aqueous solution; Mobile phase B: 0.1% TFA ACN solution; Flow rate: 1.5 mL / min.

[0302] (H): Column: Ascentis Express C18 (50x2.1) mm, 2.7 μm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Temperature: 50 °C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min.

[0303] (I) Preparative LCMS: Waters XBridge C18, 19x150mm, 5μm particles; Mobile phase A: 10mM ammonium acetate; Mobile phase B: methanol; Gradient: 10%-45% B for 20 min, then held at 100% B for 5 min; Flow rate: 20 mL / min.

[0304] Example 1

[0305] 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0306]

[0307] Intermediate 1A: 2-bromothiazol-5-carboxylic acid

[0308]

[0309] 10% NaOH (300 mL, 450 mmol) was added to a solution of methyl 2-bromothiazol-5-carboxylate (100 g, 450 mmol) in methanol (1500 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 3 h. The reactants were concentrated under vacuum to remove the solvent, and the solid was dissolved in water (200 mL), acidified to pH 4-5 with cold 1.5 N HCl, and the resulting precipitate was filtered and dried to give 2-bromothiazol-5-carboxylic acid (81 g, 389 mmol, 86% yield) as a white solid. LC-MS retention time was 0.35 min [C]. MS (E - )m / z:208.0(M+2H).

[0310] Intermediate 1B: (2-bromothiazolyl-5-yl)tert-butyl carbamate

[0311]

[0312] TEA (65.1 mL, 467 mmol) was added to a solution of 2-bromothiazol-5-carboxylic acid (81 g, 389 mmol) in t-BuOH (1000 mL) at room temperature, followed by dropwise addition of diphenylphosphoazide (111 mL, 506 mmol), and the resulting solution was heated at 80 °C for 12 h. The reaction mixture was concentrated under vacuum, diluted with water (500 mL), brine (300 mL), and extracted with ethyl acetate (3 x 500 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by combiflash on a 120 g silica gel column (eluting the compound with 15% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl (2-bromothiazol-5-yl)carbamate (52 g, 186 mmol, 47.8% yield) as a grayish-white solid. LCMS retention time: 1.57 min [G]. MS(E-)m / z:281.1(M+2H).

[0313] Intermediate 1C: 4-(5-((tert-butoxycarbonyl)amino)thiazolyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0314]

[0315] A solution of tert-butyl (2-bromothiazolyl-4-yl)carbamate (15 g, 53.7 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carbamate (19.94 g, 64.5 mmol) in dioxane (300 mL) and water (34 mL) was treated with tripotassium phosphate (34.2 g, 161 mmol). The resulting solution was degassed with N2 for 10 min, followed by the addition of a PdCl2(dppf)-CH2Cl2 adduct (4.39 g, 5.37 mmol) and further degassed for 5 min. The resulting mixture was heated at 90 °C for 12 h. The reaction mixture was diluted with ethyl acetate (250 mL), washed with water (2 x 200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by combiflash on a 120 g silica gel column (eluting the compound with 45% EtOAc in petroleum ether). Fractions were collected and concentrated to give tert-butyl 4-(4-((tert-butoxycarbonyl)amino)thiazolyl)-3,6-dihydropyridine-1(2H)-carboxylate (19 g, 49.3 mmol, 92% yield) as a pale yellow solid. LC-MS retention time 3.38 min [C]. MS (E - )m / z:382.1(M+H).

[0316] Intermediate 1D: 4-(5-((tert-butoxycarbonyl)amino)thiazolyl)piperidine-1-carboxylic acid tert-butyl ester

[0317]

[0318] A solution of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)thiazolyl)-3,6-dihydropyridine-1(2H)-carboxylate (19 g, 49.8 mmol) and EtOAc (500 mL) was purged with nitrogen (N2), then Pd / C (9.54 g, 8.96 mmol) was added and the reaction was further purged three times with N2. Hydrogen was introduced into the mixture via a balloon; then the mixture was stirred at room temperature for 8 h. The suspension was filtered through a diatomaceous earth bed, the filtrate was collected and concentrated to give tert-butyl 4-(4-((tert-butoxycarbonyl)amino)thiazolyl)piperidine-1-carboxylate (18 g, 46.0 mmol, 92% yield) as a pale yellow solid. LC-MS retention time 3.24 min [C]. MS (E - )m / z:384.1(M+H).

[0319] Intermediate 1E: 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazolyl)piperidine-1-carboxylic acid tert-butyl ester

[0320]

[0321] 9.97 g (44.3 mmol) of NIS (tert-butyl 4-(5-((tert-butoxycarbonyl)amino)thiazolyl)piperidin-1-carboxylate) in acetonitrile (700 mL) was added dropwise to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)thiazolyl-2-yl)piperidin-1-carboxylate (17 g, 44.3 mmol) in acetonitrile (700 mL). The resulting solution was stirred at the same temperature for 10 min. The reaction mixture was quenched with an aqueous solution of sodium thiosulfate (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by combiflash on a 120 g silica gel column (eluting the compound with 16% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazolyl)piperidine-1-carboxylate (17 g, 33.0 mmol, 74.5% yield) as a pale yellow solid. LC-MS retention time: 3.40 min [C]. MS (E) - )m / z:510.1(M+H).

[0322] Intermediate 1F: 4-(5-((tert-butoxycarbonyl)(3-methylbut-2-en-1-yl)amino)-4-iodothiazo-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0323]

[0324] NaH (1.335 g, 33.4 mmol) was added to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazolyl)piperidin-1-carboxylate (17 g, 33.4 mmol) in DMF (250 mL) at 0 °C, and the mixture was stirred for 10 min at the same temperature. Then, 1-bromo-3-methylbut-2-ene (4.27 mL, 36.7 mmol) was added dropwise, and stirring was allowed to continue for 10 min at the same temperature. The reaction mixture was quenched with ice water (250 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give tert-butyl 4-(5-((tert-butoxycarbonyl)(3-methylbut-2-en-1-yl)amino)-4-iodothiazolyl)piperidin-1-carboxylate (17.2 g, 28.3 mmol, 85% yield), a pale yellow oil. LC-MS retention time: 4.13 min [C]. MS (E) - )m / z:578.1(M+H).

[0325] Intermediate 1G: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0326]

[0327] Tetrabutylammonium bromide (1.675 g, 5.19 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (3.0 g, 5.19 mmol) and potassium carbonate (1.077 g, 7.79 mmol) in DMF (90 mL). The mixture was degassed for 10 min and Pd(OAc)₂ (0.035 g, 0.156 mmol) was added, followed by further degassed for 5 min and heating the resulting reaction mixture at 100 °C for 12 h. The reaction mixture was filtered through diatomaceous earth, washed with EtOAc (100 mL), and the filtrate was concentrated to give the crude product. The crude product was purified by combiflash on a 40 g silica gel column (eluting the compound with 18%–45% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (510 mg, 0.245 mmol, 27.71% yield) as a pale yellow solid. LC-MS retention time: 4.29 min [C]. MS (E) - )m / z:450.1(M+2).

[0328] Intermediate 1H: 5-bromo-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0329]

[0330] NBS (269 mg, 1.511 mmol) dissolved in DCE (10 mL) was added dropwise to a solution of 4-(6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidine-1-carboxylic acid tert-butyl ester (480 mg, 1.373 mmol) in DCE (10 mL). The resulting solution was stirred at room temperature for 15 min. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by combiflash on a 24 g silica gel column (eluting the compound with 8% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl 4-(5-bromo-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidine-1-carboxylate (100 mg, 0.233 mmol, 17.00% yield) as a white solid. LC-MS retention time 4.29 min [C]. MS (E) - )m / z:528.1(M+H).

[0331] Intermediate 1I: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0332]

[0333] A solution of 5-bromo-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (150 mg, 0.284 mmol) and 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (94 mg, 0.341 mmol) in dioxane (5 mL) and water (0.556 mL) was treated with tripotassium phosphate (148 mg, 0.851 mmol). The resulting solution was degassed with N2 for 10 min, and a PdCl2(dppf)-CH2Cl2 adduct (11.59 mg, 0.014 mmol) was added, followed by further degassed for 5 min. The resulting mixture was then heated at 85 °C for 3 h. The reaction mixture was diluted with EtOAc (200 mL), washed with water (2 x 100 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by combiflash on a 24 g silica gel column (eluting the compound with 48% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (130 mg, 0.302 mmol, 76% yield) as a brown solid. LC-MS retention time 1.43 min [C]. MS (E - )m / z:597.1(M+H).

[0334] Example 1: 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0335] Add hydrochloric acid (1 mL, 32.9 mmol) in dioxane to a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (95 mg, 0.159 mmol) in DCM (1 mL), and stir the resulting solution at room temperature for 30 min. The reactants were concentrated under vacuum to remove volatiles, washed with diethyl ether (2 x 5 ml), the ether layer was decanted, and the solid was dried to give a yellow solid of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (62 mg, 0.156 mmol, 98% yield). LC-MS retention time was 0.93 min [A]. MS (E) - )m / z:397.1(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.48(s,2H),7.11(d,J=1.2Hz,1H),4.09-3.98(m,3H),3.23-3.19( m,2H),2.92-2.84(m,3H),2.13(d,J=10.0Hz,2H),1.90(s,1H),1.88-1.73(m,2H),1.43(d,J=6.8Hz,6H).

[0336] The following examples were prepared according to the general procedure described in Example 1.

[0337] Table 1

[0338]

[0339] Example 6

[0340] 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetoone

[0341]

[0342] TEA (0.011 mL, 0.081 mmol) was added to a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16 mg, 0.040 mmol) and dimethylglycine (4.99 mg, 0.048 mmol) in DMF (2 mL), followed by HATU (16.88 mg, 0.044 mmol). The resulting reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to yield a pale yellow solid of 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)ethyl-1-one (4.4 mg, 9.14 μmol, 22.64% yield). LCMS retention time was 1.14 min [A]. MS (E) - )m / z:482.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.55-8.37(m,2H),7.10(s,1H),4.39(d,J=13.0Hz,1H),4.10-3.98(m,3H),3.36-3.27(m,4H),3.2 1-3.13(m,3H),2.88-2.78(m,1H),2.31(s,4H),2.07(d,J=15.4Hz,3H),1.73(d,J=10.3Hz,1H),1.64-1.50(m,1H),1.42(d,J=6.8Hz,6H).

[0343] Example 7

[0344] 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide

[0345]

[0346] TEA (0.017 mL, 0.121 mmol) was added to a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16 mg, 0.040 mmol) and 2-chloro-N,N-dimethylacetamide (7.07 μL, 0.069 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (9.5 mg, 0.019 mmol, 46.3% yield) as a pale yellow solid. LCMS retention time was 1.29 min [A]. MS (E) - )m / z:482.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.53-8.39(m,2H),7.10(s,1H),4.11-4.02(m,2H),3.21-3.10(m,3H),3.06-2.97(m,3H),2.9 2(d,J=11.0Hz,2H),2.82(s,3H),2.23(t,J=10.6Hz,2H),2.10-1.99(m,2H),1.90(s,2H),1.83-1.67(m,2H),1.42(d,J=6.8Hz,6H).

[0347] The following examples were prepared according to the general procedure described in Example 7.

[0348] Table 2

[0349]

[0350]

[0351] Example 10

[0352] 6-Isopropyl-2-(1-Isopropylpiperidin-4-yl)-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole

[0353]

[0354] TEA (0.013 mL, 0.091 mmol) and acetone (5.80 mg, 0.050 mmol) were added to a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (18 mg, 0.045 mmol) in MeOH (2 mL) at 0 °C, followed by dropwise addition of acetic acid (0.260 μL, 4.54 μmol). The resulting solution was stirred at room temperature for 12 h. Sodium cyanoborohydride (5.71 mg, 0.091 mmol) was then added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using method I. After preparative LCMS purification, fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 6-isopropyl-2-(1-isopropylpiperidin-4-yl)-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole as a pale yellow solid (4.14 mg, 0.09 mmol, 20.3% yield). LCMS retention time: 1.15 min [A]. MS (E) - )m / z:439.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.48(s,2H),7.18-7.05(m,1H),4.06(s,2H),3.58-3.46(m,3H),3.25-3.08(m,2H),2.93( dd,J=12.7,6.6Hz,2H),2.31(br.s.,2H),2.13-2.00(m,2H),1.44(d,J=6.8Hz,2H),1.28(d,J=6.6Hz,5H),1.16(t,J=7.2Hz,6H).

[0355] The following examples were prepared according to the general procedure described in Example 10.

[0356] Table 3

[0357]

[0358]

[0359] Example 15

[0360] 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-2-methylprop-2-ol

[0361]

[0362] Potassium carbonate (18.82 mg, 0.136 mmol) was added to a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (18 mg, 0.045 mmol) and 1-chloro-2-methylprop-2-ol (4.93 mg, 0.045 mmol) in DMF (2 mL). The resulting solution was heated at 85 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-2-methylprop-2-ol (5.4 mg, 0.012 mmol, 25.4% yield) as a pale yellow solid. LCMS 1.37 min [A]. MS (E) - )m / z:469.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.46(d,J=1.5Hz,2H),7.09(s,1H),5.30(br.s.,2H),4.05( s,3H),3.24-3.14(m,4H),3.11(br.s.,3H),2.23(br.s.,4H),1.43(d,J=6.8Hz,6H),1.26(s,6H).

[0363] Example 16

[0364] 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0365]

[0366] DIPEA (0.017 mL, 0.121 mmol) was added to a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16 mg, 0.040 mmol) and 1-chloro-2-(methanesulfonyl)ethane (9.78 mg, 0.069 mmol) in DMF (1 mL). The resulting solution was heated at 85 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (7.7 mg, 0.015 mmol, 38% yield) as a pale yellow solid. LCMS 1.35 min [A]. MS (E) - )m / z:503.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),8.46(s,2H),7.11(s,1H),4.05(s,3H),3.31(d,J=6.1Hz,2H),3.22-3.13(m,1H), 3.09-2.91(m,6H),2.75(br.s.,2H),2.17(br.s.,2H),2.07(d,J=8.3Hz,2H),1.82-1.65(m,2H),1.43(d,J=6.8Hz,6H).

[0367] Example 17

[0368] 2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide

[0369]

[0370] At room temperature, TEA (0.018 mL, 0.126 mmol) was added to a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16 mg, 0.042 mmol) in DMF (2 mL), followed by the addition of 2-chloro-N,N-dimethylacetamide (7.36 μl, 0.071 mmol). The resulting reaction mixture was then stirred at the same temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (4.1 mg, 8.37 μmol, 19.89% yield) as a pale yellow solid. LCMS 1.33 min [A]. MS (E-) m / z: 466.2 (M+H). 1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.71(s,1H),8.50(s,1H),7.55(s,1H),4.26(s,3H),3.18-3.0 8(m,4H),2.99-2.85(m,5H),2.61(s,3H),2.29(br.s.,3H),2.23-2.12(m,2H),1.42(d,J=6.6Hz,6H)

[0371] Example 18

[0372] 1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-2-methylprop-2-ol

[0373]

[0374] Potassium carbonate (19.61 mg, 0.142 mmol) was added to a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (18 mg, 0.047 mmol) in DMF (2 mL), followed by dropwise addition of 1-chloro-2-methylprop-2-ol (5.14 mg, 0.047 mmol). The resulting pale yellow solution was heated at 85 °C for 6 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-2-methylprop-2-ol (2.6 mg, 5.51 μmol, 11.66% yield) as a pale yellow solid. LCMS 1.41 min [A]. MS (E) - )m / z:453.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.69-11.54(m,1H),8.73(s,1H),8.51(s,1H),7.55(s,1H),5.24(br.s.,1H),3.72(d,J=10.5Hz,2H),3.22(br. s.,2H),3.17(s,3H),3.12(br.s.,3H),2.93(dd,J=12.1,7.0Hz,2H),2.62(s,3H),2.24(br.s.,3H),2.19(s,3H),1.42(d,J=6.8Hz,6H).

[0375] Example 19

[0376] 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetoone

[0377]

[0378] TEA (0.012 mL, 0.084 mmol) was added to a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16 mg, 0.042 mmol) and dimethylglycine (5.20 mg, 0.050 mmol) in DMF (2 mL), followed by HATU (17.59 mg, 0.046 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acet-1-one (1 mg, 2.083 μmol, 4.95% yield) as a pale yellow solid. LCMS retention time: 1.19 min [A]. MS (E) - )m / z:466.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.58(br.s.,1H),8.71(s,1H),8.50(s,1H),7.55(s,1H),4.39(d,J=13.0Hz,1H),4.12(d,J=13.7Hz,1H ),3.14-3.06(m,6H),2.84-2.71(m,2H),2.61(s,3H),2.19(s,4H),2.15-2.02(m,2H),1.80-1.63(m,2H),1.41(d,J=6.8Hz,6H).

[0379] Example 20

[0380] 6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0381]

[0382] TEA (7.33 μL, 0.053 mmol) and oxetane-3-one (2.083 mg, 0.029 mmol) were added dropwise to a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (10 mg, 0.026 mmol) in MeOH (2 mL). The resulting solution was stirred at room temperature for 12 h. Then, sodium cyanoborohydride (3.30 mg, 0.053 mmol) was added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I to obtain 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (1 mg, 2.268 μmol, 8.63% yield) as a pale yellow solid. LCMS retention time was 1.43 min [A]. MS (E) - )m / z:437.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.50(s,2H),7.55(s,1H),4.55(t,J=6.5Hz,2H),4.48-4.40(m,2H),3.16-3.10(m,2H),3.04(d, J=2.9Hz,2H),2.76(s,2H),2.78(s,1H),2.61(s,2H),2.12-2.02(m,2H),1.98-1.86(m,1H),1.84-1.70(m,2H),1.41(d,J=6.6Hz,6H).

[0383] The following examples were prepared according to the general procedure described in Example 20.

[0384] Table 4

[0385]

[0386]

[0387] Example 24

[0388] 2-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide

[0389]

[0390] TEA (0.024 mL, 0.169 mmol) and 2-chloro-N,N-dimethylacetamide (9.88 μL, 0.096 mmol) were added to a solution of 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.056 mmol) in DMF (2 mL) solvent at room temperature. The resulting reaction mixture was then stirred at the same temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (5.4 mg, 0.012 mmol, 21.12% yield) as a pale yellow solid. LCMS retention time: 1.50 min [A]. MS (E) - )m / z:440.2(M+H). 1 HNMR(400MHz,DMSO-d6)δ11.57(s,1H),7.08(s,2H),3.27(d,J=6.8Hz,2H),3.18(br.s,1H) ), 2.49-2.36 (m, 7H), 2.12-1.98 (m, 4H), 1.92 (s, 4H), 1.42 (d, J = 6.8Hz, 6H), 1.15 (s, 6H).

[0391] Example 25

[0392] 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0393]

[0394] TEA (0.016 mL, 0.113 mmol) and acetone (3.60 mg, 0.062 mmol) were added to a solution of 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.056 mmol) in MeOH (2 mL) at 0 °C, followed by dropwise addition of acetic acid (0.323 μL, 5.64 μmol). The resulting solution was stirred at room temperature for 12 h. Sodium cyanoborohydride (7.09 mg, 0.113 mmol) was then added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (10.6 mg, 0.027 mmol, 47.4% yield) as a pale yellow solid. LCMS retention time was 1.38 min [A]. MS (E) - )m / z:397.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),7.72(d,J=9.8Hz,1H),7.43-7.32(m,1H),4.06(s,2H),3.58-3.46(m,3H),3.25-3.08(m,2H),2 .93(dd,J=12.7,6.6Hz,2H),2.31(br.s.,2H),2.13-2.00(m,3H),1.44(d,J=6.8Hz,4H),1.28(d,J=6.6Hz,5H),1.16(t,J=7.2Hz,6H).

[0395] The following examples were prepared according to the general procedure described in Example 25.

[0396] Table 5

[0397]

[0398] Example 28

[0399] 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetoone

[0400]

[0401] TEA (0.016 mL, 0.113 mmol) was added to a solution of 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.056 mmol) and dimethylglycine (6.98 mg, 0.068 mmol) in DMF (2 mL), followed by HATU (23.60 mg, 0.062 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)ethyl-1-one (7.9 mg, 0.018 mmol, 31.9% yield) as a pale yellow solid. LCMS retention time was 1.36 min [A]. MS (E) - )m / z:440.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),,7.72(d,J=9.8Hz,1H),7.43-7.32(m,1 H),4.43(d,J=13.7Hz,1H),4.39-4.24(m,2H),3.72(br.s.,1H),3.25(br.s., 1H),3.18(s,1H),2.94(t,J=11.7Hz,1H),2.83(s,6H),2.65(s,6H),2.22-2.0 9(m,2H),1.83(d,J=9.5Hz,1H),1.64(d,J=8.6Hz,1H),1.46(d,J=6.8Hz,6H).

[0402] Example 29

[0403] 1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-2-methylprop-2-ol

[0404]

[0405] Potassium carbonate (23.39 mg, 0.169 mmol) was added to a solution of 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.056 mmol) in DMF (2 mL), followed by the addition of 1-chloro-2-methylprop-2-ol (6.12 mg, 0.056 mmol). The resulting pale yellow solution was heated at 80 °C for 6 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-2-methylprop-2-ol (2.8 mg, 6.56 μmol, 11.63% yield) as a pale yellow solid. LCMS 1.61 min [A]. MS (E) - )m / z:427.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),,7.72(d,J=9.8Hz,1H),7.43-7.32(m,1H),5.24(br.s.,1H),3.72(d,J=10.5Hz,2H),3.22(br.s .,3H),3.17(s,3H),3.12(br.s.,4H),2.93(dd,J=12.1,7.0Hz,2H),2.62(s,3H),2.24(br.s.,3H),2.19(s,3H),1.42(d,J=6.8Hz,6H).

[0406] Example 30

[0407] 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide

[0408]

[0409] TEA (0.013 mL, 0.092 mmol) and 2-chloro-N,N-dimethylacetamide (45 mg, 0.370 mmol) were added to a solution of 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (35 mg, 0.092 mmol) in DMF (2 mL) solvent at room temperature. The resulting reaction mixture was then stirred at the same temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (7.0 mg, 0.014 mmol, 14.95% yield) as a pale yellow solid. LCMS retention time: 1.56 min [A]. MS (E) - )m / z:465.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.34(dd,J=4.5,1.6Hz,1H),7.99(dd,J=7.8 ,1.5Hz,1H),7.60(s,1H),7.17(dd,J=7.9,4.5Hz,1H),3.91(d,J=4.6Hz,3H),3.22 (br.s.,2H),3.11-2.99(m,3H),2.95(br.s.,2H),2.90(s,1H),2.87-2.78(m,2H), 2.26(br.s.,2H),2.07(d,J=15.2Hz,3H),1.87-1.64(m,3H),1.38(d,J=6.8Hz,6H).

[0410] The following examples were prepared according to the general procedure described in Example 30.

[0411] Table 6

[0412]

[0413]

[0414] Example 32

[0415] 2-(dimethylamino)-1-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetoone

[0416]

[0417] TEA (0.013 mL, 0.092 mmol) was added to a solution of 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (35 mg, 0.092 mmol) and dimethylglycine (45 mg, 0.436 mmol) in DMF (2 mL), followed by HATU (35.1 mg, 0.092 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(dimethylamino)-1-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl)piperidin-1-yl)acet-1-one (12 mg, 0.024 mmol, 26.2% yield) as a pale yellow solid. LCMS retention time: 1.44 min [A]. MS (E) - )m / z:465.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),8.34(dd,J=4.6,1.5Hz,1H),7.99(dd,J=7.8,1.5Hz ,1H),7.60(s,1H),7.18(dd,J=8.1,4.6Hz,1H),4.41(d,J=12.7Hz,1H),4.13(d,J=13.7Hz ,1H),3.93-3.86(m,4H),3.22-3.04(m,3H),2.79(t,J=11.6Hz,1H),2.26-2.15(m,2H),2. 14-1.99(m,3H),1.92(s,2H),1.81-1.66(m,2H),1.66-1.47(m,2H),1.38(d,J=6.8Hz,6H).

[0418] Example 33

[0419] 6-Isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0420]

[0421] TEA (0.018 mL, 0.132 mmol) was added to a solution of 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.066 mmol) and 1-chloro-2-(methanesulfonyl)ethane (9.39 mg, 0.066 mmol) in DMF (1 mL). The resulting solution was heated at 90 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (4.4 mg, 8.82 μmol, 13.40% yield) as a pale yellow solid. LCMS 1.63 min [A]. MS (E) - )m / z:486.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.33(dd,J=4.6,1.5Hz,1H),7.99(dd,J=7.9,1.6Hz,1H),7.60(s,1H),7.17(dd,J=7.9,4.5Hz,1H),3.91(d,J=4. 9Hz,4H),3.33(br.s.,2H),3.12-2.88(m,6H),2.75(br.s.,2H),2.16(br.s .,2H),2.07(d,J=7.6Hz,2H),1.75(d,J=9.5Hz,2H),1.38(d,J=6.8Hz,6H).

[0422] Example 34

[0423] 6-Isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0424]

[0425] TEA (0.018 mL, 0.132 mmol) and oxetane-3-one (5.22 mg, 0.072 mmol) were added to a solution of 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.066 mmol) in MeOH (2 mL) at 0 °C, followed by dropwise addition of acetic acid (0.377 μL, 6.59 μmol). The resulting solution was stirred at room temperature for 12 h. Sodium cyanoborohydride (8.28 mg, 0.132 mmol) was then added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to obtain 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(oxecyclobutan-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole as a pale yellow solid. LCMS retention time: 1.65 min [A]. MS(E) - )m / z:436.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.34(dd,J=4.6,1.5Hz,1H),7.99(dd,J=7.8,1.5Hz,1H), 7.69-7.46(m,2H),7.18(dd,J=7.9,4.5Hz,1H),4.56(t,J=6.5Hz,2H),4.46(t,J=6.1Hz,2H),3.9 9-3.86(m,2H),3.42(d,J=4.9Hz,1H),3.18(d,J=5.1Hz,1H),3.12-2.93(m,2H),2.79(d,J=10.3 Hz, 2H), 2.07 (d, J = 8.1Hz, 2H), 1.94 (t, J = 11.0Hz, 2H), 1.86-1.70 (m, 2H), 1.38 (d, J = 7.1Hz, 6H).

[0426] The following examples were prepared according to the general procedure described in Example 34.

[0427] Table 7

[0428]

[0429] Example 37

[0430] 5-(6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile

[0431]

[0432] Oxycyclobutane-3-one (4.49 mg, 0.062 mmol) and TEA (8.68 μL, 0.062 mmol) were added to a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile (25 mg, 0.062 mmol) in MeOH (2 mL) at 0 °C, followed by dropwise addition of acetic acid (0.356 μL, 6.23 μmol). The resulting solution was stirred at room temperature for 12 h. Sodium cyanoborohydride (7.83 mg, 0.125 mmol) was then added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile (9.1 mg, 0.020 mmol, 31.4% yield) as a pale yellow solid. LCMS retention time was 1.74 min [A]. MS (E) - )m / z:458.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),9.13(dd,J=4.2,1.7Hz,1H),8.45(d,J=7.6Hz,1H ),8.40(dd,J=8.6,1.7Hz,1H),7.75(dd,J=8.7,4.3Hz,1H),7.72(d,J=7.6Hz,1H),4.57 (t,J=6.5Hz,2H),4.47(t,J=6.1Hz,2H),3.91(s,2H),3.44(br.s.,1H),2.90-2.71(m,2 H), 2.10 (d, J = 12.2Hz, 2H), 1.97 (br.s., 2H), 1.88-1.69 (m, 2H), 1.34 (d, J = 6.8Hz, 6H).

[0433] The following examples were prepared according to the general procedure described in Example 37.

[0434] Table 8

[0435]

[0436] Example 39

[0437] 5-(2-(1-(dimethylglycyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile

[0438]

[0439] TEA (0.014 mL, 0.100 mmol) was added to a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile (20 mg, 0.050 mmol) and dimethylglycine (5.14 mg, 0.050 mmol) in DMF (2 mL), followed by HATU (18.94 mg, 0.050 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(2-(1-(dimethylglycyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile (10.5 mg, 0.020 mmol, 40.2% yield) as a pale yellow solid. LCMS retention time: 1.50 min [A]. MS (E) - )m / z:487.2(M+H). 1HNMR(400MHz,DMSO-d6)δ11.71(s,1H),9.13(dd,J=4.2,1.5Hz,1H),8.49-8.42(m ,1H),8.39(dd,J=8.7,1.6Hz,1H),7.83-7.64(m,2H),4.43(d,J=12.2Hz,1H),4.15 (d,J=12.2Hz,1H),3.91(s,1H),3.24-3.08(m,3H),2.96-2.86(m,1H),2.84-2.70 (m,2H),2.30-2.17(m,6H),2.16-2.04(m,2H),1.92(s,1H),1.34(d,J=6.8Hz,6H).

[0440] Example 40

[0441] 2-(4-(5-(8-cyanoquinoline-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide

[0442]

[0443] TEA (0.014 mL, 0.100 mmol) was added to a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)quinoline-8-carboxynitrile (20 mg, 0.050 mmol) in DMF (2 mL), followed by dropwise addition of 2-chloro-N,N-dimethylacetamide (6.06 mg, 0.050 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(4-(5-(8-cyanoquinolin-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (7.2 mg, 0.015 mmol, 29.7% yield) as a pale yellow solid. LCMS retention time was 1.64 min [A]. MS (E) - )m / z:487.2(M+H). 1H NMR (400MHz, DMSO-d6) δ11.70(s,1H),9.13(d,J=4.2Hz,1H),8.45(d,J=7.3Hz,1H),8.40(d,J=8.6Hz,1H),7.80-7.65 (m,1H),3.04(s,6H),2.85(br.s.,4H),2.79-2.73(m,2H),2.09(br.s.,4H),1.83(br.s.,2H),1.34(d,J=6.8Hz,6H).

[0444] Example 41

[0445] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0446]

[0447] Intermediate 41A: 4-(5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)thiazolyl)piperidine-1-carboxylic acid tert-butyl ester

[0448]

[0449] While purging with argon, copper iodide (I) (0.075 g, 0.393 mmol) and triphenylphosphine (0.103 g, 0.393 mmol) were added to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazo-2-yl)piperidin-1-carboxylate (2 g, 3.93 mmol) in a mixture of toluene (40 mL) and diisopropylamine (10 mL). Bis(triphenylphosphine)palladium dichloride (II) (0.138 g, 0.196 mmol) was added, the reaction mixture was stirred for 5 min, 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (1.008 g, 5.89 mmol) was added, and the mixture was heated at 45 °C for 3 h in a sealed tube. The reactants were diluted with DCM, filtered through diatomaceous earth and washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel (eluting with 60% EtOAc in petroleum ether) to give tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)thiazolyl-2-yl)piperidin-1-carboxylate as a pale yellow solid. LCMS retention time 2.07 min [F]. MS (E -)m / z:553.5(M+H).

[0450] Intermediate 41B: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0451]

[0452] Silver acetate (0.574 g, 3.44 mmol) was added to a stirred solution of tert-butyl piperidine-1-carboxylate (1.9 g, 3.44 mmol) in toluene (40 mL), and the mixture was stirred in a sealed tube at 100 °C for 30 min. The reaction mixture was filtered through diatomaceous earth, concentrated, and purified by column chromatography (40 g silica gel column, eluted with 0 to 70% EtOAc in petroleum ether) to give tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (1.8 g, 3.26 mmol, 95% yield) as a grayish-white solid. LC-MS retention time 2.12 min [F]. MS (E - )m / z:553.6(M+H).

[0453] Intermediate 41C: 6-bromo-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0454]

[0455] A solution of NBS (0.725 g, 4.07 mmol) in DMF (5 mL) was added to a solution of tert-butyl 2-(1.5 g, 2.71 mmol) of 2-(1,2,4)triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (30 mL) in DMF at 0 °C, and then stirred overnight at room temperature. Next, water (40 mL) was added to the reactants, and the mixture was stirred for 20 min at room temperature. The obtained solid was collected by filtration and then dried under vacuum to give tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (1.4 g, 2.217 mmol, 82% yield) as a grayish-white solid. LC-MS retention time 1.16 min [F]. MS (E) - )m / z:633.4(M+2H).

[0456] Intermediate 41D: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0457]

[0458] Tripotassium phosphate (1.512 g, 7.12 mmol) was added to a solution of 6-bromo-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (1.5 g, 2.375 mmol) in 1,4-dioxane (30 mL) and water (3 mL), followed by purging with nitrogen for 5 min. The PdCl2(dppf)-CH2Cl2 adduct (0.194 g, 0.237 mmol) was then added and the reaction was purged again for 2 min. The reaction mixture was heated at 90 °C for 4 h in a sealed tube. The reaction mixture was filtered through diatomaceous earth, concentrated, and purified by silica gel (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (1.3 g, 2.193 mmol, 92% yield). LC-MS retention time 1.4 min [F]. MS (E - )m / z:593.4(M+H).

[0459] Intermediate 41E: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0460]

[0461] 1.3 g (2.193 mmol) of tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate was added to ethyl acetate (30 mL). The flask was purged with nitrogen and Pd-C (0.233 g, 2.193 mmol) was added. After purging with nitrogen, hydrogen was introduced via a balloon. The reaction mixture was stirred at ambient temperature for 4 h. The flask was emptied and filled with nitrogen. The suspension was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel (eluted with 50% EtOAc in petroleum ether) to give tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (0.95 g, 1.597 mmol, 72.8% yield). LC-MS retention time 1.57 min [F]. MS (E - )m / z:595.5(M+H).

[0462] Example 41: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0463] TFA (2.91 mL, 37.8 mmol) was added to a stirred solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (0.45 g, 0.757 mmol) in DCM (5 mL) at 0 °C, and the reaction mixture was then stirred at room temperature for 16 h. The reactants were concentrated, and 12 mL of MTBE was added to the residue. The mixture was stirred at room temperature for 5 min. The resulting solid was collected by filtration to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (0.28 g, 0.710 mmol, 94% yield) as a light brown solid. LCMS retention time: 1.127 min [A]. MS (E-) m / z: 395.2 (M+H). 1H NMR(400MHz,DMSO-d6)δ11.37-11.30(m,1H),8.72(s,1H),8.45(s,1H),3.20-3.00(m,4H),2.75-2 .63(m,3H),2.58(s,3H),2.18(s,3H),2.06-1.98(m,2H),1.74-1.63(m,2H),1.31(d,J=6.8Hz,6H).

[0464] The following intermediates are prepared according to the general procedure described in intermediate 41.

[0465] Table 9

[0466]

[0467] Example 43

[0468] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0469]

[0470] AcOH (0.290 μL, 5.07 μmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.051 mmol) and oxetane-3-one (18.27 mg, 0.253 mmol) in methanol (2 mL), and the mixture was stirred overnight at room temperature. Sodium cyanoborohydride (6.37 mg, 0.101 mmol) was then added to the reactants at 0 °C, and the mixture was stirred for 2 h at room temperature. The reactants were diluted with water (2 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (12.1 mg, 0.026 mmol, 52.1% yield). LCMS retention time: 1.443 min [A]. MS (E-) m / z: 451.3 (M+H). 1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.72(s,1H),8.45(s,1H),4.65-4.51(m ,2H),4.46(t,J=6.2Hz,2H),3.91(s,2H),3.44(br.s.,1H),3.05(br.s.,1H), 2.78(br.s.,2H),2.74-2.65(m,1H),2.64-2.53(m,3H),2.19(s,3H),2.14-2. 04(m,2H),1.94.(d,J=17.9Hz,2H),1.85-1.71(m,2H),1.31(d,J=6.8Hz,6H).

[0471] The following examples were prepared according to the general procedure described in Example 43.

[0472] Table 10

[0473]

[0474]

[0475] Example 55

[0476] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0477]

[0478] TEA (7.07 μL, 0.051 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.051 mmol) and 1-chloro-2-(methanesulfonyl)ethane (7.23 mg, 0.051 mmol) in a mixture of THF (1.5 mL) and DMF (0.5 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (7.4 mg, 0.015 mmol, 29.2% yield). LCMS retention time was 0.974 min [B]. MS (E) - )m / z:501.3(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.72(s,1H),8.45(s,1H),3.06(s,4H),3.01(br.s.,2H),2.82-2 .63(m,4H),2.58(s,3H),2.18(s,6H),2.11-1.99(m,2H),1.76(d,J=11.5Hz,2H),1.31(d,J=6.8Hz,6H).

[0479] The following examples were prepared according to the general procedure described in Example 55.

[0480] Table 11

[0481]

[0482] Example 59

[0483] 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetoone

[0484]

[0485] TEA (26.5 μL, 0.190 mmol) and acetyl chloride (24.87 mg, 0.317 mmol) were added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.063 mmol) in DCM at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-1-yl)acetophenone (15.5 mg, 0.035 mmol, 54.5% yield). LCMS retention time was 1.387 min [A]. MS (E) - )m / z:437.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.72(s,1H),8.45(s,1H),4.44(d,J=12.7Hz,1H),3.99-3.89(m,1H),3.27-3.17(m,1H),2.90(s,1H),2.8 0-2.62(m,5H),2.58(s,3H),2.19(s,3H),2.15-1.95(m,2H),1.74(dd,J=12.3,3.5Hz,1H),1.57(dd,J=12.3,3.8Hz,1H),1.31(d,J=6.8Hz,6H).

[0486] Example 60

[0487] 5-(6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one

[0488]

[0489] AcOH (0.595 μL, 10.40 μmol) was added to a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazo-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (40 mg, 0.104 mmol) and oxetane-3-one (37.5 mg, 0.520 mmol) in methanol (2 mL), and the mixture was stirred overnight at room temperature. Sodium cyanoborohydride (13.07 mg, 0.208 mmol) was added to the reactants at 0 °C, and the mixture was stirred at room temperature for 2 h. The reactants were diluted with water (2 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(6-isopropyl-2-(1-(oxecyclobutane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one as a white solid (17 mg, 0.037 mmol, 35.9% yield). LCMS retention time was 1.925 min [C]. MS(E) - )m / z:441.2(M+H). 1 H NMR(400MHz, DMSO-d6)δ11.05(s,1H)7.53(s,1H)4.52-4.58(m,2H)4.45(t,J=6.02Hz,2H)3.46(s,3H)3.40-3.44(m,1H)3.37(s,1H)2.95- 3.05(m,2H)2.66-2.81(m,3H)2.54-2.63(m,1H)2.31-2.36(m,2H)2.04(s,3H)1.88-1.98(m,2H)1.70-1.83(m,2H)1.29(d,J=7.03Hz,6H).

[0490] Example 61

[0491] 5-(6-isopropyl-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one

[0492]

[0493] TEA (0.014 mL, 0.104 mmol) was added to a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazo-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (40 mg, 0.104 mmol) and 1-chloro-2-(methanesulfonyl)ethane (14.83 mg, 0.104 mmol) in a mixture of THF (1.5 mL) and DMF (0.5 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(6-isopropyl-2-(1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (16 mg, 0.032 mmol, 30.5% yield). LCMS retention time 1.949 min [C]. MS(E) - )m / z:491.2(M+H). 1 HNMR(400MHz,DMSO-d6)δppm 11.06(s,1H)7.53(s,1H)3.46(s,3H)3.05(s,3H)2.98(d,J=11.55Hz,3H)2.63-2. 79(m,5H)2.10-2.34(m,3H)2.04(s,5H)1.65-1.82(m,4H)1.29(d,J=7.03Hz,6H).

[0494] The following examples were prepared according to the general procedure described in Example 61.

[0495] Table 12

[0496]

[0497] Examples 65 and 66

[0498] N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)oxetane-3-amine

[0499]

[0500] Intermediate 65A: (2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazolyl)tert-butyl carbamate

[0501]

[0502] A solution of (2-bromothiazolyl-5-yl)carbamate tert-butyl ester (70 g, 251 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxacyclopentaborane (100 g, 376 mmol) in dioxane (1500 mL) was prepared by adding tripotassium phosphate (160 g, 752 mmol) dissolved in 375 mL of water. The reaction mixture was degassed with argon for 20 min beforehand, and then the PdCl2(dppf)-CH2Cl2 adduct (20.48 g, 25.08 mmol) was added. The reaction mixture was degassed again for 5 min, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with EtOAc (3000 mL), poured into a separatory funnel, and washed with water (2 x 1500 mL) and brine (1500 mL). The mixture was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel chromatography (eluting with 30% ethyl acetate in hexane). The fractions were collected and concentrated to give tert-butyl 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazolyl)carbamate (75 g, 84% yield) as a yellow solid. LC-MS retention time 2.44 min [C]. MS (E - )m / z:339.2(M+H).

[0503] Intermediate 65B: (2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl)tert-butyl carbamate

[0504]

[0505] (75 g, 222 mmol) tert-butyl (2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazolyl-5-yl)carbamate was added to a solution of MeOH (1000 mL) and ethyl acetate (1000 mL). The flask was purged with N2 and Pd / C (23.58 g, 222 mmol) was added. After three N2 pumping / purging cycles, H2 gas was introduced via a balloon. The reaction mixture was stirred at ambient temperature for 12 h. The flask was emptied and filled with N2. The suspension was filtered and the filtrate was concentrated to give the crude product. The crude sample was purified by silica gel chromatography (eluting with 30% EtOAc in petroleum ether), and the fractions were collected and concentrated to give (70 g, 88% yield) tert-butyl (2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl-5-yl)carbamate as a pale white solid. LCMS retention time 2.36 min [C], MS (E) -)m / z:341(M+H).

[0506] Intermediate 65C: (4-iodo-2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl)tert-butyl carbamate

[0507]

[0508] To a solution of (2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl-5-yl)carbamate tert-butyl ester (50 g, 147 mmol) in acetonitrile (2000 mL), NIS (36.3 g, 162 mmol) dissolved in acetonitrile (2000 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with ethyl acetate (2000 mL), washed with water (1500 mL) and saturated NaCl (1500 mL), dried over sodium sulfate, and concentrated at 45 °C to obtain the crude product. The crude product was purified by silica gel chromatography (eluting with 30% EtOAc in petroleum ether), and the fractions were collected and concentrated to give (4-iodo-2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl-5-yl)carbamate tert-butyl ester (45 g, 66% yield) as a yellow solid. LCMS retention time: 3.05 min [C]. MS(E-) m / z: 467.2 (M+H).

[0509] Intermediate 65D: (4-iodo-2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl)(3-methylbut-2-en-1-yl)tert-butyl carbamate

[0510]

[0511] NaH (5.15 g, 129 mmol) was slowly added in portions to a solution of (30 g, 64.3 mmol, 4-iodo-2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl-5-yl)carbamate in 100 mL of DMF. Next, 1-bromo-3-methylbut-2-ene (18.44 mL, 96 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at the same temperature for 20 min. The reaction mixture was quenched with ice-cold water and diluted with EtOAc (1000 mL), poured into a separatory funnel, washed with brine (1000 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (eluting with 30% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl)carbamate (28 g, 81% yield) as a white solid. LC-MS retention time 2.5 min [C]. MS (E - )m / z:535.2(M+H).

[0512] Intermediate 65E: 6-Isopropyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0513]

[0514] Potassium carbonate (14.48 g, 105 mmol) and tetrabutylammonium bromide (50.7 g, 157 mmol) were added to a solution of (28 g, 52.4 mmol) of tert-butyl carbamate in DMF (600 mL), followed by degassing with argon for 10 min and the addition of PdOAc2 (1.176 g, 5.24 mmol). The reaction mixture was heated to 90 °C for 12 h. The reactants were diluted with EtOAc and passed through a diatomaceous earth mat. The combined organic extracts were concentrated to give the crude product. The crude product was purified by silica gel chromatography (eluting with 10% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl 6-isopropyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (9.5 g, 40% yield) as a pale yellow solid. LC-MS retention time 2.5 min [C]. MS (E - )m / z:535.2(M+H).

[0515] Intermediate 65F: 5-bromo-6-isopropyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0516]

[0517] NBS (3.74 g, 21.03 mmol) was added dropwise to 6-isopropyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (9.5 g, 23.37 mmol) in DCE (100 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 20 min. The reaction mixture was quenched with saturated sodium sulfite (50 mL) and diluted with DCM (500 mL), poured into a separatory funnel and washed with brine (500 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (eluting with 30% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl 5-bromo-6-isopropyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (6.2 g, 54% yield) as a pale yellow solid. LC-MS retention time 2.3 min [C]. MS (E - )m / z:485.2(M+H).

[0518] Intermediate 65G: 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0519]

[0520] To a solution of 5-bromo-6-isopropyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (5.5 g, 11.33 mmol) in dioxane (150 mL) and water (20 mL), tripotassium phosphate (7.21 g, 34.0 mmol) and 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (6.23 g, 22.66 mmol) were added. The reaction mixture was degassed with argon for 10 min and a PdCl2(dppf)-CH2Cl2 adduct (0.925 g, 1.133 mmol) was added. The reaction mixture was heated to 75 °C for 4 h. The reaction mixture was diluted with EtOAc (3000 mL), poured into a separatory funnel, and washed with water (2 x 500 mL) and brine (500 mL). The mixture was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel chromatography (eluting with 40% EtOAc in petroleum ether). The fractions were collected and concentrated to give tert-butyl (2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazolyl)carbamate (3.7 g, 60% yield) as a yellow solid. LC-MS retention time was 3.58 min [C]. MS (E - )m / z:554.2(M+H).

[0521] Intermediate 65H: 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one

[0522]

[0523] TFA (55 mL) was added to a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (3.5 g, 6.32 mmol) in DCM (55.0 mL), and the mixture was stirred at ambient temperature for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was ground with n-hexane to give 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (2.5 g, 92%) as a pale yellow solid. LCMS retention time 2.82 min [C]. MS(E - )m / z:410.2(M+H). 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.57-8.38(m,2H),7.13(d,J=1.0Hz,1H),4.07(s,3H),3.64-3.51( m,1H),3.25-3.14(m,1H),2.65-2.53(m,2H),2.44-2.28(m,4H),2.12-1.93(m,2H),1.45(d,J=6.8Hz,6H).

[0524] The following intermediates are prepared according to the general procedure described in intermediate 65H.

[0525] Table 13

[0526]

[0527] Examples 65 and 66: N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine

[0528] Acetic acid (0.363 mL, 6.35 mmol) and oxetane-3-amine (9.28 g, 127 mmol) were added to a solution of 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one (2.6 g, 6.35 mmol) in THF (20 mL) and DMF (20.00 mL), and stirred at ambient temperature for 12 h. The reaction mixture was concentrated to remove DMF and THF, and the resulting residue was absorbed in 30 mL of Aldrich-grade dry methanol and cooled to -78 °C under a nitrogen atmosphere. NaCNBH4 (1.995 g, 31.7 mmol) was added to a pot. The reaction was continued at the same temperature (-78 °C) for 3 h and reached 0 °C after 1 h. The reaction was quenched with 10 mL of ice-cold water and the reaction mixture was concentrated. The residue was extracted with 10% methanol (100 mL x 2) in DCM. The organic layer was concentrated and the crude product obtained was purified by preparative LCMS using method I. Fractions corresponding to peak 1 (isomer 1) and peak 2 (isomer 2) were collected and concentrated. They were further ground with anhydrous ethanol (100 mL x 2) and the resulting white solid was absorbed in deionized water (150 mL) and lyophilized for 2 days. NMR showed the presence of ethanol. The lyophilized compound was further absorbed in deionized water (150 mL) and the lyophilization was repeated for another 2 days.

[0529] Example 65 (Isomer 1): LCMS retention time 1.62 min [C]. MS(E) - )m / z:467.3(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.56-8.37(m,2H),7.10(s,1H),4.64(t, J=6.6Hz,2H),4.33(t,J=6.4Hz,2H),4.05(s,3H),3.98(t,J=6.7Hz,1H),3.23-3 .12(m,1H),2.99-2.89(m,1H),2.43(t,J=11.0Hz,1H),2.17-2.04(m,2H),1.85 (d,J=10.5Hz,2H),1.59-1.46(m,2H),1.42(d,J=6.6Hz,6H),1.28-1.10(m,2H).

[0530] Example 66 (Isomer 2): LCMS retention time 2.82 min [C]. MS(E) - )m / z:467.3(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.56-8.38(m,2H),7.12(s,1H),4.63 (t,J=6.6Hz,2H),4.35(t,J=6.4Hz,2H),4.17(d,J=4.9Hz,1H),4.06(s,3H), 3.98-3.85(m,1H),3.26-3.06(m,1H),2.09-1.95(m,2H),1.80(br.s.,2H),1 .65-1.54(m,3H),1.49(d,J=7.8Hz,1H),1.44(d,J=6.8Hz,6H),1.24(s,2H).

[0531] The following examples were prepared according to the general procedures described in Examples 65 and 66.

[0532] Table 14

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] Example 126

[0542] 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide

[0543]

[0544] Dimethylglycine (5.02 mg, 0.049 mmol), TEA (6.79 μL, 0.049 mmol), and HATU (18.52 mg, 0.049 mmol) were added to 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-amine (20 mg, 0.049 mmol) in DMF (5 mL). The reaction mixture was stirred at ambient temperature for 12 h, then quenched with 1 mL of ice-cold water and concentrated under vacuum. The residue was extracted with 10% methanol (5 mL x 2) in DCM. The organic layer was concentrated and the resulting crude product was purified by preparative LCMS using method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide (4.6 mg, 18% yield) as a pale white solid. LCMS retention time: 1.42 min [C]. MS (E) - )m / z:496.2(M+H). 1H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.55-8.38(m,2H),7.75-7.63(m,1H),7.12(d,J=1.2Hz,1H),4.06(s,3H),3.75-3.62(m,1H),3. 24-3.13(m,1H),3.06-2.89(m,3H),2.33-2.23(m,6H),2.20-2.12(m,2H),1.97-1.83(m,2H),1.71-1.54(m,2H),1.44(d,J=6.8Hz,6H).

[0545] Example 127

[0546] N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)methanesulfonamide

[0547]

[0548] TEA (6.79 μL, 0.049 mmol) and methanesulfonyl chloride (5.58 mg, 0.049 mmol) were added to 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-amine (20 mg, 0.049 mmol) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 12 h. The reaction was quenched with 1 mL of ice-cold water and the reactants were concentrated. The residue was extracted with 10% methanol (5 mL x 2) in DCM. The organic layer was concentrated and the crude product obtained was purified by preparative LCMS using method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)methanesulfonamide (3.6 mg, 15% yield) as a pale white solid. LCMS retention time: 1.42 min [C]. MS (E) - )m / z:489.2(M+H). 1H NMR (400MHz, DMSO-d6) δ11.61(s,1H),8.52-8.44(m,2H),7.12(d,J=1.2Hz,1H),7.08(d,J=7.3Hz,1H),4.06(s,3H ),3.27-3.13(m,2H),2.94(s,4H),2.20-2.10(m,2H),2.07-1.96(m,2H),1.71-1.57(m,2H),1.43(d,J=6.8Hz,7H).

[0549] Example 128

[0550] trans-2-(ethyl(methyl)amino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide

[0551]

[0552] Intermediate 128A: Chloro-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide

[0553]

[0554] TEA (0.068 mL, 0.487 mmol) and 2-chloroacetyl chloride (27.5 mg, 0.244 mmol) were added to a mixture of trans-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-amine (100 mg, 0.244 mmol) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 12 h. The reactants were diluted with DCM, washed with water, and concentrated to give 2-chloro-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide (80 mg, 0.164 mmol, 68%) as a colorless liquid. The LC-MS retention time was 1.26 min [C]. MS (E) - )m / z:488.1(M+H).

[0555] Example 128:

[0556] TEA (5.72 μL, 0.041 mmol) and N-methylethylamine (3.64 mg, 0.062 mmol) were added to 2-chloro-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide (10 mg, 0.021 mmol) in DCM (5 mL), and the mixture was stirred at ambient temperature for 12 h. The reaction was quenched with 1 mL of ice-cold water and the reactants were concentrated. The residue was extracted with 10% methanol (5 mL x 2) in DCM. The organic layer was concentrated and the crude product obtained was purified by preparative LCMS using method I. After preparative LCMS purification, the fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(ethyl(methyl)amino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)acetamide (6.3 mg, 60% yield) as a pale white solid. LCMS retention time: 1.58 min [C]. MS (E - )m / z:510.1(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.55-8.41(m,2H),7.75-7.54(m,1H) ),7.12(d,J=1.2Hz,1H),4.06(s,3H),3.75-3.62(m,1H),3.18(td,J=6.9, 13.6Hz,1H),3.09-2.92(m,3H),2.29(s,3H),2.19-2.10(m,2H),1.97-1.8 1(m,3H),1.69-1.54(m,2H),1.44(d,J=6.8Hz,6H),1.04(t,J=7.1Hz,3H).

[0557] The following examples were prepared according to the general procedure described in Example 128.

[0558] Table 15

[0559]

[0560] Examples 130 and 131

[0561] N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)oxetane-3-amine

[0562]

[0563] N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one (0.1 g, 0.254 mmol) was prepared as an intermediate using 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine as described in Examples 65 and 66.

[0564] Example 130 (Isomer 1): After preparative LCMS purification, the fraction containing isomer 1 was collected and evaporated to dryness to give a pale white solid (0.0016, 1.4% yield). LCMS retention time 1.42 min [C]. MS (E - )m / z:451.3(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),8.69(s,1H),8.49(s,1H),7.54(s,1H),4.75(t,J=7.2Hz,2H),4.56(t,J=6.6Hz,2H) ,3.19-3.07(m,4H),2.61(s,3H),2.17(d,J=12.2Hz,2H),1.98(br.s.,2H),1.59(d,J=12.5Hz,2H),1.40(d,J=6.8Hz,8H).

[0565] Example 131 (Isomer 2): After preparative LCMS purification, the fraction containing isomer 2 was collected and evaporated to dryness to give a pale white solid (0.0074, 6.4% yield). LCMS retention time 1.58 min [C]. MS (E - )m / z:451.3(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),8.70(s,1H),8.49(s,1H),7.56(s,1H),4.63(t,J=6.6Hz,2H),4.35(t,J=6.2Hz,2H),3.99-3.92(m,1H) ,3.22-3.06(m,3H),2.68(d,J=2.2Hz,1H),2.61(s,3H),2.07-1.97(m,2H),1.77(d,J=13.4Hz,2H),1.65-1.48(m,4H),1.42(d,J=6.8Hz,6H).

[0566] The following examples were prepared according to the general procedures described in Examples 130 and 131.

[0567] Table 16

[0568]

[0569]

[0570]

[0571] Examples 144 and 145

[0572] N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)-3-methyloxacyclobutane-3-amine

[0573]

[0574] Intermediate 144A: (4-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)thiazolyl)tert-butyl carbamate

[0575]

[0576] A solution of (4-iodo-2-(1,4-dioxaspiro[4.5]dec-8-yl)thiazolyl)carbamate tert-butyl (4.0 g, 8.58 mmol) in toluene (50 mL) and DIPEA (10.00 mL) was added to a mixture of triphenylphosphine (0.225 g, 0.858 mmol) and copper iodide (I) (0.163 g, 0.858 mmol), and degassed with argon for 10 min. Next, 6-ethynyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (1.753 g, 11.15 mmol) was added, followed by bis(triphenylphosphine)palladium(II) dichloride (0.33 g, 0.429 mmol), and degassed again for 5 min. The resulting reaction mixture was heated at 45 °C for 3 h. The reaction mixture was filtered, washed with ethyl acetate (100 mL), and the filtrate was concentrated to give the crude product. The crude product was purified by combiflash on a 40 g silica gel column (eluting with 60% EtOAc / petroleum ether). After fractional concentration, tert-butyl carbamate (4-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)thiazolyl-5-yl)carbamate (2.0 g, 4.04 mmol, 47.0% yield) was collected as a pale yellow solid. LC-MS retention time was 3.01 min [E]. MS (E) - )m / z:496.2(M+H).

[0577] Intermediate 144B: 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0578]

[0579] Silver acetate (1.179 g, 7.06 mmol) was added to a solution of (3.5 g, 7.06 mmol) tert-butyl carbamate in toluene (50 mL). The resulting solution was heated at 100 °C for 45 min. The reactants were filtered through diatomaceous earth, washed with EtOAc (10 mL), and the filtrate was concentrated to give tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (2.0 g, 4.04 mmol, 57.1% yield) as a pale yellow solid. The LC-MS retention time was 2.91 min [E]. MS (E) - )m / z:496.2.1(M+H).

[0580] Intermediate 144C: ​​6-bromo-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0581]

[0582] NBS (0.790 g, 4.44 mmol) in DMF (20 mL) was added dropwise to a solution of 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (2.0 g, 4.04 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with ice water (70 ml), stirred for 10 min, and the resulting precipitate was filtered and dried to give tert-butyl 6-bromo-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (1.6 g, 2.79 mmol, 69.0% yield) as a pale yellow solid. LC-MS retention time: 3.24 min [E]. MS (E - )m / z:576.2(M+2H).

[0583] Intermediate 144D: 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0584]

[0585] Tripotassium phosphate (0.970 g, 5.57 mmol) was added to a solution of 6-bromo-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxane[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (1.6 g, 2.79 mmol) in dioxane (15 mL) and water (1.667 mL). The solution was degassed for 10 min, and PdCl2(dppf)-CH2Cl2 adduct (0.227 g, 0.279 mmol) was added. The reaction mixture was degassed again for 5 min, and then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (2.63 mL, 13.93 mmol) was added. The resulting reaction mixture was heated at 70 °C for 4 h. The reactants were concentrated, diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by combiflash on a 40 g silica gel column (eluting with 80% EtOAc / petroleum ether). After fractional concentration, tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (1.1 g, 2.054 mmol, 73.7% yield) was collected as a pale yellow solid. LC-MS retention time: 3.59 min [E]. MS (E - )m / z:536.2(M+H).

[0586] Intermediate 144E: 6-Isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0587]

[0588] A solution of 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (1.1 g, 2.054 mmol) in methanol (75 mL) and DCM (25 mL) was purged with nitrogen and Pd / C (0.874 g, 4.11 mmol) was added. The system was purged under vacuum and purged with hydrogen and stirred under a hydrogen atmosphere for 24 h. The reaction mixture was filtered through a diatomaceous earth stopper. The diatomaceous earth pad was washed with additional methanol and the filtrate was concentrated to dryness to give 0.85 g, 92%, 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester as a white solid. LC-MS retention time 2.22 min [F]. MS (E) - )m / z:538.2(M+H).

[0589] Intermediate 144F: 4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one

[0590]

[0591] TFA (10 mL, 130 mmol) was added dropwise to a solution of 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (1.1 g, 2.046 mmol) in DCM (20 mL) and stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (20 mL) and eluted with 10% NaHCO3 (20 mL). The reactants were concentrated and co-distilled with DCM and petroleum ether (3 x 20 mL) and dried under vacuum to give 4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (0.8 g, 2.033 mmol, 99% yield) as a yellow solid. LC-MS retention time 1.34 min [F]. MS (E) - )m / z:394.2(M+H).

[0592] The following intermediates were prepared in a manner similar to that used for intermediates 144 and 145:

[0593] Table 17

[0594]

[0595] Examples 144 and 145: N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-3-methyloxacyclobutane-3-amine

[0596] Add 3-methyloxetane-3-amine (16.60 mg, 0.191 mmol) to a solution of 4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (75 mg, 0.191 mmol) in THF (5 mL) and DMF (5 mL), then add TEA (0.027 mL, 0.191 mmol) dropwise. Stir the resulting pale yellow solution under nitrogen at room temperature for 12 h. Then add sodium cyanoborohydride (23.95 mg, 0.381 mmol) at 0 °C and continue stirring at room temperature for 2 h. Concentrate the reaction mixture to remove volatiles, dilute the crude product with DCM (30 mL), and wash with water (25 mL). Dry the separated organic layer with sodium sulfate, filter, and concentrate. The crude product obtained was purified by preparative LCMS using method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator to obtain isomers 1 and 2.

[0597] Example 144 (isomer 1) was obtained as a pale yellow solid (23 mg, 0.048 mmol, 24.93% yield). LCMS retention time was 1.38 min [A]. MS (E) - )m / z:465.3. 1 H NMR(400MHz, DMSO-d6)δ11.32(s,1H)8.84(s,1H)8.49(s,1H)7.80(s,1H)4.41(d,J=5.38Hz,2H)4.21(d,J=5.62Hz,2H)2.91-2.98(m,1H)2.68-2 .77(m,2H)2.57-2.65(m,2H)2.28(s,3H)2.06-2.15(m,2H)1.73-1.81(m ,2H)1.58(qd,J=12.76,2.81Hz,2H)1.44(s,3H)1.31(d,J=6.85Hz,6H).

[0598] Example 145 (isomer 2) was obtained as a pale yellow solid. LCMS retention time: 1.58 min [A]. MS (E) - )m / z:465.3. 1 H NMR(400MHz, DMSO-d6)δ11.31-11.38(m,1H)8.86(s,1H)8.49(s,1H)7.81(s,1H)4.42(d,J=5.62Hz,2H)4.18(d,J=5.62Hz,2H)3 .13-3.18(m,1H)2.79-2.86(m,1H)2.71-2.78(m,1H)2.29(s,3H)2.03-2.14(m,2H)1.78-1.88(m,2H)1.54-1.64(m,2H)1.49(br d,J=3.18Hz,2H)1.42(s,3H)1.33(d,J=6.85Hz,6H).

[0599] The following examples were prepared according to the general procedures described in Examples 144 and 145.

[0600] Table 18

[0601]

[0602]

[0603]

[0604] Examples 162 and 163

[0605] 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide

[0606]

[0607] Intermediate 162A: 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine

[0608]

[0609] Methylamine (4.88 mL, 9.77 mmol) in THF was added to a solution of 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one (200 mg, 0.488 mmol) in THF (5 mL) and DMF (5 mL), followed by dropwise addition of acetic acid (2.80 μl, 0.049 mmol). The resulting pale yellow solution was stirred at room temperature under nitrogen for 12 h. Sodium cyanoborohydride (61.4 mg, 0.977 mmol) was then added at 0 °C, and stirring continued at room temperature for 2 h. The reactants were concentrated to remove volatiles. The crude product was diluted with DCM (30 mL) and washed with water (25 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine (250 mg, 0.353 mmol, 72.3% yield) as a yellow solid. LC-MS retention time 1.6 min [C]. MS (E - )m / z:425.3.

[0610] Examples 162 and 163: 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide

[0611] TEA (0.046 mL, 0.330 mmol) was added to a solution of 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-methylcyclohexyl-1-amine (70 mg, 0.165 mmol) in THF (2 mL) and DMF (1 mL), followed by the addition of 2-chloro-N,N-dimethylacetamide (20.04 mg, 0.165 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product obtained was purified by preparative LCMS using method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator to obtain isomers 1 and 2.

[0612] Example 162 (isomer 1) was obtained as a pale yellow solid (19.8 mg, 0.036 mmol, 22.01% yield). LCMS retention time was 1.30 min [A]. MS (E) - )m / z:510.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.57-8.43(m,2H),7.12(s,1H),4.12-3.99(m,3H),3.24-3.14(m,2H),3.0 1(s,5H),2.92-2.77(m,5H),2.74(s,2H),2.22(br.s.,3H),1.92(s,1H),1.60(br.s.,3H),1.44(d,J=6.8Hz,6H).

[0613] Example 163 (isomer 2) was obtained as a pale yellow solid (4.1 mg, 7.32 μmol, 4.44% yield). LCMS retention time was 1.44 min [A]. MS (E) - )m / z:510.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),8.55-8.42(m,2H),7.14(d,J=1.2Hz,1H),4.07(s,3H),3.28(br.s.,1H),3.25-3.15(m,2H),3.09- 2.93(m,3H),2.82(s,3H),2.55(s,2H),2.30-2.16(m,3H),2.16-2.03(m,2H),1.81(d,J=9.0Hz,3H),1.64(br.s.,2H),1.52-1.37(m,6H).

[0614] The following examples were prepared according to the general procedures described in Examples 162 and 163.

[0615] Table 19

[0616]

[0617] The following examples were prepared according to the general procedures described in intermediates 144 and 145.

[0618] Table 20

[0619]

[0620]

[0621] Examples 172 and 173

[0622] 4-(6-Isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexyl-1-amine

[0623]

[0624] (3-methyloxetane-3-yl)methylamine (19.33 mg, 0.191 mmol) was added to a solution of 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one (75 mg, 0.191 mmol) in THF (3 mL) and DMF (2 mL) at 0 °C, followed by dropwise addition of acetic acid (1.094 μL, 0.019 mmol). The resulting pale yellow solution was stirred under nitrogen at room temperature for 12 h. Sodium cyanoborohydride (24.01 mg, 0.382 mmol) was then added at 0 °C, and stirring continued at room temperature for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by preparative LCMS using method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator.

[0625] Example 172 (isomer 1) was obtained as a pale yellow solid (2.7 mg, 5.42 μmol, 2.84% yield). LCMS retention time was 1.48 min [A]. MS (E) - )m / z:478.3(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.39-8.28(m,1H),8.00-7.97(m,1H),7.60(s,1H),7.18(dd,J=8.1,4.6Hz,1H),4.43(d,J=6.4Hz,2H) ,4.28(d,J=6.4Hz,2H),3.91(d,J=3.4Hz,4H),3.23(br.s.,3H),3.13-3.00(m,3H),2.23(br.s.,3H),1.69-1.46(m,4H),1.43-1.32(m,6H).

[0626] Example 173 (Isomer 2) yielded a pale yellow solid (3.0 mg, 5.69 μmol, 2.98% yield). LCMS retention time 1.53 min [A]. MS (E) - )m / z:478.3(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),8.34(d,J=4.4Hz,1H),7.98(d,J=7.8Hz,1H),7.60( s,2H),7.18(dd,J=7.7,4.5Hz,1H),4.38(d,J=6.1Hz,2H),4.28-4.13(m,2H),3.96-3.86( m,3H),3.18-3.02(m,2H),2.90(s,1H),2.74(s,1H),2.28(br.s.,2H),2.08(br.s.,1H),2 .02(s,1H),1.92(s,2H),1.89-1.79(m,2H),1.74(d,J=12.0Hz,2H),1.40(d,J=6.8Hz,6H).

[0627] The following examples were prepared according to the general procedures described in Examples 172 and 173.

[0628] Table 21

[0629]

[0630]

[0631] Examples 184 and 185

[0632] N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)oxetane-3-amine

[0633]

[0634] AcOH (7.02 μL, 0.123 mmol) was added to a solution of 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (50 mg, 0.123 mmol) and oxetane-3-amine (90 mg, 1.227 mmol) in a mixture of DMF (1 mL) and THF (1 mL) at 0 °C and stirred overnight at room temperature. Sodium cyanoborohydride (15.42 mg, 0.245 mmol) was added to the reaction mixture at 0 °C and stirring was continued at room temperature for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by preparative LCMS using Method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator.

[0635] Example 184 (Isomer 1): (9.9 mg, 0.021 mmol, 17.19% yield). LCMS retention time 1.348 min [A]. MS (E) - )m / z:465.3(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),8.72(s,1H),8.46(s,1H),4.65(t,J= 6.7Hz,2H),4.35(t,J=6.1Hz,2H),4.07-3.96(m,1H),2.95(tt,J=11.9,3.6H z,2H),2.76-2.66(m,2H),2.57(s,3H),2.18(s,3H),2.15-2.04(m,2H),1.86 (d,J=11.0Hz,2H),1.63-1.42(m,2H),1.41-1.12(m,7H),1.12-0.97(m,1H).

[0636] Example 185 (Isomer 2): (9.1 mg, 0.018 mmol, 14.64% yield). LCMS retention time 1.514 min [A]. MS (E) - )m / z:465.3(M+H). 1H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.72(d,J=8.8Hz,1H),8.47(d,J=0.7Hz,1H),4.68-4. 59(m,2H),4.55(d,J=4.9Hz,2H),3.63(qd,J=11.5,5.4Hz,1H),3.25-3.18(m,1H),2.97-2.8 6(m,1H),2.79-2.68(m,1H),2.65-2.55(m,3H),2.40-2.32(m,1H),2.19(s,3H),1.9(d,J=9. 3Hz, 1H), 1.93-1.82 (m, 3H), 1.82-1.59 (m, 2H), 1.34 (d, J = 6.8Hz, 6H), 1.17 (t, J = 7.2Hz, 2H).

[0637] The following examples were prepared according to the general procedures described in Examples 184 and 185.

[0638] Table 22A

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646] Table 22B

[0647] The following examples were prepared according to the general procedure described in intermediate 162.

[0648]

[0649]

[0650]

[0651] Examples 241 and 242

[0652] 5-(6-isopropyl-2-(4-(oxacyclobutane-3-ylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one

[0653]

[0654] AcOH (7.20 μL, 0.126 mmol) was added to a solution of 5-(6-isopropyl-2-(4-oxocyclohexyl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (50 mg, 0.126 mmol) and oxetane-3-amine (92 mg, 1.258 mmol) in a mixture of DMF (1 mL) and THF (1 mL) at 0 °C and stirred overnight at room temperature. Sodium cyanoborohydride (15.42 mg, 0.245 mmol) was added to the reaction mixture at 0 °C and stirring was continued at room temperature for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by preparative LCMS using Method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator.

[0655] Example 241 (Isomer 1): (13.6 mg, 0.028 mmol, 22.29% yield). LCMS retention time 1.523 min [A]. MS (E) - )m / z:455.3(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.52(s,1H),4.64(t,J=6.6Hz,2H),4.34(t,J=6.4Hz,2H),4.06-3.94(m,1H),3.94-3.86(m,1H),3.46 (s,3H),2.98-2.87(m,2H),2.74-2.68(m,1H),2.18-1.97(m,6H),1.93 (s,2H),1.85(d,J=10.3Hz,2H),1.61-1.45(m,2H),1.36-1.08(m,8H).

[0656] Example 242 (Isomer 2): (7.8 mg, 0.016 mmol, 12.89% yield). LCMS retention time 1.702 min [A]. MS (E) - )m / z:455.3(M+H). 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),7.53(s,1H),4.64(t,J=6.6Hz,2H),4.35(t,J=6.2Hz,2H),3.97(br.s.,1H),3.46(s, 3H),3.12-3.05(m,2H),2.79-2.64(m,2H),2.13-1.86(m,8H),1.85-1.69(m,2H),1.57(d,J=4.6Hz,4H),1.37-1.24(m,6H).

[0657] The following examples were prepared according to the general procedures described in Examples 241 and 242.

[0658] Table 23

[0659]

[0660]

[0661]

[0662]

[0663]

[0664] Examples 269 and 270

[0665] 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane

[0666]

[0667] Intermediate 269A: 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-6-vinyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylic acid tert-butyl ester

[0668]

[0669] To a solution of 6-bromo-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (220 mg, 0.373 mmol) in dioxane (10 mL) and water (2.500 mL), vinylboric acid (34.8 mg, 0.484 mmol) and tripotassium phosphate (237 mg, 1.118 mmol) were added. The solution was degassed with argon for 10 min and a PdCl2(dppf)-CH2Cl2 adduct (30.4 mg, 0.037 mmol) was added. The resulting reaction mixture was heated at 90 °C for 12 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Combiflash on a 40 g silica gel column (eluting with 40% EtOAc / petroleum ether). After fractional concentration, 0.18 g of tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-6-vinyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (90% yield) was collected as a pale yellow solid. LC-MS retention time 3.35 min [C]. MS (E - )m / z:538.2(M+H).

[0670] Intermediate 269B: 6-Ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0671]

[0672] A solution of 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-6-vinyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (0.18 g, 0.335 mmol) in THF (10 mL) and methanol (2.5 mL) was purged with nitrogen and Pd-C (0.036 g, 0.335 mmol) was added. The system was purged under vacuum and purged with hydrogen, and stirred under a hydrogen atmosphere for 24 h. The reactants were filtered through a diatomaceous earth stopper to obtain a yellow solid, tert-butyl 6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid (0.15 g, 83%). The LC-MS retention time was 1.48 min [C]. MS (E) - )m / z:540.2(M+H).

[0673] Intermediate 269C: 4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one

[0674]

[0675] TFA (5 mL) was added to a solution of 6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (120 mg, 0.222 mmol) in DCM (5.00 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated to give a yellow solid of 4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (80 mg, 91%). LC-MS retention time 2.31 min [C]. MS (E - )m / z:396.2(M+H).

[0676] Examples 269 and 270: 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane

[0677] Acetic acid (0.014 mL, 0.253 mmol) was added to a solution of 4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one (100 mg, 0.253 mmol) in THF (5 mL) and DMF (5.00 mL), followed by the addition of 2-oxa-6-azaspiro[3.3]heptane (376 mg, 3.79 mmol) and stirring at ambient temperature for 12 h. The reaction mixture was concentrated to remove DMF and THF, and the resulting residue was absorbed in 3 mL of dry methanol and cooled to -78 °C under a nitrogen atmosphere. NaCNBH4 (79 mg, 1.264 mmol) was added in a single step. The reaction was continued at the same temperature (-78 °C) for 3 h, followed by 1 h to 0 °C. The reaction was quenched with 10 mL of ice-cold water and concentrated. The residue was extracted with 10% methanol (10 mL x 2) in DCM. The organic layer was concentrated and the crude product obtained was purified by preparative LCMS using method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator.

[0678] Example 269 (isomer 1) (3 mg, 2.3%) was obtained as a pale yellow solid. LCMS retention time: 1.12 min [A]. MS (E) - )m / z:479.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.53(d,J=1.5Hz,1H),8.50-8.44(m,1H),7.17(d,J=1.2Hz,1H),4.61(s,4H),4.06(s,3H) ,2.95-2.80(m,4H),2.15-2.07(m,2H),1.91(s,1H),1.85-1.77(m,2H),1.57-1.41(m,2H),1.36-1.28(m,3H),1.15-0.97(m,3H).

[0679] Example 270 (isomer 2) (2.5 mg, 1.9%) was obtained as a pale yellow solid. LCMS retention time was 1.02 min [A]. MS (E) - )m / z:479.2(M+H). 1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.53(d,J=1.5Hz,1H),8.47(s,1H),7.1 8(d,J=1.2Hz,1H),4.62(s,4H),4.10-4.01(m,4H),3.30-3.21(m,4H),3.08-3. 00(m,1H),2.90-2.79(m,4H),2.74(s,1H),2.29-2.14(m,1H),1.97-1.84(m,3H ),1.81-1.63(m,3H),1.61-1.41(m,4H),1.37-1.29(m,3H),1.17-1.06(m,3H).

[0680] The following examples were prepared according to the general procedures described in Examples 269 and 270.

[0681] Table 24

[0682]

[0683]

[0684] Example 273

[0685] N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazo-2-yl)cyclohexyl)oxetane-3-amine

[0686]

[0687] Intermediate 273A: 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-2-(1,4-dioxaspiro[4,5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0688]

[0689] To a solution of 6-bromo-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (600 mg, 1.016 mmol) in THF (30 mL) and water (7.5 mL), methylboronic acid (304 mg, 5.08 mmol) and tripotassium phosphate (702 mg, 3.05 mmol) were added. The solution was degassed with argon for 10 min and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (80 mg, 0.102 mmol) was added. The resulting reaction mixture was heated at 70 °C for 12 h. The reactants were concentrated, diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by combiflash on a 40 g silica gel column (eluting with 40% EtOAc / petroleum ether). After fractional concentration, 0.35 g (65% yield) of tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate was collected as a pale yellow solid. LC-MS retention time: 2.78 min [C]. MS (E-) m / z: 526.2 (M+H).

[0690] Intermediate 273B: 4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl-1-one

[0691]

[0692] TFA (10 mL) was added to a solution of 350 mg (1.142 mmol) of 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester in DCM (10.00 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated to give a yellow solid of 4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (250 mg, 58%). LC-MS retention time 1.64 min [C]. MS (E) - )m / z:382.2(M+H).

[0693] Example 273: N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexyl)oxetane-3-amine

[0694] Acetic acid (0.012 mL, 0.210 mmol) was added to a solution of 4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)cyclohexane-1-one (80 mg, 0.210 mmol) in THF (2 mL) and DMF (2.00 mL), followed by the addition of oxetane-3-amine (0.012 mL, 0.210 mmol) and stirring at ambient temperature for 12 h. NaCNBH3 (13.18 mg, 0.210 mmol) was added and the reaction was continued at room temperature for 1 h. The reaction was quenched with 10 mL of water and extracted with 10% methanol (10 mL x 2) in DCM. The organic layer was concentrated. The obtained crude product was purified by preparative LCMS using method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator to obtain Example 273 (isomer 1: 3.5 mg, 3.7%) and Example 273 (isomer 2: 3.5 mg, 3.7%), which were pale yellow solids.

[0695] Example 273 (Isomer 1): LCMS retention time 1.20 min [A]. MS (E-) m / z: 439.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ11.72 (s, 1H), 8.59 (d, J = 1.2Hz, 1H), 8.46 (s, 1H), 7. 23(d,J=1.2Hz,1H),4.64(t,J=6.5Hz,2H),4.32(t,J=6.2Hz,2H),4.07(s,3H) ,3.98(quin,J=6.8Hz,1H),2.97-2.90(m,1H),2.47-2.36(m,4H),2.16-2.04( m,2H),1.91(s,2H),1.88-1.78(m,2H),1.61-1.45(m,2H),1.27-1.11(m,2H).

[0696] The following examples were prepared according to the general procedure described in Example 273.

[0697] Table 25

[0698]

[0699] Intermediate 277B

[0700] 6-Ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0701]

[0702] Intermediate 277A: 7,8-Dimethyl-6-((trimethylsilyl)ethynyl)-[1,2,4]triazolo[1,5-a]pyridine

[0703]

[0704] Copper iodide (I) (1.264 g, 6.63 mmol) was added to a solution of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (15 g, 66.3 mmol) in TEA (100 mL), and the mixture was degassed with argon for 10 min. Then, bis(triphenylphosphine)palladium dichloride (II) (3.26 g, 4.64 mmol) was added, followed by trimethylsilylacetylene (13.03 g, 133 mmol). The resulting reaction mixture was heated at 80 °C for 12 h. The reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate (200 mL). The filtrate was diluted with water (250 mL) and extracted with ethyl acetate (2 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give 7,8-dimethyl-6-((trimethylsilyl)ethynyl)-[1,2,4]triazolo[1,5-a]pyridine (16 g, 55.9 mmol, 84% yield), a brown oil. LC-MS 1.90 min [F]. MS (E) - )m / z:244.2(M+H).

[0705] Intermediate 277B: 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0706] Potassium carbonate (18.17 g, 131 mmol) was added to a solution of 7,8-dimethyl-6-((trimethylsilyl)ethynyl)-[1,2,4]triazolo[1,5-a]pyridine (16 g, 65.7 mmol) in methanol (150 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, diluted with water (150 mL), and extracted with DCM (3 x 250 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Combiflash on a 120 g silica gel column (eluted with 75% EtOAc / petroleum ether). After fractional concentration, 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (7.2 g, 42.1 mmol, 64.0% yield) was collected as a white solid. LC-MS 1.81 min [C]. MS (E - )m / z:172.2(M+H).

[0707] The following intermediates are prepared according to the general procedure described in intermediate 277B.

[0708] Table 26

[0709]

[0710] Example 278

[0711] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0712]

[0713] Intermediate 278A: Methyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate

[0714]

[0715] DPPF (3.97 g, 7.16 mmol) and PdOAc2 (0.804 g, 3.58 mmol) were added to a solution of (2-bromothiazol-5-yl)carbamate tert-butyl ester (10 g, 35.8 mmol) in methanol (75 mL) and DMF (75 mL). The solution was degassed with argon for 10 min. The reactants were saturated with CO gas, and then TEA (19.97 mL, 143 mmol) was added. The mixture was then heated to 10 kg / cm³. 2The mixture was stirred at 80°C for 7 h under pressure in the presence of CO. The reactants were concentrated, and the residue was dissolved in DCM (100 mL), washed with water (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give the crude compound. The crude product was purified by ISCO chromatography on a 120 g silica gel column (eluting the compound with 35% ethyl acetate in petroleum ether). The fractions were collected and concentrated to give methyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate (7.5 g, 29.0 mmol, 81% yield) as a grayish-white solid. LC-MS retention time 2.10 min [C]. MS (E - )m / z:259.1(M+H).

[0716] Intermediate 278B: Methyl 5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-carboxylate

[0717]

[0718] NIS (6.53 g, 29.0 mmol) in acetonitrile (50 mL) was added dropwise to a solution of methyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate (7.5 g, 29.0 mmol) in acetonitrile (150 mL) at 0 °C, and the mixture was stirred for 10 min at the same temperature. The reaction was quenched with water (250 mL) and extracted with ethyl acetate (3 x 200 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by Combiflash on an 80 g silica gel column (eluted with 31% EtOAc / petroleum ether). After fractional concentration, methyl 5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-carboxylate (8.2 g, 21.34 mmol, 73.5% yield) was collected as a pale yellow solid. LC-MS retention time: 1.64 min [F]. MS (E - )m / z:384.1(M+H).

[0719] Intermediate 278C: methyl 5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)thiazolyl-2-carboxylate

[0720]

[0721] A solution of methyl 5-((tert-butoxycarbonyl)amino)-4-iodothiazolyl-2-carboxylate (2.0 g, 5.21 mmol) in toluene (50 mL) and DIPEA (10.00 mL) was added to a mixture of triphenylphosphine (0.137 g, 0.521 mmol) and copper iodide (I) (0.099 g, 0.521 mmol), and degassed with argon for 10 min. Then, 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (1.159 g, 6.77 mmol) was added, followed by bis(triphenylphosphine)palladium(II) dichloride (0.183 g, 0.260 mmol), and degassed again for 5 min. The resulting reaction mixture was heated at 45 °C for 3 h. The reaction mixture was filtered, washed with ethyl acetate (100 mL), and the filtrate was concentrated to give the crude product. The crude product was purified by combiflash on a 40 g silica gel column (eluting with 4% MeOH / CHCl3). After fractional concentration, methyl 5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)thiazolyl-2-carboxylate (1.4 g, 3.28 mmol, 62.9% yield) was collected as a pale yellow solid. LC-MS retention time was 2.71 min [C]. MS (E) - )m / z:428.2.1(M+H).

[0722] Intermediate 278D: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester

[0723]

[0724] Silver acetate (0.508 g, 3.04 mmol) was added to a solution of methyl 5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)thiazole-2-carboxylate (1.3 g, 3.04 mmol) in toluene (15 mL), and the resulting solution was heated at 100 °C for 45 min. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate (10 mL), and the filtrate was concentrated to give 4-(tert-butyl)-2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.3 g, 2.80 mmol, 92% yield) as a pale yellow solid. LCMS retention time: 2.71 min [C]. MS(E - )m / z:428.2.1(M+H).

[0725] Intermediate 278E: 6-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester

[0726]

[0727] NBS (0.541 g, 3.04 mmol) in DMF (5 mL) was added dropwise to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (1.3 g, 3.04 mmol) in DMF (15 mL) at 0 °C, and stirring was allowed at room temperature for 12 h. The reactants were quenched with ice water (70 mL), stirred for 10 min, and the resulting precipitate was filtered and dried to give 6-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (0.9 g, 1.777 mmol, 58.4% yield), a pale yellow solid. LC-MS retention time: 3.01 min [C]. MS (E) - )m / z:508.2(M+2H).

[0728] Intermediate 278F: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester

[0729]

[0730] Add tripotassium phosphate (1.445 g, 8.29 mmol) to a solution of 2.1 g (4.15 mmol) of 6-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (2.1 g, 4.15 mmol) in THF (15 mL) and water (1.667 mL), degas for 10 min, and then add chlorine. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.326 g, 0.415 mmol) was added, and the reaction mixture was degassed again for 5 min. Then, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (3.48 g, 20.74 mmol) was added. The reaction mixture was heated at 70 °C for 4 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Combiflash on a 24 g silica gel column (eluted with 41% EtOAc / petroleum ether). After fractional concentration, 1.3 g (2.78 mmol, 67.0% yield) of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester was collected as a pale yellow solid. LCMS retention time was 1.86 min [F]. MS (E) - )m / z:468.2(M+H).

[0731] Intermediate 278G: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester

[0732]

[0733] A solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (1.3 g, 2.78 mmol) in methanol (75 mL) was purged with nitrogen and Pd / C (0.444 g, 0.417 mmol). The system was purged under vacuum and purged with hydrogen, and stirred under a hydrogen atmosphere for 24 h. The reaction mixture was filtered through a diatomaceous earth stopper. The diatomaceous earth pad was washed with additional methanol and the filtrate was concentrated to dryness to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (1.15 g, 2.449 mmol, 88% yield) as a white solid. LC-MS retention time 1.92 min [F]. MS (E) - )m / z:470.2(M+H).

[0734] Intermediate 278H: methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylate

[0735]

[0736] TFA (1.805 mL, 23.43 mmol) was added dropwise to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (1.1 g, 2.343 mmol) in DCM (10 mL) and stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (20 mL) and eluted with 10% NaHCO3 (20 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylate (0.86 g, 2.328 mmol, 99% yield) as a pale yellow solid. LC-MS retention time: 2.39 min [C]. MS (E) - )m / z:370.2(M+H).

[0737] Intermediate 278I: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carboxylic acid

[0738]

[0739] Methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylic acid (0.86 g, 2.328 mmol) in methanol (10 mL) was added dropwise with 10% sodium hydroxide (5 mL, 2.328 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated, the aqueous layer was acidified to pH 4-5, the resulting precipitate was filtered and dried to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylic acid (0.7 g, 1.970 mmol, 85% yield) as a grayish-white solid. LC-MS retention time: 0.94 min [C]. MS (E - )m / z:355.2(M+H).

[0740] The following intermediates were prepared according to the general procedure described in Intermediate 278I.

[0741] Table 27

[0742]

[0743] Intermediate 278K: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0744]

[0745] A solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carboxylic acid (400 mg, 1.125 mmol) in THF (10 mL) was heated at 70 °C for 1 h. The reaction mixture was concentrated to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl (340 mg, 1.092 mmol, 97% yield) as a pale yellow solid. LC-MS retention time: 1.26 min [F]. MS (E) - )m / z:3122(M+H).

[0746] Intermediate 278L: 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0747]

[0748] NBS (194 mg, 1.092 mmol) in DMF (3 mL) was added dropwise to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (340 mg, 1.092 mmol) in DMF (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL), stirred for 10 min, and the resulting precipitate was filtered and dried to give 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (275 mg, 0.705 mmol, 64.5% yield) as a grayish-white solid. LCMS retention time: 1.52 min [G]. MS(E - )m / z:390.2(M+H).

[0749] The following intermediates were prepared according to the general procedure described in intermediate 278L.

[0750] Table 28

[0751]

[0752] Intermediate 278N: 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0753]

[0754] Cesium carbonate (417 mg, 1.281 mmol) was added to a solution of 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (250 mg, 0.641 mmol) and piperazine-1-carboxylic acid tert-butyl ester (179 mg, 0.961 mmol) in toluene (7 mL). The resulting solution was degassed with N2 for 10 min and Pd2(dba)3 (58.7 mg, 0.064 mmol) was added, followed by the addition of BINAP (399 mg, 0.641 mmol), at which point the solution was degassed again for 5 min. The resulting mixture was heated at 90 °C for 12 h. The cooled reaction mixture was diluted with ethyl acetate (500 mL), washed with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by combiflash on a 24 g silica gel column (eluting the compound with 75% ethyl acetate in petroleum ether). Fractions were collected and concentrated to give tert-butyl 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazine-1-carboxylate (210 mg, 0.424 mmol, 66.1% yield) as a pale yellow solid. LC-MS retention time 3.48 min [C]. MS (E) - )m / z:496.2(M+H).

[0755] Example 278: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0756] HCl (2 mL, 8.00 mmol) in dioxane was added dropwise to a solution of 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazine-1-carboxylic acid tert-butyl ester (210 mg, 0.424 mmol) in DCM (10 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (20 mL) and eluted with 10% NaHCO3 (20 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (170 mg, 100% yield) as a pale yellow solid. LC-MS retention time 1.62 min [C]. MS (E) -)m / z:396.2(M+H).

[0757] The following examples were prepared according to the general procedure described in Example 278.

[0758] Table 29

[0759]

[0760] Example 280

[0761] 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazin-1-yl)-2-(dimethylamino)ethyl-1-one

[0762]

[0763] HATU (65.4 mg, 0.172 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (68 mg, 0.172 mmol) and dimethylglycine (17.73 mg, 0.172 mmol) in DMF (1 mL), followed by TEA (0.024 mL, 0.172 mmol). The resulting solution was stirred at room temperature for 12 h. The reactants were diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated. The LC-MS retention time was 1.76 min [C]. - )m / z:481.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.68(s,1H),8.44(s,1H),4.17(s,4H),3.91(s,4H),3.3 7(br.s.,2H),2.77-2.58(m,4H),2.27(s,6H),2.18(s,3H),1.98(s,2H),1.26(d,J=6.8Hz,6H).

[0764] Example 281

[0765] 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazin-1-yl)-2-methylprop-2-ol

[0766]

[0767] Potassium carbonate (17.47 mg, 0.126 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.063 mmol) and 1-chloro-2-methylprop-2-ol (6.86 mg, 0.063 mmol) in DMF (1 mL). The resulting solution was heated at 80 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The reactants were purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazin-1-yl)-2-methylprop-2-ol (16.7 mg, 0.035 mmol, 55.9% yield) as a pale yellow solid. LCMS retention time: 2.01 min [A]. MS (E) - )m / z:468.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.68(s,1H),8.44(s,1H),4.17(s,1H),3.91(s,1H),3.37(br.s., 3H),2.77-2.58(m,5H),2.58-2.53(m,3H),2.27(s,2H),2.18(s,3H),1.26(d,J=6.8Hz,6H),1.13(s,6H).

[0768] Example 282

[0769] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(2-(methanesulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0770]

[0771] TEA (8.81 μL, 0.063 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.063 mmol) and 1-chloro-2-(methanesulfonyl)ethane (9.01 mg, 0.063 mmol) in DMF (1 mL). The resulting solution was heated at 90 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The reactants were purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to obtain a pale yellow solid, 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(2-(methanesulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole. LCMS retention time: 1.70 min [A]. MS(E) - )m / z:502.3(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.69(s,1H),8.46(s,1H),3.36(br.s.,8H), 3.13(s,3H),2.68-2.61(m,2H),2.60-2.53(m,6H),2.17(s,3H),1.34-1.18(m,6H).

[0772] Example 283

[0773] 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazin-1-yl)-N,N-dimethylacetamide

[0774]

[0775] TEA (8.81 μL, 0.063 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.063 mmol) and 2-chloro-N,N-dimethylacetamide (7.68 mg, 0.063 mmol) in DMF (1 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The reactants were purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperazin-1-yl)-N,N-dimethylacetamide (19.5 mg, 0.039 mmol, 62.3% yield) as a pale yellow solid. LCMS retention time: 1.72 min [A]. MS (E) - )m / z:481.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.68(s,1H),8.44(s,1H),3.39(br.s.,4H),3.23(s,2H) ,3.03(s,3H),2.83(s,3H),2.66-2.58(m,5H),2.56(s,3H),2.18(s,3H),1.26(d,J=6.8Hz,6H).

[0776] The following examples were prepared according to the general procedure described in Example 283.

[0777]

[0778] Example 286

[0779] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0780]

[0781] TEA (0.023 mL, 0.164 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (65 mg, 0.164 mmol) and oxetane-3-one (11.84 mg, 0.164 mmol) in methanol (2 mL) at 0 °C, followed by the addition of acetic acid (9.41 μL, 0.164 mmol). The resulting solution was stirred at room temperature for 12 h. Sodium cyanoborohydride (10.33 mg, 0.164 mmol) was then added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried. LCMS retention time: 2.16 min [C]. MS(E) - )m / z:452.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.68(s,1H),8.44(s,1H),4.59(s,2H),4.48(s,2H) ,3.37(m,5H),2.81(s,1H),2.52(s,3H),2.27(m,4H),2.18(s,3H),1.26(d,J=6.8Hz,6H).

[0782] The following examples were prepared according to the general procedure described in Example 286.

[0783]

[0784]

[0785] Example 290

[0786] 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(3-methyloxetane-3-yl)piperidin-4-amine

[0787]

[0788] Intermediate 290A: 8-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane

[0789]

[0790] Cesium carbonate (835 mg, 2.56 mmol) was added to a solution of 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (500 mg, 1.281 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (275 mg, 1.922 mmol) in toluene (15 mL). The solution was degassed for 10 min, and then Pd2(dba)3 (117 mg, 0.128 mmol) was added, followed by BINAP (80 mg, 0.128 mmol). The reaction mixture was degassed again for 5 min and heated at 90 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by Combiflash on a 24 g silica gel column (eluted with 45% ethyl acetate / DCM). After fractional concentration, 8-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-1,4-dioxa-8-azaspiro[4,5]decane (490 mg, 1.083 mmol, 85% yield) was collected as a pale yellow solid. LC-MS retention time was 1.54 min [F]. MS (E) - )m / z:453.2(M+H).

[0791] Intermediate 290B: 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-4-one

[0792]

[0793] TFA (3 mL, 38.9 mmol) was added dropwise to a solution of 8-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (450 mg, 0.994 mmol) in DCM (10 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated to give 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-4-one (400 mg, 0.979 mmol, 98% yield) as a yellow oil. LCMS retention time: 1.36 min [F]. MS(E - )m / z:409.2(M+H).

[0794] Example 290: 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(3-methyloxetane-3-yl)piperidin-4-amine

[0795] Acetic acid (3.50 μL, 0.061 mmol) was added to a solution of 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)piperidin-4-one (25 mg, 0.061 mmol) and 3-methyloxetane-3-amine (5.33 mg, 0.061 mmol) in methanol (1 mL) at 0 °C. The resulting solution was stirred at room temperature for 12 h, and then sodium cyanoborohydride (7.69 mg, 0.122 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The reactants were purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-N-(3-methyloxetane-3-yl)piperidin-4-amine (14.1 mg, 48%) as a pale yellow solid. LCMS retention time: 1.75 min [A]. MS (E) - )m / z:480.2(M+H). 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.67(s,1H),8.44(s,1H),4.42(d,J=5.1Hz,2 H),4.21(d,J=5.4Hz,2H),3.91(s,1H),3.82(d,J=12.2Hz,2H),3.01(t,J=11.6Hz,2 H),2.81(br.s.,1H),2.63(dt,J=13.6,6.8Hz,1H),2.59-2.53(m,2H),2.18(s,3H), 1.70(d,J=12.5Hz,2H), 1.46(s,2H), 1.37(d,J=11.2Hz,2H), 1.26(d,J=6.8Hz,6H).

[0796] The following examples were prepared according to the general procedure described in Example 290.

[0797] Table 30

[0798]

[0799]

[0800] Example 300

[0801] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3.3]hept-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0802]

[0803] Intermediate 300A: 6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester

[0804]

[0805] Cesium carbonate (1.419 g, 4.36 mmol) was added to a solution of 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (0.85 g, 2.178 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.518 g, 2.61 mmol) in toluene (15 mL). The mixture was degassed for 10 min, then Pd2(dba)3 (0.199 g, 0.218 mmol) was added, followed by BINAP (0.136 g, 0.218 mmol), and the solution was degassed again for 5 min. The resulting reaction mixture was heated at 90 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Combiflash on a 24 g silica gel column (eluting with 45% ethyl acetate / DCM). After fractional concentration, tert-butyl 6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (550 mg, 1.083 mmol, 49.7% yield) was collected as a yellow solid. LC-MS retention time 1.80 min [F]. MS (E) - )m / z:508.2(M+H).

[0806] Intermediate 300B: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3,3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole

[0807]

[0808] TFA (3 mL, 38.9 mmol) was added dropwise to a solution of 6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (400 mg, 0.788 mmol) in DCM (10 mL) and the solution was stirred at room temperature for 12 h. The reaction mixture was concentrated to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl (400 mg, 0.979 mmol, 98% yield) as a yellow solid. LCMS retention time 1.32 min [A]. MS(E) - )m / z:408.2(M+H). 1 H NMR (400MHz, DMSO-d6) δ11.00(d,J=4.2Hz,1H),8.67(s,1H),8.44(d,J=2.0Hz,1H),4.32(s,1H),4.18(s,2H),4.15(s,3H), 4.05(s,1H),2.65-2.59(m,1H),2.58-2.54(m,2H),2.16(d,J=2.4Hz,3H),1.91(s,1H),1.76(s,1H),1.25(d,J=7.1Hz,6H).

[0809] Example 300: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3.3]hept-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0810] Acetic acid (7.02 μL, 0.123 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.123 mmol) and isobutyraldehyde (8.85 mg, 0.123 mmol) in methanol (1 mL) at 0 °C. The resulting solution was stirred at room temperature for 12 h, and then sodium cyanoborohydride (15.42 mg, 0.245 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The reactants were purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3,3]hept-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole as a pale yellow solid (18.9 mg, 0.039 mmol, 31.9% yield). LCMS retention time was 1.52 min [A]. MS (E) - )m / z:464.2(M+H).

[0811] The following examples were prepared according to the general procedure described in Example 300.

[0812] Table 31

[0813]

[0814]

[0815] Example 303

[0816] 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,6-diazaspiro[3.3]hept-2-yl)-2-methylprop-2-ol

[0817]

[0818] Potassium carbonate (16.96 mg, 0.123 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.123 mmol) and 1-chloro-2-methylprop-2-ol (13.32 mg, 0.123 mmol) in DMF (1 mL). The resulting solution was heated at 80 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-2,6-diazaspiro[3.3]hept-2-yl)-2-methylprop-2-ol (5.6 mg, 0.011 mmol, 9.04% yield) as a pale yellow solid. LCMS retention time: 1.28 min [A]. MS (E) - )m / z:480.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.00-10.95(m,1H),8.66(s,1H),8.44(s,1H),4.14-4.05(m,2H),3.91(s,2H),2 .65-2.59(m,2H),2.56(s,3H),2.19-2.13(m,2H),1.92(s,2H),1.25(d,J=6.8Hz,5H),1.15-1.00(m,6H).

[0819] Example 304

[0820] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-(2-(methanesulfonyl)ethyl)-2,6-diazaspiro[3,3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole

[0821]

[0822] TEA (0.034 mL, 0.245 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (100 mg, 0.245 mmol) and 1-chloro-2-(methanesulfonyl)ethane (35.0 mg, 0.245 mmol) in THF (1 mL) and DMF (1 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-(2-(methanesulfonyl)ethyl)-2,6-diazaspiro[3,3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (23 mg, 0.044 mmol, 18.02% yield) as a pale yellow solid. LCMS retention time was 1.81 min [C]. MS (E) - )m / z:514.2(M+H).

[0823] Example 305

[0824] 5-(6-isopropyl-2-(6-(2-(methanesulfonyl)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one

[0825]

[0826] TEA (8.77 μL, 0.063 mmol) was added to a solution of 5-(6-isopropyl-2-(2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (25 mg, 0.063 mmol) and 1-chloro-2-(methanesulfonyl)ethane (8.97 mg, 0.063 mmol) in THF (1 mL) and DMF (1 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give a pale yellow solid of 5-(6-isopropyl-2-(6-(2-(methanesulfonyl)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (13.3 mg, 0.026 mmol, 41.6% yield). LCMS retention time was 1.24 min [A]. MS(E) - )m / z:504.2(M+H).

[0827] Example 306

[0828] 5-(6-isopropyl-2-(6-(oxecyclobutane-3-yl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one

[0829]

[0830] TEA (10.52 μL, 0.075 mmol) was added to a solution of 5-(6-isopropyl-2-(2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (30 mg, 0.075 mmol) and oxetane-3-one (5.44 mg, 0.075 mmol) in methanol (1 mL) at 0 °C, followed by the addition of acetic acid (4.32 μL, 0.075 mmol). The resulting solution was stirred at room temperature for 12 h, and then sodium cyanoborohydride (9.48 mg, 0.151 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 5-(6-isopropyl-2-(6-(oxecyclobutane-3-yl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazolyl-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (1.0 mg, 2.205 μmol, 2.92% yield) as a pale yellow solid. LCMS retention time was 1.27 min [A]. MS(E) - )m / z:454.2(M+H).

[0831] The following examples were prepared according to the general procedure described in Example 306.

[0832] Table 32

[0833]

[0834]

[0835] Example 308

[0836] (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl

[0837]

[0838] Intermediate 308A: (R)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0839]

[0840] Potassium carbonate (2.125 g, 15.37 mmol) was added to a solution of 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (2.0 g, 5.12 mmol) and (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.539 g, 7.69 mmol) in dioxane (60 mL). The solution was degassed for 10 min, then XPhos Pd G2 (0.403 g, 0.512 mmol) was added and the reaction mixture was degassed again for 5 min. The resulting reaction mixture was heated at 110 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by combiflash on a 40 g silica gel column (eluting with 65% ethyl acetate / DCM). After fractional concentration, (R)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.2 g, 4.32 mmol, 84% yield) was collected as a yellow solid. LC-MS retention time was 3.62 min [C]. MS (E) - )m / z:508.2(MH).

[0841] The following intermediates are prepared according to the general procedure described in intermediate 308A.

[0842] Table 33

[0843]

[0844]

[0845] Example 308: (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl

[0846] To a solution of (R)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.2 g, 4.32 mmol) in DCM (10 mL), 4 M hydrochloric acid (10 mL, 329 mmol) in dioxane was added dropwise and stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole, a pale yellow solid, in HCl (1.9 g, 4.18 mmol, 97% yield). LCMS retention time was 1.31 min [A]. MS (E) - )m / z:410.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H)8.65(s,1H)8.43(s,1H)3.92(br dd,J=5.14,2.69Hz,1H)3.45-3.49(m,1H)2.93-2.98(m,1H)2.85-2.91(m,1H)2. 74-2.80(m,1H)2.60-2.71(m,1H)2.56(s,3H)2.19(s,3H)1.26(d,J=6.85Hz,9H).

[0847] The following examples were prepared according to the general procedure described in Example 308.

[0848] Table 34

[0849]

[0850] Example 312

[0851] (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide

[0852]

[0853] TEA (0.017 mL, 0.122 mmol) was added to a solution of (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.122 mmol) and 2-chloro-N,N-dimethylacetamide (14.84 mg, 0.122 mmol) in DMF (1 mL) and THF (2 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I to obtain (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide (27 mg, 0.054 mmol, 44.3% yield) as a pale yellow solid. LCMS retention time was 1.71 min [A]. MS (E) - )m / z:495.3(M+H). 1 H NMR(400MHz, DMSO-d6)δ10.94(s,1H)8.66(s,1H)8.43(s,1H)3.99-4.10(m,1H)3.51-3.62(m,1H)3.12-3.28(m,3H)3.08(s,3H)2.89(br d,J=11.49Hz,1H)2.84(s,3H)2.74(br d,J=11.00Hz,1H)2.63(dt,J=13.63,6.76Hz,1H)2.56(s,3H)2.39(dd,J=11.25,3.42Hz,1H)2.19-2.29(m,1H)2.19(s,2H)1.24-1.31(m,9H).

[0854] The following examples were prepared according to the general procedure described in Example 312.

[0855] Table 35

[0856]

[0857] Example 316

[0858] (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0859]

[0860] TEA (0.017 mL, 0.122 mmol) was added to a solution of (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.122 mmol) and oxetane-3-one (8.80 mg, 0.122 mmol) in methanol (1 mL) at 0 °C. The resulting solution was stirred at room temperature for 12 h. Then, sodium cyanoborohydride (15.34 mg, 0.244 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (22 mg, 0.043 mmol, 35.6% yield) as a pale yellow solid. LCMS retention time: 1.78 min [A]. MS (E) - )m / z:466.2(M+H).

[0861] The following examples were prepared according to the general procedure described in Example 316.

[0862] Table 36

[0863]

[0864] Example 325

[0865] (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol

[0866]

[0867] Potassium carbonate (16.87 mg, 0.122 mmol) was added to a solution of (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.122 mmol) and 1-chloro-2-methylprop-2-ol (13.25 mg, 0.122 mmol) in DMF (1 mL). The resulting solution was heated at 80 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol (14.9 mg, 0.030 mmol, 24.83% yield) as a pale yellow solid. LCMS retention time: 2.03 min [A]. MS (E) - )m / z:482.2(M+H). 1 H NMR(400MHz,DMSO-d6)δppm 10.92(s,1H)8.66(s,1H)8.43(s,1H)4.16(s,1H)3.95-4.04(m,1H)3.52(br d,J=12.23Hz,1H)3.27(td,J=12.10,2.93Hz,1H)3.18(d,J=5.14Hz,1H)2.99(br d,J=11.00Hz,1H)2.90(br d,J=11.00Hz,2H)2.59-2.67(m,1H)2.56(s,2H)2.43(dd,J=11.37,3.30Hz, 1H)2.16-2.32(m,4H)2.08(s,2H)1.24-1.36(m,6H)1.14(d,J=6.11Hz,6H).

[0868] Example 326

[0869] (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-(methylamino)acetyl-1-one

[0870]

[0871] Intermediate 326A: (R)-(2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-2-oxoethyl)(methyl)carbamate tert-butyl ester

[0872]

[0873] HATU (46.4 mg, 0.122 mmol) was added to a solution of (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.122 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (23.10 mg, 0.122 mmol) in DMF (1 mL), followed by TEA (0.017 mL, 0.122 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried to give (R)-(2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-2-oxoethyl)(methyl)carbamate tert-butyl ester (50 mg, 0.086 mmol, 70.5% yield) as a yellow solid. LCMS retention time 1.88 min [F]. MS (E) - )m / z:581.2.

[0874] Example 326: (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-2-(methylamino)ethyl-1-one

[0875] To a solution of (R)-(2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-2-oxoethyl)(methyl)carbamate tert-butyl ester (50 mg, 0.086 mmol) in DCM (2 mL), 4M hydrochloric acid (1 mL, 32.9 mmol) in dioxane was added dropwise and stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-2-(methylamino)ethyl-1-one (27 mg, 0.053 mmol, 61.3% yield) as a pale yellow solid. LCMS retention time: 1.29 min [A]. MS (E-) m / z: 481.2 (M+H). 1H NMR(400MHz,DMSO-d6)δppm10.96-11.03(m,1H)8.64-8.84(m,3H)8.45(s,1H)6.96-7.27(m,1H)3.96-4.44(m,5H)3.65-3 .80(m,3H)3.33(brd,J=9.54Hz,1H)3.09-3.25(m,2H)2.80-3.05(m,1H)2.54-2.69(m,6H)2.18(s,3H)1.21-1.30(m,6H).

[0876] The following examples were prepared according to the general procedure described in Example 326:

[0877]

[0878] Example 328

[0879] 2-((2S,5R)-2,5-dimethyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0880]

[0881] Acetic acid (6.76 μL, 0.118 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.118 mmol) and oxetane-3-one (8.51 mg, 0.118 mmol) in methanol (1 mL) at 0 °C. The resulting solution was stirred at room temperature for 12 h. Then, sodium cyanoborohydride (14.84 mg, 0.236 mmol) was added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to obtain a pale yellow solid, 2-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole. LCMS retention time: 1.88 min [A]. MS(E) - )m / z:480.2(M+H).

[0882] The following examples were prepared according to the general procedure described in Example 328.

[0883] Table 37

[0884]

[0885]

[0886] Example 335

[0887] 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-N,N-dimethylacetamide

[0888]

[0889] TEA (0.016 mL, 0.118 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.118 mmol) and 2-chloro-N,N-dimethylacetamide (14.35 mg, 0.118 mmol) in DMF (1 mL) and THF (2 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-N,N-dimethylacetamide (19 mg, 0.037 mmol, 31.3% yield) as a pale yellow solid. LCMS retention time was 1.79 min [A]. MS (E) - )m / z:509.2(M+H).

[0890] The following examples were prepared according to the general procedure described in Example 335.

[0891] Table 38

[0892]

[0893]

[0894] Example 339

[0895] 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-methylprop-2-ol

[0896]

[0897] Potassium carbonate (32.6 mg, 0.236 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.118 mmol) and 1-chloro-2-methylprop-2-ol (12.82 mg, 0.118 mmol) in DMF (1 mL). The resulting solution was heated at 80 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-methylprop-2-ol (14 mg, 0.027 mmol, 22.97% yield) as a pale yellow solid. LCMS retention time: 2.13 min [A]. MS (E) - )m / z:496.2(M+H).

[0898] Example 340

[0899] 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-(methylamino)ethyl-1-one

[0900]

[0901] Intermediate 340A: (2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-oxoethyl)(methyl)carbamate tert-butyl ester

[0902]

[0903] HATU (44.9 mg, 0.118 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.118 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (22.33 mg, 0.118 mmol) in DMF (1 mL), followed by TEA (0.016 mL, 0.118 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and dried to give a yellow solid (2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-oxoethyl)(methyl)carbamate tert-butyl ester (45 mg, 0.076 mmol, 64.1% yield). LCMS retention time 2.09 min [F]. MS (E-) m / z: 595.2.

[0904] Example 340: 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-(methylamino)ethyl-1-one

[0905] To a solution of (2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-oxoethyl)(methyl)carbamate tert-butyl ester (45 mg, 0.076 mmol) in DCM (2 mL), 4M hydrochloric acid (1 mL, 32.9 mmol) in dioxane was added dropwise and stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-2,5-dimethylpiperazin-1-yl)-2-(methylamino)ethyl-1-one (22 mg, 0.044 mmol, 58.2% yield) as a pale yellow solid. LCMS retention time was 1.34 min [A]. MS (E) - )m / z:495.2(M+H).

[0906] The following examples were prepared according to the general procedure described in Example 340.

[0907] Table 39

[0908]

[0909] Example 342

[0910] (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide

[0911]

[0912] TEA (10.21 μl, 0.073 mmol) was added to a solution of (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and 2-bromo-N-methylacetamide (11.13 mg, 0.073 mmol) in DMF (1 mL) and THF (2 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (8 mg, 0.017 mmol, 22.72% yield) as a pale yellow solid. LCMS retention time was 1.60 min [A]. MS (E) - )m / z:481.2(M+H).

[0913] The following examples were prepared according to the general procedure described in Example 342.

[0914] Table 40

[0915]

[0916] Example 345

[0917] (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol

[0918]

[0919] Potassium carbonate (10.12 mg, 0.073 mmol) was added to a solution of (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and 1-chloro-2-methylprop-2-ol (11.21 mg, 0.073 mmol) in DMF (1 mL). The resulting solution was heated at 80 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol (4.1 mg, 8.51 μmol, 11.62% yield) as a pale yellow solid. LCMS retention time: 2.09 min [A]. MS (E) - )m / z:482.2(M+H).

[0920] Example 346

[0921] (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-(dimethylamino)aceto-1-one

[0922]

[0923] HATU (27.9 mg, 0.073 mmol) was added to a solution of (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and dimethylglycine (7.55 mg, 0.073 mmol) in DMF (1 mL), followed by TEA (10.21 μL, 0.073 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl)-3-methylpiperazin-1-yl)-2-(dimethylamino)ethyl-1-one (17 mg, 0.032 mmol, 44.1% yield) as a pale yellow solid. LCMS retention time: 1.50 min [A]. MS (E) - )m / z:495.2(M+H).

[0924] The following examples were prepared according to the general procedure described in Example 346.

[0925] Table 41

[0926]

[0927] Example 348

[0928] (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0929]

[0930] TEA (10.21 μL, 0.073 mmol) was added to a solution of (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and oxetane-3-one (5.28 mg, 0.073 mmol) in methanol (1 mL) at 0 °C. The resulting solution was stirred at room temperature for 12 h. Then, sodium cyanoborohydride (9.21 mg, 0.147 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole as a pale yellow solid (15 mg, 0.032 mmol, 44.0% yield). LCMS retention time was 1.78 min [A]. MS (E) - )m / z:466.2(M+H).

[0931] The following examples were prepared according to the general procedure described in Example 348.

[0932] Table 42

[0933]

[0934]

[0935] Example 353

[0936] (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide

[0937]

[0938] TEA (0.018 mL, 0.126 mmol) was added to a solution of (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.126 mmol) and 2-bromo-N-methylacetamide (19.21 mg, 0.126 mmol) in DMF (1 mL) and THF (2 mL). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (24 mg, 0.047 mmol, 37.5% yield) as a pale yellow solid. LCMS retention time was 1.45 min [A]. MS (E) - )m / z:467.2(M+H).

[0939] The following examples were prepared according to the general procedure described in Example 353.

[0940] Table 43

[0941]

[0942]

[0943] Example 359

[0944] (R)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol

[0945]

[0946] Potassium carbonate (34.9 mg, 0.253 mmol) was added to a solution of (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.126 mmol) and 1-chloro-2-methylprop-2-ol (13.72 mg, 0.126 mmol) in DMF (1 mL). The resulting solution was heated at 80 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)-2-methylprop-2-ol (4.2 mg, 8.98 μmol, 7.10% yield) as a pale yellow solid. LCMS retention time was 1.68 min [A]. MS (E) - )m / z:468.2(M+H).

[0947] Example 360

[0948] (R)-2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazo-2-yl)-3-methylpiperazin-1-yl)acetoone

[0949]

[0950] HATU (48.1 mg, 0.126 mmol) was added to a solution of (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.126 mmol) and dimethylglycine (13.04 mg, 0.126 mmol) in DMF (1 mL), followed by TEA (0.018 mL, 0.126 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-yl)-3-methylpiperazin-1-yl)ethyl-1-one (18 mg, 0.037 mmol, 29.3% yield) as a pale yellow solid. LCMS retention time was 1.27 min [A]. MS (E) - )m / z:481.2(M+H).

[0951] Example 361

[0952] (R)-2-(4-isobutyl-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole

[0953]

[0954] TEA (0.018 mL, 0.126 mmol) was added to a solution of (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.126 mmol) and isobutyraldehyde (9.12 mg, 0.126 mmol) in methanol (1 mL) at 0 °C. The resulting solution was stirred at room temperature for 12 h. Then, sodium cyanoborohydride (15.89 mg, 0.253 mmol) was added at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give (R)-2-(4-isobutyl-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (27 mg, 0.060 mmol, 47.3% yield) as a pale yellow solid. LCMS retention time was 1.27 min [B]. MS(E) - )m / z:452.2(M+H).

[0955] The following examples were prepared according to the general procedure described in Example 361.

[0956] Table 44

[0957]

[0958]

[0959] Examples 368 and 369

[0960] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(4-(dimethylamino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide

[0961]

[0962] DIPEA (9.83 μL, 0.056 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carboxylic acid (20 mg, 0.056 mmol) and N1,N1-dimethylcyclohexane-1,4-diamine (8.00 mg, 0.056 mmol) in DMF (1 mL), followed by HATU (21.40 mg, 0.056 mmol). The resulting solution was stirred at room temperature for 4 h. The reaction mixture was concentrated to obtain the crude product. The crude sample was purified by preparative LCMS using Method I. After preparative LCMS purification, fractions containing isomers 1 and 2 were collected separately and dried using a Genevac centrifugal evaporator to obtain Example 368A (isomer 1) (7.0 mg, 0.014 mmol, 25.7% yield) and Example 368B (isomer 2) (6.1 mg, 0.013 mmol, 22.60% yield) as pale yellow solids.

[0963] Example 368, Isomer 1: LCMS retention time 1.26 min [A]. MS(E-) m / z: 480.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.83(s,1H),8.53-8.42(m,1H),8.12(d,J=7.8Hz,1H),3.94(d,J=3.7Hz,1H),2.86-2.71(m,1 H),2.59(s,3H),2.23(br.s.,5H),2.17(s,3H),2.14-1.97(m,2H),1.93-1.73(m,4H),1.54(d,J=11.5Hz,4H),1.37(d,J=6.8Hz,5H).

[0964] Example 369, Isomer 2: LCMS retention time 1.29 min [A]. MS(E) - )m / z:480.2(M+H). 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.83(s,1H),8.47(s,1H),8.23(d,J=9.3Hz,1H),3.91(s,1H),3.78(br.s.,2H),2.84-2.7 2(m,1H),2.59(s,3H),2.34(br.s.,1H),2.27(br.s.,4H),2.17(s,3H),1.89(br.s.,4H),1.63-1.49(m,3H),1.42-1.28(m,6H).

[0965] The following examples were prepared according to the general procedure described in Example 368.

[0966] Table 45

[0967]

[0968]

[0969]

[0970]

[0971] Example 391

[0972] 6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-carboxamide

[0973]

[0974] DIPEA (0.012 mL, 0.088 mmol) was added to a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazolyl-2-carboxylic acid (30 mg, 0.088 mmol), ammonium acetate (33.9 mg, 0.439 mmol), and ammonium chloride (23.50 mg, 0.439 mmol) in DMF (1 mL), followed by HATU (33.4 mg, 0.088 mmol). The resulting solution was stirred at room temperature for 4 h. The reaction mixture was concentrated to give the crude product. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-carboxamide (2.9 mg, 8.52 μmol, 9.69% yield) as a pale yellow solid. LCMS retention time: 1.37 min [A]. MS (E) - )m / z:341.2(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.83(s,1H),8.53(s,1H),7.90(br s,1H),7.61(s,2H),3.22-3.13(m,1H),2.63(s,3H),1.48(d,J=6.8Hz,6H).

[0975] The following examples were prepared according to the general procedure described in Example 391.

[0976] Table 46

[0977]

[0978]

[0979] Example 401

[0980] N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazo-2-yl)methyl)-1-isopropylpiperidin-4-amine

[0981]

[0982] Intermediate 401A: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(hydroxymethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester

[0983]

[0984] Diisobutylaluminum hydride (4.44 mL, 5.32 mmol) was added dropwise to a solution of 4-(tert-butyl)-2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2,4-dicarboxylic acid 4-(tert-butyl) 2-methyl ester (1.0 g, 2.130 mmol) in toluene (25 mL) at -78 °C, and the resulting reaction mixture was stirred at the same temperature for 3 h. The reaction was quenched with 1.5 N HCl (15 mL) at -78 °C. The reactants were extracted with EtOAc (3 x 50 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(hydroxymethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (0.9 g, 2.038 mmol, 96% yield) as a yellow solid. LC-MS retention time 1.54 min [F]. MS (E) - )m / z:442.2(M+H).

[0985] Intermediate 401B: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-formyl-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylic acid tert-butyl ester

[0986]

[0987] Diatomaceous earth (0.488 g, 1.310 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(hydroxymethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylic acid tert-butyl ester (1.0 g, 2.265 mmol) in DCM (25 mL), followed by fractional addition of pyridinium chloride chromate (0.488 g, 2.265 mmol). The resulting solution was stirred at room temperature for 3 h. The reaction mixture was filtered through a diatomaceous earth bed and washed with another DCM (60 mL). The filtrate was concentrated to give the crude product. The crude product was purified by Combiflash on a 24 g silica gel column (eluting with 40% ethyl acetate / petroleum ether). After fractional concentration, tert-butyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-carboxyloyl-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-4-carboxylate (0.65 g, 1.479 mmol, 65.3% yield) was collected as a pale yellow solid. LC-MS retention time was 3.43 min [C]. MS (E) - )m / z:44202(M+H).

[0988] Intermediate 401C: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carboxaldehyde

[0989]

[0990] TFA (3 mL, 38.9 mmol) was added dropwise to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-carboxyloyl-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylic acid tert-butyl ester (0.65 g, 1.479 mmol) in DCM (10 mL) and stirred at room temperature for 12 h. The reactants were diluted with DCM (25 mL) and washed with cold 10% sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated to give 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxaldehyde (0.42 g, 1.237 mmol, 84% yield) as a pale yellow solid. LCMS retention time: 2.41 min [C]. MS(E-) m / z: 440.2 (M+H).

[0991] Example 401: N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)methyl)-1-isopropylpiperidin-4-amine

[0992] 1-Isopropylpiperidin-4-amine (12.57 mg, 0.088 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-carboxaldehyde (30 mg, 0.088 mmol) in methanol (1 mL) at 0 °C, followed by the addition of acetic acid (5.06 μL, 0.088 mmol). The resulting solution was stirred at room temperature for 12 h, and then sodium cyanoborohydride (11.11 mg, 0.177 mmol) was added at 0 °C, with stirring continued at room temperature for another 2 h. The reaction mixture was concentrated, and the residue was dissolved in water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified by preparative LCMS using method I. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to give N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazolyl-2-yl)methyl)-1-isopropylpiperidin-4-amine (7.8 mg, 0.017 mmol, 18.70% yield) as a pale yellow solid. LCMS retention time was 1.44 min [A]. MS (E) - )m / z:466.3(M+H). 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.72(s,1H),8.45(s,1H),4.06(s,2H),2.79-2.64(m,4H),2.57(s,3H),2.47-2.3 8(m,1H),2.18(s,3H),2.13-2.03(m,2H),1.90(s,2H),1.88-1.79(m,2H),1.30(d,J=6.8Hz,6H),0.95(d,J=6.6Hz,6H).

[0993] The following examples were prepared according to the general procedure described in Example 401.

[0994] Table 47

[0995]

[0996]

[0997] Example 410

[0998] 6-Isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole

[0999]

[1000] Intermediate 410A: Ethyl 2-bromothiazol-4-carboxylate

[1001]

[1002] 11.23 g (109 mmol) of tert-butyl nitrite was added dropwise to a solution of ethyl 2-aminothiazolium-4-carboxylate (12.5 g (72.6 mmol) and copper bromide (24.32 g (109 mmol)) in acetonitrile (350 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reactants were diluted with water (150 mL), acidified to pH 1 with concentrated HCl, and the aqueous layer was extracted with dichloromethane (3 x 150 mL). The combined organics were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude material was purified by Combiflash on an 80 g silica gel column (eluting with 10% EtOAc / petroleum ether). After fractional concentration, ethyl 2-bromothiazolium-4-carboxylate (10.5 g, 43.1 mmol, 59.4% yield) was collected as a white solid. LCMS retention time: 1.79 min [F]. MS(E-)m / z:237.2(M+H).

[1003] Intermediate 410B: 2-bromothiazol-4-carboxylic acid

[1004]

[1005] 10% NaOH (45 mL, 44.5 mmol) was added dropwise to a solution of ethyl 2-bromothiazol-4-carboxylate (10.5 g, 44.5 mmol) in methanol (150 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated under vacuum to remove volatiles, and the aqueous layer was acidified to pH 4–5 with 1.5 N HCl. The solid precipitate was filtered and dried to give 2-bromothiazol-4-carboxylic acid (8.7 g, 41.4 mmol, 93% yield) as a white solid. LC-MS retention time was 0.33 min [C]. MS (E - )m / z:208.0(M+2H).

[1006] Intermediate 410C: (2-bromothiazolyl-4-yl)tert-butyl carbamate

[1007]

[1008] TEA (6.99 mL, 50.2 mmol) and diphenylphosphoazide (10.13 mL, 46.0 mmol) were added to a solution of 2-bromothiazol-4-carboxylic acid (8.7 g, 41.8 mmol) in t-BuOH (130 mL) at 0 °C. The resulting solution was heated at 80 °C for 12 h. The reaction was quenched with water (250 mL). The mixture was concentrated under vacuum to remove volatiles and the aqueous layer was extracted with DCM (3 x 200 mL). The separated organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by combiflash on an 80 g silica gel column (eluting with 12% EtOAc / petroleum ether). After fractional concentration, tert-butyl (2-bromothiazol-4-yl)carbamate (7.2 g, 24.24 mmol, 58.0% yield) was collected as a white solid. LCMS retention time 2.84...

Claims

1. A compound of formula (I) or a salt thereof, wherein: X is N and Y is S; or X is S and Y is N or CH; R1 is -CH3, -CH2CH3 or -CH(CH3)2; G is: Each R2 is independently -CN, -CH3 or -OCH3; A is: (i) -CH2NHCH2C(O)NH2; (ii)-CH2R3, -CH2NHR3, -CH2NHCH2R3, -C(O)NHR3, -C(O)NR x R4 or -C(O)R3; or (iii) cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl or diazaspiro[3.3]heptyl, each of which is replaced by 0 to 1 R 3a replace; R3 is azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, piperazinonyl, morpholinyl, dioxythiomorpholinyl, oxazepanyl, diazaspiro[3.3]heptyl, dioxythioazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl or oxazaspiro[3.5]nonyl, each substituted by 0 to 1 R 3a and 0 to 2 R 3b replace; R 3a is F, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH2CH3)2, -CH2CN, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2S(O)2CH3, -CH2C(O)NR x R x , -OCH3, -C(O)CH3, -C(O)CH2N(CH3)2, -NH2, -NH(CH3), -NH(CH(CH3)2), -NH(CH2C(CH3)3), -NH(CH2C(CH3)2OH), -NH(CH2CHFC(CH3 )2OH), -NH(CH2C(CH3)2OCH3), -N(CH3)(CH2CH3), -N(CH3)(CH(CH3)2), -N(CH3)CH2CH(CH3)2, -N(CH3)CH2C(O)N(CH3)2, -N(CH3)CH 2CH2S(O)2CH3, -NHC(O)CH2N(CH3)2, -NHC(O)CH2N(CH3)(CH2CH3), -NHC(O)CH2NH(CH2CH(CH3)2), -NHCH2C(O)NH2, -NHCH2C(O)NH(CH3), -NHCH2C(O)N(CH3)2, -NHCH2CH2NH(CH3), -NHS(O)2CH3, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetane), -CH2(tetrahydropyranyl), -C(O)(tetrahydro thiopyranyl), -NH(cyanocyclopropyl), -NH(cyclobutyl), -NH(methylcyclobutyl), -NH(oxetanyl), -NH(methyloxetanyl), -NH(ethyloxetanyl), -NH(isopropylpiperidinyl), -NH(tetrahydropyranyl), -NH(bicyclo[1.1.1]pentyl), -NHCH2(methyloxetanyl), -NH(dioxidetetrahydrophenylthio), -NHCH2(hydroxymethylcyclopropyl), -NHCH2(methylsulfonylcyclopropyl), -NHCH2(methylcyclobutyl), -NHCH2C(O)(morpholinyl), azetidinyl, fluoroazetidinyl, difluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, oxetanyl, pyrrolidinyl, acetamidopyrrolidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, dioxothiomorpholinyl, oxazepanyl, bicyclo[1.1.1]pentanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, dioxothioazaspiro[3.3]heptanyl, oxazabicyclo[3.2.1]octanyl, oxazaspiro[3.5]nonanyl, or diazaspiro[4.4]nonanyl; Each R 3b is -CH3; R4 is H, -CH2CHF2, -CH2CF3, -CH2CH2N(CH3)2, -CH2R3, -CH2CR x R x R3 or -(CH2)3R3; R5 is H or -CH2CF3; Each R x are independently H or -CH3; and p is 0, 1 or 2. 2 . The compound according to claim 1 , or a salt thereof, wherein X is N and Y is S.

3. The compound or salt thereof according to claim 1, wherein A is piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl or diazaspiro[3.3]heptyl, each of which is replaced by 0 to 1 R 3a replace.

4. The compound or salt thereof according to claim 1, wherein A is -CH2R3, -CH2NHR3, -CH2NHCH2R3 or -CH2NHCH2C(O)NH2.

5. The compound or salt thereof according to claim 1, wherein A is -C(O)NHR3 or -C(O)NR x R4.

6. The compound or salt thereof according to claim 1, wherein A is -C(O)R3. The compound according to claim 1 , or a salt thereof, wherein X is S and Y is N.

8. The compound or salt thereof according to claim 1, wherein X is S and Y is CH.

9. A compound or a salt thereof, wherein the compound is: 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (1); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (2); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (3); 5-(2, 6-dimethylpyridin-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)quinoline-8-carbonitrile (5); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)ethan-1-one (6); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (7); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N-methylacetamide (8); 6-isopropyl-2-(1-isopropylpiperidin-4-yl)-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N-methylacetamide (10); 6-isopropyl-5-(8-methoxy-[1 ,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (11); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (12); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(neopentylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (13);6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (14); 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-2-methylpropan-2-ol (15); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-2-methylpropan-2-ol (16); pyrrolo[3,2-d]thiazole (16); 2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (17); 1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-2-methylpropan-2-ol (18); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-2-methylpropan-2-ol (19); pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)ethan-1-one (19); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20); 6-isopropyl-2-( 1-(Isopropylpiperidin-4-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (21); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (21); pyridin-4-yl)-4H-pyrrolo[3,2-d]thiazole (22); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (23); 2-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (24); 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (25);5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (26); 5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (27); 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)ethan-1-one (28); 1-(4-(5-(2,6-dimethylpyridin-4-yl) 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (30); 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)acetamide (31); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)acetamide (32); 3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)ethan-1-one (32); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (33); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (34); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (35); 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (35); 6-isopropyl-2-(1-isopropylpiperidin-4-yl)-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole (36); 5-(6-isopropyl- 2-(1-(Oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)quinoline-8-carbonitrile (37); 5-(6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)quinoline-8-carbonitrile (38);5-(2-(1-(dimethylglycyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl)quinoline-8-carbonitrile (39); 2-(4-(5-(8-cyanoquinolin-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (40); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (41); 5-(6-isopropyl-2-(piperidin-4-yl)-4 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (43); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (44); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-isopropylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (45); -yl)-6-isopropyl-2-(1-(methylsulfonyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (45); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (46); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (47); 5-(7,8- 5-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (48); 5-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-methylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (49); 5-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-ethylpiperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-propylpiperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (51); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-isobutylpiperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (52); 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (53); 5-(7,8-dimethyl-[1 ,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-(2-ethylbutyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (54); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (55); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N-methylacetamide (56); 2-(4 -(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (57); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)acetamide (58); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)ethan-1-one (59); 5-(6-isopropyl-2-(1-(oxetan-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (60); 5-(6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (61); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (62);2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)-N-methylacetamide (63); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-1-yl)acetamide (64); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane- 3-Amine (65-66); (1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)azetidine-3,3-diyl)dimethanol (67); 6-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (68-69); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (68-69); -6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-3-methyloxetane-3-amine (70-71); N-ethyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methylcyclohexan-1-amine (72-73); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methylcyclohexan-1-amine (74-75); 2-(4-(azetidin-1-yl)cyclohexane =N-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexan-1-amine (78-79); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)thiomorpholine 1,1-dioxide (82-83);1-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (84-85); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexan-1-amine (86-87); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl) -6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methylcyclohexan-1-amine (88-89); (R)-3-fluoro-4-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-2-methylbutan-2-ol (90-91); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexan-1-amine (92-93); 3-ethyl-N-( 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (94-95); 6-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (96-97); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2- (4-(Pyrrolidin-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (98-99); (R)-N-(1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)pyrrolidin-3-yl)acetamide (100-101); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-1,4-oxazepane (102-103);(1R,5S)-8-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-3-oxa-8-azabicyclo[3.2.1]octane (104-105); 1-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)cyclopropane-1-carbonitrile (106-107); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-7-oxa-2-azaspiro[3.5]nonane (110-111); 7-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-7-azaspiro[3.5]nonane alkane (112-113); 2-(4-(2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (114-115); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-azaspiro[3.3]hept-6-amine (116-117); 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-3-(trifluoromethyl)azetidin-3-ol (118-119); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (120-121); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol (122-123);N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-N-methyloxetan-3-amine (124-125); 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)acetamide (126); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)acetamide (127); )-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)methanesulfonamide (127); trans-2-(ethyl(methyl)amino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)acetamide (128); 2-(isobutylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)acetamide (129); N-(4-(6 -isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (130-131); N-ethyl-4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methylcyclohexan-1-amine (132); 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl) -N-((3-methyloxetan-3-yl)methyl)cyclohexan-1-amine (134-135); 6-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (136-137); N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)bicyclo[1.1.1]pentan-1-amine (138-139);1-((4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (140-141); (1-(((4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)methyl)cyclopropyl)methanol (142-143); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a] 4-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-1,4-oxazepane (146-147); 4-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (14 8-149); 6-isopropyl-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (150-151); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (152-153); 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2 -(4-(pyrrolidin-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (154-155); 1-((4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (156-157); N-isopropyl-4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methylcyclohexan-1-amine (158-159); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (160-161); 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide (162-163); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl) )-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methyl-N-(2-(methylsulfonyl)ethyl)cyclohexan-1-amine (164-165); 1-isopropyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperidin-4-amine (166-167); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)bicyclo[1.1.1]pentane -1-amine (168-169); N1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-N2-methylethane-1,2-diamine (170-171); 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexan-1-amine (172-173); N-ethyl-4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl) Pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-methylcyclohexan-1-amine (174-175); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)bicyclo[1.1.1]pentan-1-amine (176-177); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (178-179);6-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (180-181); 1-((4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (182-183); N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexan-1-amine (186-187); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol-2-yl (188-189); ); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-ethyl-N-methylcyclohexan-1-amine (190-191); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (192-193); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) -6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-isopropylcyclohexan-1-amine (194-195); 1-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (196-197); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-neopentylcyclohexan-1-amine (198-199);N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (200-201); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-((1-methylcyclobutyl)methyl)cyclohexan-1-amine (202-203); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)- 6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-N,N-dimethylacetamide (204-205); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-1-morpholinoethan-1-one (206-207); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)-N-methylacetamide amine (208-209); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)acetamide (210-211); 4-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)morpholine (212-213); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-morpholine (212-213); 2-(4-(azetidin-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (216-217); 2-(4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (218-219);4-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (220-221); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-isopropyl-N-methylcyclohexan-1-amine (222-223); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d ]thiazol-2-yl)cyclohexyl)azetidin-3-ol (224-225); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(3-fluoroazetidin-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-isobutyl-N-methylcyclohexan-1-amine (228-229); 3-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(4-(3-fluoroazetidin-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-isobutyl-N-methylcyclohexan-1-amine (228-229); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)amino)tetrahydrothiophene 1,1-dioxide (230-232); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (233-234); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d ]thiazol-2-yl)cyclohexyl)-3-(trifluoromethyl)azetidin-3-ol (235-236); 7-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-7-azaspiro[3.5]nonane (237-238); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-7-oxa-2-azaspiro[3.5]nonane (239-240);5-(6-isopropyl-2-(4-(oxetan-3-ylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (241-242); 5-(6-isopropyl-2-(4-((2-methoxy-2-methylpropyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (243-244); 5-(2-(4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl) -1,3,4-trimethylpyridin-2(1H)-one (245-246); 5-(2-(4-(ethyl(methyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (247-248); 5-(6-isopropyl-2-(4-((tetrahydro-2H-pyran-4-yl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (249-250); 5-(2-(4-((2-hydroxy-2-methylpropyl)amino)cyclohexyl)-6-isopropyl -4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (251-252); 5-(6-isopropyl-2-(4-(isopropylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (253-254); 5-(2-(4-(azetidin-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (255-256); 5-(6-isopropyl-2-(4-(((1-(methylsulfonyl) 4-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (259-260); 5-(6-isopropyl-2-(4-(isopropyl(methyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (261-262);5-(2-(4-(3-Hydroxyazetidin-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (263-264); 5-(2-(4-(3-Fluoroazetidin-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (265-266); 5-(2-(4-(3-Hydroxy-3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3, 4-Trimethylpyridin-2(1H)-one (267-268); 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (269-270); N-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (271-272); N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (271-272); [1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)oxetane-3-amine (273); 4-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (275-276); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (278); 5-(6-isopropyl-2-(piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)cyclohexyl)piperazin-2-one (276-277); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one (280); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperazin-1-yl)-2-methylpropan-2-ol (281);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (282); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazin-1-yl)-N,N-dimethylacetamide (283); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole- 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperazin-1-yl)acetamide (285); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(oxetane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)piperazin-1-yl)acetamide (286); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(tetrahydro 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-isopropylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (288); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-((3-methyloxetane-3-yl)methyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (289); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-isopropylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (287); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-isopropylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (288); 1-((1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-(3-methyloxetan-3-yl)piperidin-4-amine (290); 1-((1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-4-yl)amino)-2-methylpropan-2-ol (291); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-isopropyl-N-methylpiperidin-4-amine (292);N-cyclobutyl-1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-4-amine (293); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-(2-methoxy-2-methylpropyl)piperidin-4-amine (294); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)- [3,2-d]thiazol-2-yl)-N-((3-methyloxetane-3-yl)methyl)piperidin-4-amine (295); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-(oxetane-3-yl)piperidin-4-amine (296); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-isopropylpiperidin-4-amine (297); 1-(5-( 7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-ethyl-N-methylpiperidin-4-amine (298); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperidin-4-amine (299); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3.3]hept-2-yl)-6-isopropyl -4H-pyrrolo[3,2-d]thiazole (300); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (301); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (302);1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2,6-diazaspiro[3.3]hept-2-yl)-2-methylpropan-2-ol (303); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazole (304); 5-(6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)- )-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (305); 5-(6-isopropyl-2-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (306); 5-(6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)-4H-pyrrolo[3,2-d]thiazol-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (306); )-1,3,4-trimethylpyridin-2(1H)-one (307); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl (308); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (309); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-6-isopropyl-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (310); (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (311); (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide (312);(R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)acetamide (313); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (314); (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)acetamide (313); (R)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (315); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (316); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-4H -pyrrolo[3,2-d]thiazole (317); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (318); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(2,4-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (319); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a] pyridin-6-yl)-2-(4-ethyl-2-methylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (320); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (321); (R)-2-(4-cyclobutyl-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (322);(R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-(1-isopropylpiperidin-4-yl)-2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (323); (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazin-1-yl)-2-methylpropan-2-ol (325); (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl -4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-2-(methylamino)ethan-1-one (326); (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-2-(dimethylamino)ethan-1-one (327); 2-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2 -d]thiazole (328); 2-((2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (329); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (330); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2- ((2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (331); 2-((2S,5R)-4-(cyclopropylmethyl)-2,5-dimethylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (332); 2-((2S,5R)-4-cyclobutyl-2,5-dimethylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (333);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (334); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazin-1-yl)-N,N-dimethylacetamide (335); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4] triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2,5-dimethylpiperazin-1-yl)-N-methylacetamide (336); 2-((2S,5R)-2,5-dimethyl-4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2,5-dimethylpiperazin-1-yl)-N-methylacetamide (337); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2,5-dimethylpiperazin-1-yl)-2-methylpropan-2-ol (339); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2,5-dimethylpiperazin-1-yl)-2-methylpropan-2-ol (339); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2,5-dimethylpiperazin-1-yl)-2-(dimethylamino)ethan-1-one (341); (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (342);(S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide (343); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (344); (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)- 6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-2-methylpropan-2-ol (345); (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-2-(dimethylamino)ethan-1-one (346); (S)-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl) (1,1 -tetrahydro-2H-thiopyran-4-yl)methanone (347); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (348); (S)-2-(4-cyclobutyl-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (349); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (349); -6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (350); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(4-isopropyl-2-methylpiperazin-1-yl)-4H-pyrrolo[3,2-d]thiazole (351); (S)-2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (352);(R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-N-methylacetamide (353); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-N,N-dimethylacetamide (354); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)acetamide (355); (R)-6-isopropyl-2-(2-methyl-4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (356); (R)-6-isopropyl-2-(4-(2-methoxyethyl)-2-methylpiperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (357 ); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)acetonitrile (358); (R)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)-2-methylpropan-2-ol (359); (R)-2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1 ,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)-3-methylpiperazin-1-yl)ethan-1-one (360); (R)-2-(4-isobutyl-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (361); (R)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (363);(R)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (364); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole (365); (R)-2-(2,4-dimethylpiperazin-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)-4H-pyrrolo[3,2-d]thiazole (367); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(4-(dimethylamino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (368-369); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-(pyrrolidin-1-yl)ethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (370); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-(pyrrolidin-1-yl)ethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (371); Propyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (371); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(dimethylamino)ethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (372); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)(1,1-dioxythiomorpholino)methanone (373); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (374); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-methyl-2-morpholinopropyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (374); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carbonyl)piperazin-1-yl)ethan-1-one (375); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(4-(dimethylamino)piperidin-1-yl)methanone (376);(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(pyrrolidin-1-yl)methanone (377); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-carbonyl)piperazin-2-one (378); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(3-fluoroazetidine -1-yl)methanone (379); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(4-isopropylpiperazin-1-yl)methanone (380); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(2-(1-methylpiperidin-4-yl)ethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (381); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(dimethylpiperidin-4-yl)ethyl)- (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(3-(dimethylamino)azetidin-1-yl)methanone (383); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone (384); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)(3-(dimethylamino)azetidin-1-yl)methanone (385); 8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (385); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(morpholin-2-ylmethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (386); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (387);N-(2-(Dimethylamino)ethyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (388); N-(2,2-difluoroethyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (389); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(2,2,2-trifluoroethyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (390); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (391); 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carbonyl)piperazin-2-one (392); (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)(pyrrolidin-1-yl)methanone (393); (6-isopropyl-5-(8-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)(1,4-oxazepan-4-yl)methanone (394); (4-(dimethylamino)piperidin-1-yl)(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)methanone (395); (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazol-2-yl)(3-methoxyazetidin-1-yl)methanone (396); 6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(oxetan-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (397); (6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)(morpholino)methanone (398); 6-Isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (399);N-(2-(Dimethylamino)ethyl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (400); N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)-1-isopropylpiperidin-4-amine (401); 2-(((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl )amino)acetamide (402); 6-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (403); 2-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)-7-oxa-2-azaspiro[3.5]nonane (404); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a] pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)methanamine (405); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)piperazin-2-one (406); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)morpholine (407); 6-((5-(7,8-dimethyl-[1 2-((2,6-diazaspiro[3.3]hept-2-yl)methyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (408); 2-((2,6-diazaspiro[3.3]hept-2-yl)methyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)methyl)-2-oxa-6-azaspiro[3.3]hept-2-yl)methyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol (409); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazol (410);6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (411); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (412); or 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-thieno[3,2-b]pyrrole (413). ; 10 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating TLR7-related autoimmune diseases or chronic inflammatory diseases.

12. The use according to claim 11, wherein the TLR7-related autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjögren's syndrome.

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