Substituted noncyclic heteroaryl compounds

Abstract

A compound of the following chemical formula (I), its N-oxide, or salt is disclosed: Herein, X, Y, A, G, R1, and R5 are defined herein. Additionally, a method of using these compounds as inhibitors of signal transduction through Toll-like receptor 7, or 8, or 9, and a pharmaceutical composition comprising these compounds are disclosed. These compounds are useful for treating inflammatory and autoimmune diseases.

Description

Technology Field

[0001] Cross-reference

[0002] This application claims priority to U.S. provisional application serial number 62 / 908,840 filed on October 1, 2019, the entirety of which is incorporated herein.

[0003] explanation

[0004] The present invention relates to substituted noncyclic heteroaryl compounds that are generally useful as inhibitors of signal transduction through Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Substituted noncyclic heteroaryl compounds, compositions comprising such compounds, and methods of using the same are provided herein. The present invention further relates to pharmaceutical compositions containing at least one compound according to the present invention that are useful for the treatment of conditions associated with TLR modulation, e.g., inflammatory and autoimmune diseases, and methods for inhibiting TLR activity in mammals. Background Technology

[0005] 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 (Reference [Kawai, T. et al., Nature Immunol. (Reviewed in , 11:373-384 (2010)). Ligand binding to the receptor induces dimerization and the recruitment of adapter molecules to a conserved cytoplasmic motif within the receptor called the Toll / IL-1 receptor (TIR) ​​domain, and with the exception of TLR3, all TLRs recruit the adapter molecule MyD88. The IL-1 receptor family also contains cytoplasmic TIR motifs and recruits MyD88 upon ligand binding (Reference [Sims, JE et al., Nature Rev. Immunol. Reviewed in , 10:89-102 (2010)).

[0006] Toll-like receptors (TLRs) are a family of evolutionarily conserved transmembrane innate immune receptors involved in primary defense. As pattern recognition receptors, TLRs are activated by pathogen-associated molecular patterns (PAMPs) to protect against foreign molecules, or by danger-associated molecular patterns (DAMPs) to protect against damaged tissue. A total of 13 members of the TLR family have been identified, 10 of which are found in humans, and they are located across the cell surface or endosome compartments. TLR7 / 8 / 9 are among the endosome-located sets and respond to single-stranded RNA (TLR7 and TLR8) or to unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR9).

[0007] Activation of TLR7 / 8 / 9 can initiate various inflammatory responses (cytokine production, B cell activation and IgG production, and type I interferon response). In the case of autoimmune disorders, abnormally sustained activation of TLR7 / 8 / 9 leads to the exacerbation of the disease state. While overexpression of TLR7 in mice has been shown to exacerbate autoimmune diseases, TLR7 knockout in mice was found to be protective against the disease in lupus-tendency MRL / lpr mice. Dual knockout of TLR7 and 9 demonstrated additionally enhanced protection.

[0008] Since numerous conditions can benefit from therapies involving the modulation of cytokines, IFN production, and B cell activity, it is immediately apparent that novel compounds capable of modulating TLR7 and / or TLR8 and / or TLR9, and the methods of using these compounds, can provide substantial therapeutic benefits to a wide variety of patients.

[0009] The present invention relates to a novel class of substituted non-cyclic heteroaryl compounds found to be effective inhibitors of signal transduction via TLR7 / 8 / 9. These compounds are provided as useful pharmaceuticals having desirable stability, bioavailability, therapeutic index, and toxicity values ​​important for their pharmacological properties.

[0010] The present invention provides a compound of formula (I), or its stereoisomer, N-oxide, tautomer, pharmaceutically acceptable salt, solvate, or prodrug that is useful as an inhibitor of signal transduction through Toll-like receptors 7, 8, or 9 and is useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases, and inflammatory diseases.

[0011] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug.

[0012] The present invention also provides a method for inhibiting Toll-like receptor 7, 8, or 9, comprising administering a therapeutically effective amount of at least one compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug to a host requiring inhibition of Toll-like receptor 7, 8, or 9.

[0013] The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune, and inflammatory diseases, comprising administering a therapeutically effective amount of at least one compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug to a host requiring treatment for proliferative, metabolic, allergic, autoimmune, and inflammatory diseases.

[0014] The present invention also provides a method for treating a disease or disorder associated with Toll-like receptor 7, 8, or 9 activity, comprising administering at least one compound of formula (I) or its salt, solvate, and prodrug to a mammal in need of treatment for a disease or disorder associated with Toll-like receptor 7, 8, or 9 activity.

[0015] The present invention also provides a compound of formula (I), and a salt, solvate, and a method for preparing a prodrug and an intermediate therefor.

[0016] The present invention also provides at least one compound of formula (I) or its salt, solvate, and prodrug for use in therapy.

[0017] The present invention also provides the use of at least one compound of formula (I) or its salt, solvate, and prodrug for the manufacture of medicines for the prevention or treatment of Toll-like receptor 7, 8, or 9 related conditions, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.

[0018] Compounds of formula (I) and compositions comprising compounds of formula (I) may be used to treat, prevent, or cure various Toll-like receptor 7, 8, or 9 related conditions. Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of diseases or disorders in various therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.

[0019] These and other features of the present invention will be presented in an expanded form as the present disclosure continues. Specific details for implementing the invention

[0020] A first aspect of the present invention provides at least one compound of the following formula (I), its N-oxide, or salt:

[0021]

[0022] Here:

[0023] X is N and Y is S; or X is S and Y is N or CH;

[0024] R1 is H, F, Cl, -CN, C 1-4 Alkyl, C 1-3 Fluoroalkyl, -OCH3, or -S(O)2(C 1-3 alkyl) and;

[0025] G is:

[0026] ;

[0027] (iv) 9-membered heterocyclic ring selected from the following:

[0028]

[0029]

[0030]

[0031] ; or

[0032] (v) 10-circle heterocyclic ring selected from the following:

[0033]

[0034] And;

[0035] Each R2 independently consists of halo, -CN, -OH, -NO2, C 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), -O(CH2) 1-2 OC(O)(C 1-3 alkyl), -O(CH2)1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(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 x S(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), -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazollyl, imidazollyl, pyrimidinyl, triazolyl, or -C(O)(thiazolyl);

[0036] R 2a 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 3-6cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;

[0037] Each R 2b is independently H, halo, -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), -(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) and;

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

[0039] R 2d is R 2a or R 2b is; only R 2c and R 2d One of them is R 2a and R 2c and the other one of R2 is R 2b And;

[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 Rx NR x R3, -CR x R x NR x CH2R3, -C(O)NR x R3, -C(O)NR x R4, -C(O)R3, or -NR x C(O)R3; or

[0043] (iii) R3

[0044] And;

[0045] R3 is:

[0046] (i) 0 to 2 R each 3a and 0 to 2 R 3b C that is replaced by 3-5 Cycloalkyl, azetidinyl, oxetanil, pyrrolidinyl, pyrrolidinonil, piperidinyl, piperazinyl, piperazinonil, morpholinil, deoxydothiomorpholinil, oxazephanil, diazaspiro[3.3]heptanil, deoxydothiazaspiro[3.3]heptanil, oxazaspiro[3.3]heptanil, or oxazaspiro[3.5]nonanil;

[0047] (ii) -NR y R y , -NR x (C 1-6 hydroxyalkyl), -NR x (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 Ry , -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 (Azetidinyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x (ethyl oxetanil), -NR x (isopropyloxetanil), -NR x (Tetrahydropyranil), -NR x (bicyclo[1.1.1]pentyl), -NR x (CH2(methyloxetanyl)), -NR x (Dioxydotetrahydrothiophenyl), -NR x CH2(hydroxymethylcyclopropyl), -NR x CH2(methylsulfonylcyclopropyl), -NR x CH2(methylcyclobutyl), -NR x HCH2C(O)(morpholinyl), azetidinyl, fluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, pyrrolidinyl, piperazinonil, morpholinyl, dioxothiomorpholinyl, oxazepanil, bicyclo[1.1.1]fentanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, deoxydothiazspiro[3.3]heptanyl, oxaazabicyclo[3.2.1]octanyl, oxazaspiro[3.5]nonanyl, or cyclohexyl substituted with diazspiro[4.4]nonanyl; or

[0048] (iii) C 1-6 Alkyl, C 1-6 hydroxyalkyl, -(CH2) 1-3 S(O)2(C 1-6Diazaspiro[3.3]heptanyl substituted with alkyl), oxetanyl, or -CH2(tetrahydropyranyl).

[0049] And;

[0050] Each R 3a is independently F, Cl, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Fluoroalkyl, C 1-6 hydroxyalkyl, -(CH2) 1-3 O(C 1-3 alkyl), -C(O)(C 1-6 alkyl), -CH2C(O)NR y R y , -NR y R y , -NR x (C 1-4 hydroxyalkyl), -C(O)(CH2) 1-3 NR y R y , -C(O)(C 1-6 alkyl), -(CH2) 0-2 S(O)2(C 1-3 alkyl), -(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 (Oxetanil), -CH2(methyltriazolyl), C 3-6 Cycloalkyl, oxetanyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, -CH2(C 3-6 Cycloalkyl), -CH2(Oxetanil), -CH2(Methyl Oxetanil), -CH2(Tetrahydropyranil), -NR x (C 3-6 cycloalkyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR xCH2(methyloxetanyl) or -C(O)(deoxydotetrahydrothiopyranyl);

[0051] Each R 3b is -CH3 and;

[0052] R4 is H, C 1-2 Fluoroalkyl, -(CR x R x ) 1-2 NR y R y , or -(CR x R x ) 1-3 It is R3;

[0053] R5 is H, C 1-3 alkyl, or C 1-3 It is a fluoroalkyl and;

[0054] Each R x is independently H or -CH3;

[0055] Each R y is independently H or C 1-6 It is alkyl;

[0056] p is 0, 1, or 2.

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

[0058] .

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

[0060] .

[0061] One embodiment provides a compound of formula (I) in which X is S and Y is CH, its N-oxide, or salt. The compound of this embodiment has the structure of formula (IV) below:

[0062] .

[0063] One embodiment is

[0064] R1 is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3, or -S(O)2(C 1-2 alkyl) and;

[0065] G:

[0066] ;

[0067] (iv) 9-membered heterocyclic ring selected from the following:

[0068]

[0069]

[0070] ; or

[0071] (v) 10-circle heterocyclic ring selected from the following:

[0072]

[0073] And;

[0074] Each R2 independently is 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)0-2C(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;

[0075] R 2a Ga C 1-4 Alkyl, C 1-2 Fluoroalkyl, C1-4 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;

[0076] Each R 2b independently H, F, Cl, -CN, -NR x R x , C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 hydroxyalkyl, -(CH2) 0-2 O(C 1-2 alkyl), -(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) and;

[0077] A:

[0078] (i) -CH2NHCH2C(O)NR x R x ;

[0079] (ii) -CR x R x R3, -CH2NR x R3, -CH2NR x CH2R3, -C(O)NR x R3, -C(O)NR x R4, -C(O)R3, or -NR x C(O)R3; or

[0080] (iii) R3

[0081] And;

[0082] R3 is:

[0083] (i) 0 to 1 R each 3a and 0 to 2 R 3bAzetidinyl, oxetanil, cyclopropyl, pyrrolidinyl, pyrrolidinonil, piperidinyl, piperazinil, piperazinonil, morpholinil, deoxydothiomorpholinil, oxazepanil, diazaspiro[3.3]heptanil, deoxydothiaazaspiro[3.3]heptanil, oxaazaspiro[3.3]heptanil, or oxaazaspiro[3.5]nonanil substituted with;

[0084] (ii) -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 (Azetidinyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x (ethyl oxetanil), -NR x(isopropyloxetanil), -NR x (Tetrahydropyranil), -NR x (bicyclo[1.1.1]pentyl), -NR x (CH2(methyloxetanyl)), -NR x (Dioxydotetrahydrothiophenyl), -NR x CH2(hydroxymethylcyclopropyl), -NR x CH2(methylsulfonylcyclopropyl), -NR x CH2(methylcyclobutyl), -NR x HCH2C(O)(morpholinyl), azetidinyl, fluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, pyrrolidinyl, piperazinonil, morpholinyl, dioxothiomorpholinyl, oxazepanil, bicyclo[1.1.1]fentanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, deoxydothiazspiro[3.3]heptanyl, oxaazabicyclo[3.2.1]octanyl, oxazaspiro[3.5]nonanyl, or cyclohexyl substituted with diazspiro[4.4]nonanyl; or

[0085] (iii) C 1-4 Alkyl, C 1-4 hydroxyalkyl, -(CH2) 1-2 S(O)2(C 1-3 Diazaspiro[3.3]heptanyl substituted with alkyl), oxetanyl, or -CH2(tetrahydropyranyl);

[0086] And;

[0087] Each R 3a independently F, Cl, C 1-5 Alkyl, C 1-3 Cyanoalkyl, C 1-3 Fluoroalkyl, C 1-4 hydroxyalkyl, -(CH2) 1-2 O(C 1-2 alkyl), -C(O)(C 1-3 alkyl), -CH2C(O)NR x R x , -NR y R y , -NH(C1-4 hydroxyalkyl), -C(O)(CH2) 1-3 NR x R x , -C(O)(C 1-3 alkyl), -(CH2) 0-2 S(O)2(C 1-2 alkyl), -(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 (Oxetanil), -CH2(methyltriazolyl), cyclobutyl, oxetanil, pyrrolidinyl, morpholinil, tetrahydropyranil, -CH2(C 3-4 Cycloalkyl), -CH2(Oxetanil), -CH2(Methyl Oxetanil), -CH2(Tetrahydropyranil), -NR x (Cyclobutyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x CH2(methyloxetanyl) or -C(O)(deoxydotetrahydrothiopyranyl);

[0088] Each R 3b is -CH3 and;

[0089] R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2, or -CH2CF3

[0090] Provides a compound of chemical formula (I), its N-oxide, or salt.

[0091] In these embodiments, a compound in which X is N and Y is S is included. Also in these embodiments, a compound in which X is S and Y is N is included in these embodiments. Additionally, a compound in which X is S and Y is CH is included.

[0092] One embodiment is

[0093] R1 is independently -CH3, -CH2CH3, or -CH(CH3)2;

[0094] G And;

[0095] Each R2 is independently -CN, -CH3, or -OCH3;

[0096] A:

[0097] (i) -CH2NHCH2C(O)NH2;

[0098] (ii) -CH2R3, -CH2NHR3, -CH2NHCH2R3, -C(O)NHR3, -C(O)NR x R4, or -C(O)R3; or

[0099] (iii) 0 to 1 R each 3a Cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl, or diazaspiro[3.3]heptanyl substituted with

[0100] And;

[0101] R3 each has 0 to 1 R 3a and 0 to 2 R 3b Azetidinyl, oxetanil, cyclopropyl, cyclobutyl, pyrrolidinyl, pyrrolidinonil, piperidinyl, piperazinil, piperazinonil, morpholinil, deoxydothiomorpholinil, oxazepanil, diazaspiro[3.3]heptanil, deoxydothiaazaspiro[3.3]heptanil, oxaazaspiro[3.3]heptanil, or oxaazaspiro[3.5]nonanil substituted with;

[0102] R 3a A 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)CH2CH2S(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(methyl oxetanyl), -CH2(tetrahydropyranyl), -C(O)(deoxydotetrahydrothiopyranyl), -NH(cyanocyclopropyl), -NH(cyclobutyl), -NH(methylcyclobutyl), -NH(oxetanyl), -NH(methyl oxetanyl), -NH(ethyl oxetanyl), -NH(isopropylpiperidinyl), -NH(tetrahydropyranyl), -NH(bicyclo[1.1.1]pentyl), -NHCH2(methyl oxetanyl), -NH(Dioxydotetrahydrothiophenyl), -NHCH2(Hydroxymethylcyclopropyl), -NHCH2(Methylsulfonylcyclopropyl), -NHCH2(Methylcyclobutyl), -NHCH2C(O)(Morfollinyl), Cyclobutyl, Azetidinyl, Fluorozetidinyl, Difluoroazetidinyl, Hydroxyazetidinyl, Methoxyazetidinyl, Hydroxy(Trifluoromethyl)azetidinyl, Bis(Hydroxymethyl)azetidinyl, Oxetanil, Pyrrolidinyl, Acetamidopyrrolidinyl, Piperazinonil, Tetrahydropyranil, Morfollinyl, Dioxothiomorpholinyl, Oxazepanil, Bicyclo[1.1.1]fentanyl, Azaspiro[3.3]heptanil, Oxazaspiro[3.3]heptanyl, Deoxydothiazspiro[3.3]heptanil, oxaazabicyclo[3.2.1]octanil, oxaazspiro[3.5] Nonanil, or Diazaspiro[4.4] Nonanil;.

[0103] Each R 3b is -CH3 and;

[0104] R4 is H, -CH2CHF2, -CH2CF3, -CH2CH2N(CH3)2, -CH2R3, -CH2CR x R x R3, or -(CH2)3R3 and;

[0105] R5 is H or -CH2CF3;

[0106] p is 0, 1, or 2

[0107] Provides a compound of chemical formula (I), its N-oxide, or salt.

[0108] In these embodiments, a compound in which X is N and Y is S is included. Also in these embodiments, a compound in which X is S and Y is N is included in these embodiments. Additionally, a compound in which X is S and Y is CH is included.

[0109] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is a cyclohexyl substituted with , its N-oxide, or a salt. The compound of such an embodiment has the following structure:

[0110] .

[0111] In these embodiments, a compound in which X is N and Y is S is included. Also in these embodiments, a compound in which X is S and Y is N is included in these embodiments. Additionally, a compound in which X is S and Y is CH is included.

[0112] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is a cyclohexyl substituted with , its N-oxide, or a salt. The compound of such an embodiment has the following structure:

[0113] .

[0114] In this embodiment, G is: Phosphorus compounds are included. Also, in these embodiments, R 3a A 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)CH2CH2S(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(methyl oxetanyl), -CH2(tetrahydropyranyl), -C(O)(deoxydotetrahydrothiopyranyl), -NH(cyanocyclopropyl), -NH(cyclobutyl), -NH(methylcyclobutyl), -NH(oxetanyl), -NH(methyl oxetanyl), -NH(ethyl oxetanyl), -NH(isopropylpiperidinyl), -NH(tetrahydropyranyl), -NH(bicyclo[1.1.1]pentyl), -NHCH2(methyl oxetanyl), -NH(Dioxydotetrahydrothiophenyl), -NHCH2(Hydroxymethylcyclopropyl), -NHCH2(Methylsulfonylcyclopropyl), -NHCH2(Methylcyclobutyl), -NHCH2C(O)(Morfollinyl), Cyclobutyl, Azetidinyl, Fluorozetidinyl, Difluoroazetidinyl, Hydroxyazetidinyl, Methoxyazetidinyl, Hydroxy(Trifluoromethyl)azetidinyl, Bis(Hydroxymethyl)azetidinyl, Oxetanil, Pyrrolidinyl, Acetamidopyrrolidinyl, Piperazinonil, Tetrahydropyranil, Morfollinyl, Dioxothiomorpholinyl, Oxazepanil, Bicyclo[1.1.1]fentanyl, Azaspiro[3.3]heptanil, Oxazaspiro[3.3]heptanyl, Deoxydothiazspiro[3.3]heptanil, oxaazabicyclo[3.2.1]octanil, oxaazspiro[3.5]Compounds that are nonanyl, or diazaspiro[4.4]nonanyl are included.

[0115] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is 1-piperidinyl substituted with , an N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0116] .

[0117] In these embodiments, a compound in which X is N and Y is S is included. Also in these embodiments, a compound in which X is S and Y is N is included in these embodiments. Additionally, a compound in which X is S and Y is CH is included.

[0118] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is 1-piperidinyl substituted with , an N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0119] .

[0120] In this embodiment, G is Phosphorus compounds are included. Also, in these embodiments, R 3a A 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)CH2CH2S(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(methyl oxetanyl), -CH2(tetrahydropyranyl), -C(O)(deoxydotetrahydrothiopyranyl), -NH(cyanocyclopropyl), -NH(cyclobutyl), -NH(methylcyclobutyl), -NH(oxetanyl), -NH(methyl oxetanyl), -NH(ethyl oxetanyl), -NH(isopropylpiperidinyl), -NH(tetrahydropyranyl), -NH(bicyclo[1.1.1]pentyl), -NHCH2(methyl oxetanyl), -NH(Dioxydotetrahydrothiophenyl), -NHCH2(Hydroxymethylcyclopropyl), -NHCH2(Methylsulfonylcyclopropyl), -NHCH2(Methylcyclobutyl), -NHCH2C(O)(Morfollinyl), Cyclobutyl, Azetidinyl, Fluorozetidinyl, Difluoroazetidinyl, Hydroxyazetidinyl, Methoxyazetidinyl, Hydroxy(Trifluoromethyl)azetidinyl, Bis(Hydroxymethyl)azetidinyl, Oxetanil, Pyrrolidinyl, Acetamidopyrrolidinyl, Piperazinonil, Tetrahydropyranil, Morfollinyl, Dioxothiomorpholinyl, Oxazepanil, Bicyclo[1.1.1]fentanyl, Azaspiro[3.3]heptanil, Oxazaspiro[3.3]heptanyl, Deoxydothiazspiro[3.3]heptanil, oxaazabicyclo[3.2.1]octanil, oxaazspiro[3.5]Compounds that are nonanyl, or diazaspiro[4.4]nonanyl are included.

[0121] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is 4-piperidinyl substituted with N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0122] .

[0123] In these embodiments, a compound in which X is N and Y is S is included. Also in these embodiments, a compound in which X is S and Y is N is included in these embodiments. Additionally, a compound in which X is S and Y is CH is included.

[0124] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is 4-piperidinyl substituted with N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0125] .

[0126] In these embodiments, a compound is included in which G is as follows:

[0127] .

[0128] In this embodiment, R 3a -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 xCompounds include -C(O)CH3, -C(O)CH2N(CH3)2, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetanyl), -CH2(tetrahydropyranyl), -C(O)(dioxydotetrahydrothiopyranyl), cyclobutyl, azetidinyl, fluoroazetidinyl, difluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, oxetanyl, pyrrolidinyl, acetamidopyrrolidinyl, tetrahydropyranyl, oxazepanyl, or bicyclo[1.1.1]fentanyl.

[0129] One embodiment has A 0 to 1 R 3a and 0 to 2 R 3b Provides a compound of formula (I) which is a piperazinyl substituted with N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0130] .

[0131] In these embodiments, a compound in which X is N and Y is S is included. Also in these embodiments, a compound in which X is S and Y is N is included in these embodiments. Additionally, a compound in which X is S and Y is CH is included.

[0132] One embodiment has A 0 to 1 R 3a and 0 to 2 R 3b Provides a compound of formula (I) which is a piperazinyl substituted with N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0133] .

[0134] In this embodiment, G is Phosphorus compounds are included. Also, in these embodiments, R 3a-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 Compounds include -C(O)CH3, -C(O)CH2N(CH3)2, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetanyl), -CH2(tetrahydropyranyl), -C(O)(dioxydotetrahydrothiopyranyl), cyclobutyl, azetidinyl, fluoroazetidinyl, difluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, oxetanyl, pyrrolidinyl, acetamidopyrrolidinyl, tetrahydropyranyl, oxazepanyl, or bicyclo[1.1.1]fentanyl.

[0135] One embodiment has A 0 to 1 R 3a Provides a compound of formula (I) which is diazaspiro[3.3]heptanyl substituted with N-oxide, or a salt thereof. The compound of such an embodiment has the following structure:

[0136] .

[0137] In this embodiment, G is It includes phosphorus compounds.

[0138] Also, in these embodiments, R 3a -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 xCompounds include -C(O)CH3, -C(O)CH2N(CH3)2, -S(O)2CH3, -CH2(cyclopropyl), -CH2(methyloxetanyl), -CH2(tetrahydropyranyl), -C(O)(dioxydotetrahydrothiopyranyl), cyclobutyl, azetidinyl, fluoroazetidinyl, difluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, oxetanyl, pyrrolidinyl, acetamidopyrrolidinyl, tetrahydropyranyl, oxazepanyl, or bicyclo[1.1.1]fentanyl.

[0139] One embodiment is that A is H, -NR y R y , or -CH2NHCH2C(O)NR x R x Provides a compound of the chemical formula (I), its N-oxide, or a salt thereof. In these embodiments, a compound in which A is H is included. Also in these embodiments, A is -NR y R y The compound is included. Additionally, in these embodiments, A is -CH2NHCH2C(O)NR x R x It includes phosphorus compounds.

[0140] One embodiment provides a compound of formula (I) in which A is -CH2R3, -CH2NHR3, or -CH2NHCH2R3, its N-oxide, or salt. In this embodiment, G is In addition, in these embodiments, compounds are included in which R3 is isopropylpiperidinyl, dioxydothiazspiro[3.3]heptanyl, oxazaspiro[3.5]nonanyl, methylsulfonylcyclopropyl, piperazinonyl, morpholinyl, oxazaspiro[3.3]heptanyl, or diazaspiro[3.3]heptanyl.

[0141] One embodiment is that A is -C(O)NHR3 or -C(O)NR xProvides a compound of formula (I) of R4, its N-oxide, or salt. In this embodiment, G is Phosphoric compounds are included. Also, in these embodiments, R3 is dimethylaminocyclohexyl, pyrrolidinyl, pyrrolidinonyl, morpholinyl, methylpiperidinyl, morpholinyl, or methylsulfonylcyclopropyl; and R4 is H, -CH2CHF2, -CH2CF3, -CH2CH2N(CH3)2, -CH2R3, -CH2CR x R x Compounds that are R3, or -(CH2)3R3 are included.

[0142] One embodiment provides a compound of formula (I) in which A is -C(O)R3, its N-oxide, or salt. In this embodiment, G is In addition, in these embodiments, a compound is included in which R3 is azetidinyl, fluoroazetidinyl, dimethylaminoazetidinyl, deoxydothiomorpholinyl, morpholinyl, oxazepanyl, oxetanyl, piperazinonyl, acetylpiperazinyl, isopropylpiperazinyl, methylsulfonylpiperazinyl, dimethylaminopiperidinyl, or pyrrolidinyl.

[0143] One embodiment has A with 0 to 1 R each. 3a Provides a compound of formula (I) substituted with cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl, or diazaspiro[3.3]heptanyl, N-oxide, or its salt.

[0144] One embodiment is

[0145] G:

[0146] ;

[0147] (iv) 9-membered heterocyclic ring selected from the following:

[0148]

[0149]

[0150] ; or

[0151] (v) 10-circle heterocyclic ring selected from the following:

[0152]

[0153]

[0154] Provides a compound of the chemical formula (I), an N-oxide, or a salt thereof. In this embodiment, G is Phosphoric compounds are included. Also, in these embodiments, G is It includes phosphorus compounds.

[0155] In one embodiment, 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 Provides a compound of formula (I) that is cycloalkyl, -CH2(phenyl), phenyl, pyrimidinyl, or triazolyl, an N-oxide, or a salt thereof. In these embodiments, a compound is included in which each R2 is independently -CN, -CH3, or -OCH3.

[0156] One embodiment provides a compound of formula (I) in which R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2, or -CH2CF3, its N-oxide, or salt. In this embodiment, a compound in which R5 is H or -CH2CF3 is included.

[0157] One embodiment is that R1 is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3, or -S(O)2(C 1-2 Provides a compound of formula (I) that is an alkyl, its N-oxide, or a salt. In these embodiments, a compound in which R1 is independently -CH3, -CH2CH3, or -CH(CH3)2 is included. Also in these embodiments, a compound in which R1 is -CH(CH3)2 is included.

[0158] One embodiment is that R1 is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3, or -S(O)2(C 1-2 alkyl) and 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)0-2C(O)NR x R x , -(CH2) 0-2 S(O)2(C 1-3 alkyl), -CH2(C 3-6 Provides a compound of formula (I), N-oxide, or its salt, in which R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2, or -CH2CF3, and -CH2A2C

[0159] One embodiment provides a compound of formula (I), an N-oxide, or a salt thereof, 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.

[0160] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 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-dimethylpyridine-4-yl)-6-isopropyl-2-(piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (4); 5-(6-isopropyl-2-(piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (5); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)ethane-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]thiazole-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]thiazole-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)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (9); 6-isopropyl-2-(1-isopropylpiperidine-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]pyridine-6-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (11); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (12); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-2-(1-((3-methyloxetane-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-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]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)-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]thiazole-2-yl)piperidin-1-yl)ethane-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)-4H-pyrrolo[3,2-d]thiazole (22); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (23); 2-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (24); 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(1-isopropylpiperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (25); 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (26); 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(1-((3-methyloxetane-3-yl)methyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (27); 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)ethane-1-one (28); 1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-2-methylpropan-2-ol (29); 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (30); 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-2-yl)piperidin-1-yl)ethane-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-(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)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (37); 5-(6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (38); 5-(2-(1-(dimethylglycyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (39); 2-(4-(5-(8-cyanoquinoline-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-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)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (42);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (43); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-isopropylpiperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (44); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(methylsulfonyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (45); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (46); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-((3-methyloxetane-3-yl)methyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (47); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-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]pyridine-6-yl)-2-(1-isobutylpiperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (52);2-(1-(cyclopropylmethyl)piperidine-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (53); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(2-ethylbutyl)piperidine-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]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]thiazole-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]thiazole-2-yl)piperidin-1-yl)ethane-1-one (59); 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (61); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N,N-dimethylacetamide (62);2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-N-methylacetamide (63); or 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)acetamide (64).;

[0161] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (65-66); (1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)azetidine-3,3-diyl)dimethanol (67); 6-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-methyloxetane-3-amine (70-71); N-ethyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (72-73); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (74-75); 2-(4-(azetidine-1-yl)cyclohexyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (76-77); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (78-79); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)thiomorpholine 1,1-dioxide (82-83);1-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (84-85); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexane-1-amine (86-87); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (88-89); (R)-3-fluoro-4-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylbutan-2-ol (90-91); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (92-93); 3-ethyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (94-95); 6-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-thi-6-azaspiro[3,3]heptane 2,2-dioxide (96-97); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(pyrrolidine-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazolo-2-yl)cyclohexyl)pyrrolidine-3-yl)acetamide (100-101);4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-1,4-oxazepan (102-103); (1R,5S)-8-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)cyclopropane-1-carbonitrile (106-107); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(1-methylcyclobutyl)cyclohexane-1-amine (108-109); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-7-oxa-2-azspiro[3.5]nonane (110-111); 7-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-7-azspiro[3.5]nonane (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]thiazole-2-yl)cyclohexyl)-2-azspiro[3.3]heptane-6-amine (116-117); 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-(trifluoromethyl)azetidine-3-ol (118-119);4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazine-2-one (120-121); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(3-methoxyazetidine-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (122-123); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-N-methyloxetane-3-amine (124-125); 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-2-yl)cyclohexyl)methansulfonamide (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]thiazole-2-yl)cyclohexyl)acetamide (128); 2-(isobutylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide (129); N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (130-131); N-ethyl-4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazolo-2-yl)-N-methylcyclohexane-1-amine (132);4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexane-1-amine (134-135); 6-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (140-141); (1-(((4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)methyl)cyclopropyl)methanol (142-143); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-methyloxetane-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]thiazole-2-yl)cyclohexyl)-1,4-oxazepan (146-147); 4-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazine-2-one (148-149); 6-isopropyl-2-(4-(3-methoxyazetidine-1-yl)cyclohexyl)-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (150-151);N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (152-153); 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(pyrrolidine-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (158-159); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl) tetrahydro-2H-pyran-4-amine (160-161); 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide (162-163); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methyl-N-(2-(methylsulfonyl)ethyl)cyclohexane-1-amine (164-165); 1-isopropyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-N2-methylethane-1,2-diamine (170-171); 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexane-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]thiazole-2-yl)-N-methylcyclohexane-1-amine (174-175); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)bicyclo[1.1.1]pentan-1-amine (176-177); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (178-179); 6-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (180-181); 1-((4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (182-183); N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (184-185); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexane-1-amine (186-187);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(3-methoxyazetidine-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (188-189); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-ethyl-N-methylcyclohexane-1-amine (190-191); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropylcyclohexane-1-amine (194-195); 1-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (196-197); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-neopentylcyclohexane-1-amine (198-199); N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (200-201); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((1-methylcyclobutyl)methyl)cyclohexane-1-amine (202-203); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-N,N-dimethylacetamide (204-205);2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-1-morpholinoethane-1-one (206-207); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-N-methylacetamide (208-209); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)acetamide (210-211); 4-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)morpholine (212-213); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)cyclohexane-1-amine (214-215); 2-(4-(azetidine-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]thiazole-2-yl)cyclohexyl)piperazine-2-one (220-221); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropyl-N-methylcyclohexane-1-amine (222-223);1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)azetidine-3-ol (224-225); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(3-fluoroazetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (226-227); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isobutyl-N-methylcyclohexane-1-amine (228-229); 3-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)tetrahydrothiophene 1,1-dioxide (230-232); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-thi-6-azaspiro[3,3]heptane 2,2-dioxide (233-234); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-(trifluoromethyl)azetidine-3-ol (235-236); 7-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-7-azspiro[3.5]nonane (237-238); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-7-oxa-2-azspiro[3.5]nonane (239-240); 5-(6-isopropyl-2-(4-(oxetane-3-ylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (241-242);5-(6-isopropyl-2-(4-((2-methoxy-2-methylpropyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (243-244); 5-(2-(4-(2-oxa-6-azaspiro[3,3]heptane-6-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (245-246); 5-(2-(4-(ethyl(methyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (247-248); 5-(6-isopropyl-2-(4-((tetrahydro-2H-pyran-4-yl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (249-250); 5-(2-(4-((2-hydroxy-2-methylpropyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (251-252); 5-(6-isopropyl-2-(4-(isopropylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (253-254); 5-(2-(4-(azetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (255-256); 5-(6-isopropyl-2-(4-(((1-(methylsulfonyl)cyclopropyl)methyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (257-258); 4-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazine-2-one (259-260); 5-(6-isopropyl-2-(4-(isopropyl(methyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (261-262);5-(2-(4-(3-hydroxyazetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (263-264); 5-(2-(4-(3-fluoroazetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (265-266); 5-(2-(4-(3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (267-268); 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl) oxetane-3-amine (271-272); N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-2-yl)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]thiazole-2-yl)cyclohexyl)piperazine-2-one (275-276).;

[0162] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (278); 5-(6-isopropyl-2-(piperazine-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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-2-(dimethylamino)ethanol-1-one (280); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-2-methylpropan-2-ol (281); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(2-(methylsulfonyl) ethyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (282); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-N,N-dimethylacetamide (283); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-N-methylacetamide (284); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)acetamide (285); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (286);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (287); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-isopropylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (288); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-((3-methyloxetane-3-yl)methyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (289); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl (308); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-2,5-dimethylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (309); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-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-methylpiperazine-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-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)acetamide (313);(R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (314); (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N-methylacetamide (315); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (316); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (317); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (318); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(2,4-dimethylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (319); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-ethyl-2-methylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (320); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (321); (R)-2-(4-cyclobutyl-2-methylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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-methylpiperazine-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-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(methylamino)ethane-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]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(dimethylamino)ethane-1-one (327); 2-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (328); 2-((2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (329); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (330); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-4-ethyl-2,5-dimethylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (331);2-((2S,5R)-4-(cyclopropylmethyl)-2,5-dimethylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (332); 2-((2S,5R)-4-cyclobutyl-2,5-dimethylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (333); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (334); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-N,N-dimethylacetamide (335); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-N-methylacetamide (336); 2-((2S,5R)-2,5-dimethyl-4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)acetamide (338); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-methylpropan-2-ol (339);1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(methylamino) ethane-1-one (340); 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(dimethylamino) ethane-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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)piperazine-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-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)(1,1-deoxydotetrahydro-2H-thiopyran-4-yl)methanone (347);(S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (348); S)-2-(4-cyclobutyl-2-methylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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)piperazine-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-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (351); (S)-2-(4-(cyclopropylmethyl)-2-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)acetamide (355); (R)-6-isopropyl-2-(2-methyl-4-(2-(methylsulfonyl) ethyl)piperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (356);(R)-6-isopropyl-2-(4-(2-methoxyethyl)-2-methylpiperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (357); (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl) ethane-1-one (360); (R)-2-(4-isobutyl-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (361); (R)-2-(4-cyclobutyl-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (362); (R)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (363); (R)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (364); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (365);(R)-6-isopropyl-2-(4-isopropyl-2-methylpiperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (366); or (R)-2-(2,4-dimethylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (367).;

[0163] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(3-methyloxetane-3-yl)piperidine-4-amine (290); 1-((1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-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]thiazole-2-yl)-N-isopropyl-N-methylpiperidine-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]thiazole-2-yl)piperidine-4-amine (293); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(2-methoxy-2-methylpropyl)piperidine-4-amine (294); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)piperidine-4-amine (295); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(oxetane-3-yl)piperidine-4-amine (296); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropylpiperidine-4-amine (297); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-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]thiazole-2-yl)piperidine-4-amine (299).;

[0164] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3,3]heptane-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (300); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (301); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (302); 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3,3]heptane-2-yl)-2-methylpropan-2-ol (303); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (304); 5-(6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (305); 5-(6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-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]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (307).

[0165] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-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]pyridine-6-yl)-6-isopropyl-N-(3-(2-oxopyrrolidine-1-yl)propyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (371); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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[1,5-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-(morpholine-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); 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); 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).;

[0166] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: (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-deoxydothiomorpholino)methanone (373); 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)piperazine-1-yl)ethane-1-one (375); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)(4-(dimethylamino)piperidine-1-yl)methanone (376); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)(pyrrolidine-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]thiazole-2-carbonyl)piperazine-2-one (378); (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-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]thiazole-2-yl)(4-isopropylpiperazine-1-yl)methanone (380); (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-(dimethylamino)azetidine-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]thiazole-2-yl)(4-(methylsulfonyl)piperazine-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]thiazole-2-carboxamide (385); 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carbonyl)piperazine-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)methannon (393); (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)(1,4-oxazepan-4-yl)methanone (394); (4-(dimethylamino)piperidine-1-yl)(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)methanone (395); (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)(3-methoxyazetidine-1-yl)methanone (396); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(oxetane-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (397); or (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).;

[0167] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-1-isopropylpiperidin-4-amine (401); 2-(((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)amino)acetamide (402); 6-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-2-thi-6-azspiro[3.3]heptane 2,2-dioxide (403); 2-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-7-oxa-2-azspiro[3.5]nonane (404); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)methaneamine (405); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)piperazine-2-one (406); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)morpholine (407); 6-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (408); or 2-((2,6-diazaspiro[3.3]heptane-2-yl)methyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (409).

[0168] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 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 (411); or 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidine-4-yl)-4H-pyrrolo[2,3-d]thiazole (412).

[0169] One embodiment provides a compound of formula (I) as follows, its N-oxide, or salt: 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidin-4-yl)-4H-thieno[3,2-b]pyrrole (413).

[0170] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes of the present invention. The present invention encompasses all combinations of aspects and / or embodiments of the present invention as described herein. It is understood that any and all embodiments of the present invention may describe additional embodiments in combination with any other embodiments or embodiments. Furthermore, it is understood that each individual element of an embodiment is intended to describe additional embodiments by combining any and all other elements from any embodiment.

[0171] definition

[0172] The features and benefits of the present invention may be more readily understood by those skilled in the art by reading the following detailed description. For clarity, it should be recognized that specific features of the present invention described above and below in relation to individual embodiments may be combined to form a single embodiment. Conversely, for the sake of brevity, various features of the present invention described in relation to a single embodiment may also be combined to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative, not limiting.

[0173] Unless otherwise specifically stated herein, references to the singular may also include the plural. For example, the singular form may refer to one or more.

[0174] As used herein, the term "compound" refers to at least one compound. For example, a compound of formula (I) includes a compound of formula (I) and two or more compounds of formula (I).

[0175] Unless otherwise indicated, any heteroatom with an unsatisfied valence is presumed to have enough hydrogen atoms to satisfy the valence.

[0176] The definitions set forth herein shall take precedence over any definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0177] Definitions of various terms used to describe the present invention are listed below. These definitions apply to terms used throughout the specification, either individually or as part of a larger group (unless otherwise limited in specific cases).

[0178] Throughout this specification, groups and their substituents may be selected by a person skilled in the art to provide stable moiety and compounds.

[0179] In accordance with the regulations used in the relevant technical field,

[0180]

[0181] is used to illustrate a bond that is a moiety or a substituent attachment point to a core or backbone structure in the structural formula of the present invention.

[0182] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, and I.

[0183] The term "cyano" refers to the γ-CN.

[0184] The term "amino" refers to the -NH2 group.

[0185] The term "Oxo" refers to the qi = O.

[0186] As used herein, the term "alkyl" refers to both branched-chain 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 i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. Where a number appears as 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" represents a straight-chain and branched-chain alkyl group having 1 to 6 carbon atoms.

[0187] 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.

[0188] The term "cyanoalkyl" includes both branched-chain and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and C 1-4 It contains cyanoalkyl.

[0189] The term "aminoalkyl" includes both branched-chain and straight-chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C 1-4 It contains aminoalkyl.

[0190] The term "hydroxyalkyl" includes both branched-chain and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C 1-4 It contains hydroxyalkyl.

[0191] The term "hydroxy-fluoroalkyl" includes both branched-chain 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 It contains hydroxy-fluoroalkyl.

[0192] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by the removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. Where a number is indicated as 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 3 to 6 carbon atoms.

[0193] As used herein, the term "alkoxy" refers to an alkyl group attached to a parent molecular moiety via an oxygen atom, for example, a methoxy group (-OCH3). For example, "C 1-3 "Alkoxy" represents an alkoxy group having 1 to 3 carbon atoms.

[0194] As used herein, the term "alkoxyalkyl" refers to an alkoxy group in which the alkyl group is attached to a parent molecular moiety through an oxygen atom, for example, a methoxymethyl group (-CH2OCH3). For example, "C 2-4 "Alkoxyalkyl" represents an alkoxyalkyl group having 2 to 4 carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0195] The phrase "pharmaceutical acceptable" is used herein to refer to these compounds, substances, compositions, and / or dosage forms suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in accordance with a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0196] The compound of formula (I) can be provided as an amorphous solid or a crystalline solid. Freeze-drying can be used to provide the compound of formula (I) as an amorphous solid.

[0197] It should be further understood that solvates (e.g., hydrates) of the compound of formula (I) are also within the scope of the present invention. The term “solvate” means a physical association of one or more solvent molecules, whether organic or inorganic, with the compound of formula (I). Such physical associations involve hydrogen bonding. In certain cases, the solvate may be isolated, for example, when one or more solvent molecules are contained within the crystal lattice of a crystalline solid. “solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanoleates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the relevant art.

[0198] Various forms of prodrugs are widely known in the relevant technical field and are described in the following literature:

[0199] a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);

[0200] b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

[0201] c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); and

[0202] d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[0203] Additionally, a compound of formula (I) can be isolated and purified following its preparation to obtain a composition containing 99% or more of the amount of ("substantially pure") compound of formula (I) by weight, which is then used or formulated as described herein. Such "substantially pure" compound of formula (I) is also considered herein as part of the invention.

[0204] "Stable compound" and "stable structure" are intended to represent a compound that is robust enough to withstand isolation from a reaction mixture to a useful degree of purity and to be formulated into an effective therapeutic agent. The present invention is intended to provide a stable compound.

[0205] The “therapeutic effective dose” is intended to include an amount of the compound of the present invention alone, an amount of a combination of the claimed compounds, or an amount of the compound of the present invention combined with other active ingredients that is effective to act as an inhibitor on TLR7 / 8 / 9 or to treat or prevent autoimmune and / or inflammatory disease conditions, such as SLE, IBD, multiple sclerosis (MS), Sjögren’s syndrome, and rheumatoid arthritis.

[0206] As used herein, “treating” or “treatment” includes the treatment of a disease-state in mammals, particularly in humans, and includes (a) preventing the onset of the disease-state in mammals, particularly where such mammals have a predisposition to the disease-state but have not yet been diagnosed with it; (b) suppressing the disease-state, i.e., halting its progression; and / or (c) alleviating the disease-state, i.e., causing the regression of the disease-state.

[0207] The compounds of the present invention are intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon are 13 C and 14 It includes C. The isotope-labeled compounds of the present invention may be prepared by ordinary techniques generally known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeled reagent instead of an otherwise used unlabeled reagent. For example, methyl (-CH3) also includes a deuteride methyl group, e.g., -CD3.

[0208] usefulness

[0209] The human immune system has evolved to defend the body against 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. Although the initiation event is not currently well understood, in autoimmune disease states, the immune system directs its inflammatory response toward target organs in the affected individual. Different autoimmune diseases are typically characterized by the affected dominant or initial target organ or tissue; for example, the joints in the case of rheumatoid arthritis, the thyroid in the case of Hashimoto's thyroiditis, the central nervous system in the case of multiple sclerosis, the pancreas in the case of type I diabetes, and the intestines in the case of inflammatory bowel disease.

[0210] The compounds of the present invention inhibit signal transduction through Toll-like receptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or a combination thereof. Accordingly, the compounds of Formula I are useful for treating conditions associated with the inhibition of signal transduction through one or more of TLR7, TLR8, or TLR9. These conditions include TLR7, TLR8, or TLR9 receptor-associated diseases in which cytokine levels are modulated as a result of intracellular signal transduction.

[0211] As used herein, the terms “treating” or “treatment” include the treatment of a disease state in mammals, particularly humans, which includes (a) preventing or delaying the onset of a disease state in mammals, particularly where said mammals are susceptible to a disease state but have not yet been diagnosed with it; (b) suppressing the disease state, i.e., preventing its onset; and / or (c) achieving a complete or partial reduction of symptoms or a disease state and / or alleviating, improving, reducing, or curing the disease or disorder and / or its symptoms.

[0212] In terms of its activity as a selective inhibitor of TLR7, TLR8, or TLR9, the compound of Formula I is used for TLR7, TLR8, or TLR9 family receptor-associated diseases, and, to a limited extent, inflammatory diseases, e.g., Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases, e.g., Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis; auto-inflammatory diseases, e.g., cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), adult-onset Still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases, e.g., type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders, e.g., bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-associated bone disorders; It is useful for treating proliferative disorders, such as acute myeloid leukemia and chronic myeloid leukemia; angiogenic disorders, such as solid tumors, ocular neovascularization, and infantile hemangioma; infectious diseases, such as sepsis, septic shock, and shigelasis; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, cerebral ischemia, or neurodegenerative diseases caused by traumatic injury; neoplastic and viral diseases, such as metastatic melanoma, Kaposi's sarcoma, and multiple myeloma; and HIV infection, CMV retinitis, and AIDS, respectively.

[0213] More particularly, 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, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubellar arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by extensive neutrophil infiltration; Rheumatoid spondylitis, gouty arthritis and other arthritis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and shigelasis; Alzheimer's disease, Parkinson's disease, cerebral ischemia, or neurodegenerative diseases caused by traumatic injury; neovascularization disorders, e.g., solid tumors, ocular neovascularization, and infantile hemangioma; viral diseases, e.g., acute hepatitis infection (including hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignancies, and herpes; Includes stroke, myocardial ischemia, ischemia in stroke-induced heart attack, bronchohypoxia, angiogenesis, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris.These embodiments include a treatment method in which the condition is selected from lupus, including lupus nephritis and systemic lupus erythematosus (SLE); Crohn's disease; ulcerative colitis; allograft rejection; rheumatoid arthritis; psoriasis; ankylosing spondylitis; psoriatic arthritis; and pemphigus vulgaris. A treatment method is also included in which the condition is selected from ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury induced by stroke and cardiac ischemia-reperfusion injury induced by myocardial infarction. Another treatment method is that the condition is multiple myeloma.

[0214] In one embodiment, the compound of Formula I is useful for treating 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.

[0215] In addition, the TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of induced inflammatory proteins, such as prostaglandin endoperoxide synthase-2 (PGHS-2) (also referred to as cyclooxygenase-2 (COX-2)), IL1, IL-6, IL-18, and chemokines. Thus, additional TLR7 / 8 / 9 associated conditions include edema, analgesia, fever, and pain, such as neuromuscular pain, headache, pain due to cancer, toothache, and arthritis pain. The compounds of the present invention may also be used to treat veterinary viral infections, such as lentivirus infections, such as, to a non-limiting extent, equine infectious anemia virus; or retrovirus infections, such as feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.

[0216] Accordingly, the present invention provides a method for treating such a condition, comprising administering a therapeutically effective amount of at least one compound of Formula I or a salt thereof to a subject requiring treatment for such a condition. The “therapeutically effective amount” is intended to include an amount of the compound of the present invention that is effective when administered alone or in combination to suppress an autoimmune disease or a chronic inflammatory disease.

[0217] A method for treating a TLR7, TLR8, or TLR9-associated condition may involve administering the compound of Formula I alone, in combination with one another, or in combination with other suitable therapeutic agents useful for treating such condition. Accordingly, the “therapeutic effective dose” is also intended to include an amount of a combination of the claimed compound effective for inhibiting TLR7, TLR8, or TLR9 and / or treating a disease associated with TLR7, TLR8, or TLR9.

[0218] Exemplary other therapeutic agents include corticosteroids, rolipram, calpostine, cytokine-inhibiting anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, e.g., deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen, celecoxib, and rofecoxib; steroids, e.g., prednisone or dexamethasone; antivirals, e.g., abacavir; antiproliferative agents, e.g., methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); antimalarials, e.g., hydroxychloroquine; cytotoxic drugs, e.g., azathioprine and cyclophosphamide; TNF-α inhibitors, such as Tenidab, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or Rapamune®) or its derivatives are included.

[0219] When used in combination with the compound of the present invention, the other therapeutic agent(s) are, for example, in amounts as presented in the Physicians' Desk Reference (PDR) or otherwise determined by a person skilled in the art. In the method of the present invention, these other therapeutic agents(s) may be administered before, simultaneously with, or after the administration of the compound of the present invention. The present invention also provides a pharmaceutical composition capable of treating TLR7 / 8 / 9 receptor-associated conditions, including IL-1 family receptor-mediated diseases as described above.

[0220] The composition of the present invention may contain other therapeutic agents as described above, and may be formulated by using conventional solid or liquid vehicles or diluents, as well as types of pharmaceutical additives suitable for the intended mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.), according to techniques widely known in the field of pharmaceutical formulation technology.

[0221] Accordingly, the present invention further comprises a composition comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.

[0222] "Pharmaceutical acceptable carriers" refers to media generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to a sufficient number of factors within the understanding of a person skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated; the target to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication to be targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers may contain a number of different components and additives in addition to the active agent, and these additional components may be included in the formulation for various reasons widely known to a person skilled in the art, e.g., for stabilizing the active agent, binder, etc. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are available in various readily available sources, e.g., literature [ Remington's Pharmaceutical Sciences It is found in the 17th Edition (1985), the full text of which is incorporated herein by reference.

[0223] The compound according to Formula I may be administered by any means suitable for the condition to be treated, which may vary depending on the need for site-specific treatment or the amount of Formula I compound to be delivered.

[0224] The present invention also encompasses 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 ajuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compound of Formula I may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, by mucosal, or parenterally, such as intravascular, intravenous, intraperitoneal, subcutaneously, intramuscularly, and intrasternally, as a dosage unit formulation containing a conventionally pharmaceutically acceptable carrier, ajuvant, and vehicle. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components, such as a lubricant, for example, magnesium stearate, and a disintegrant, for example, crospovidone. The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, in the form of an oral dose or as an injection.

[0225] 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 prepared in the form of dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The daily dose suitable for humans or other mammals may vary widely depending on the patient's condition and other factors, but can be determined using commercial methods.

[0226] Any pharmaceutical composition considered herein may be delivered orally, for example, through any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. A pharmaceutical composition intended for oral administration may be prepared according to any method known in the relevant art for preparing a pharmaceutical composition intended for oral administration. To provide a formulation with excellent pharmaceutical taste, the pharmaceutical composition according to the present invention may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, emollients, antioxidants, and preservatives.

[0227] Tablets may be prepared, for example, by mixing at least one compound of Formula I with at least one non-toxic, pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating agents and disintegrating agents, such as microcrystalline cellulose, sodium croscarmellose, corn starch, and alginic acid; binders, such as starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricants, such as magnesium stearate, stearic acid, and talc, but are not limited thereto. Additionally, tablets may be uncoated or coated by known techniques to mask the bad taste of an unpleasant-tasting drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract to sustain 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 time-delaying materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0228] 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, for example, calcium carbonate; calcium phosphate; and kaolin.

[0229] 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.

[0230] An aqueous suspension may be prepared, for example, by mixing at least one compound of Formula I with at least one excipient suitable for the preparation of an aqueous suspension. Exemplary excipients suitable for the preparation of an aqueous suspension include, for example, suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, tragacanth gum, and acacia gum; dispersants or wetting agents, e.g., naturally occurring phosphatides, e.g., lecithin; condensation products of alkylene oxide and fatty acids, e.g., polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols, e.g., heptadecaethylene-oxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, e.g., polyoxyethylene sorbitol monooleate; and a condensation product of a partial ester derived from ethylene oxide, fatty acids, and hexitol anhydride, such as, for example, polyethylene sorbitan monooleate, but not limited thereto. The aqueous suspension may also contain at least one preservative, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetener, for example, sucrose, saccharin, and aspartame, but not limited thereto.

[0231] The oily suspension may be prepared, for example, by suspending at least one compound of Formula I in a vegetable oil, e.g., arachnid oil; olive oil; sesame oil; and coconut oil; or a mineral oil, e.g., liquid paraffin. The oily suspension may also contain at least one thickener, e.g., beeswax; hard paraffin; and cetyl alcohol. To provide an oily suspension with a good taste, at least one sweetener and / or at least one flavoring agent already described above may be added to the oily suspension. The oily suspension may further contain at least one preservative, e.g., an antioxidant, e.g., butylated hydroxyanisole and alpha-tocopherol, but not limited thereto.

[0232] Dispersible powders and granules may 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 are as already described above. Exemplary preservatives also include, but are not limited to, antioxidants, e.g., ascorbic acid. Additionally, dispersible powders and granules may also contain at least one excipient, e.g., sweeteners; flavoring agents; and coloring agents, but not limited thereto.

[0233] An emulsion of at least one compound of its formula I can be prepared, for example, as an oil-in-water emulsion. The oil phase of an emulsion containing the compound of formula I can be composed in a known manner from known components. The oil phase may be provided by, for example, vegetable oils, e.g., olive oil and arachnoid oil; mineral oils, e.g., liquid paraffin; and mixtures thereof, but is not limited thereto. The phase may comprise only an emulsifier, but may comprise at least one emulsifier and a mixture of fat or oil or both fat and oil. Suitable emulsifiers include, for example, naturally occurring phosphatides, e.g., soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, e.g., sorbitan monooleate; and condensation products of partial esters and ethylene oxide, e.g., polyoxyethylene sorbitan monooleate, but are not limited thereto. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both oil and fat. In addition, the emulsifier(s) containing or not containing the stabilizer(s) constitute a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of the cream formulation. The emulsion may also contain sweeteners, flavorings, preservatives, and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, and glyceryl distearate, either alone, together with wax, or together with other substances widely known in the art.

[0234] Compounds of Formula I may also be delivered intravenously, subcutaneously, and / or intramuscularly through any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, sterile aqueous solutions comprising, for example, acceptable vehicles and solvents, such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oil suspensions.

[0235] Preparations 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 by using one or more of the carriers or diluents mentioned for use in preparations for oral administration, or by using other suitable dispersants, 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 modes of administration are widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with a suitable carrier including saline, dextrose, or water, or with a cyclodextrin (i.e., captisol), a co-solvent solubilizer (i.e., propylene glycol), or a micelle solubilizer (i.e., Tween 80).

[0236] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixation oils are typically used as solvents or suspension media. For this purpose, any non-irritating fixation oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the manufacture of injectable preparations.

[0237] A sterile injectable oil-in-water microemulsion can be prepared by, for example, 1) dissolving at least one compound of Formula I in an oily phase, for example, a mixture of soybean oil and lecithin; 2) combining the oily phase containing Formula I with a mixture of water and glycerol; and 3) processing the mixture to form a microemulsion.

[0238] Sterile aqueous or oil suspensions may be prepared according to methods already known in the relevant art. For example, a sterile aqueous solution or suspension may be prepared using a non-toxic, parenterally acceptable diluent or solvent, such as 1,3-butanediol; a sterile oil suspension may be prepared using a sterile, non-toxic, acceptable solvent or suspension medium, such as sterile fixative oil, such as synthetic mono- or diglycerides; and a fatty acid, such as oleic acid.

[0239] Pharmaceutically acceptable carriers, ajuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, e.g., Tween, polyethoxylated castor oil, e.g., Cremophor surfactant (BASF), or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffering materials, e.g., phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, salts, or mixtures of partial glycerides of electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials. Polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fats are included but not limited thereto. Additionally, cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrins, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, such as 2- and 3-hydroxypropyl-cyclodextrin, or other solubilized derivatives may be advantageously used to promote the delivery of the compound of the formula described herein.

[0240] The pharmaceutical active compounds of the present invention may be processed according to conventional pharmaceutical methods to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical composition may be applied to conventional pharmaceutical operations, e.g., sterilization, and / or may contain conventional ajuvants, e.g., preservatives, stabilizers, humectants, emulsifiers, buffers, etc. Tablets and pills may additionally be manufactured having an enteric coating. Such compositions may also include ajuvants, e.g., humectants, sweeteners, flavoring agents, and perfumers.

[0241] The amount of compound and the dosage regimen administered to treat a diseased condition using the compounds and / or compositions of the present invention depend on various factors, including age, body weight, sex, the subject's medical condition, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound used. Accordingly, the dosage regimen may vary widely but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, most preferably about 0.005 to 10 mg / kg body weight may be appropriate. The daily dose may be administered as one to four doses per day. Other dosage schedules include a once-weekly and once-every-two-days dose cycle.

[0242] For therapeutic purposes, the active compound of the present invention is typically combined with one or more ajuvants suitable for the indicated route of administration. When administered orally, the compound may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanes, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then formed into tablets or capsules for convenient administration. Such capsules or tablets may contain a controlled-release formulation, such as provided in a dispersion of the active compound in hydroxypropylmethylcellulose.

[0243] The pharmaceutical composition of the present invention comprises at least one compound of Formula I and an additional agent selected from optionally pharmaceutically acceptable carriers, ajuvants, and vehicles. An alternative composition of the present invention comprises the compound of Formula I or a prodrug thereof described herein, and pharmaceutically acceptable carriers, ajuvants, or vehicles.

[0244] The present invention also encompasses manufactured articles. The manufactured articles used herein are intended to include, but are not limited to, kits and packages. The manufactured articles of the present invention comprise (a) a first container; (b) a pharmaceutical composition disposed within the first container (wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof); and (c) a package insert stating that the pharmaceutical composition may be used for the treatment of inflammatory disorders and / or autoimmune diseases (as previously defined). In another embodiment, the package insert mentions that the pharmaceutical composition may be used in combination with a second therapeutic agent to treat inflammatory disorders and / or autoimmune diseases (as previously defined). The manufactured articles may further comprise (d) a second container, wherein components (a) and (b) are disposed within the second container, and component (c) is disposed within or outside the second container. Disposed within the first and second containers means that each container holds the item within its boundaries.

[0245] The first container is a receptacle used to hold a pharmaceutical composition. Such containers may be intended for manufacturing, storage, transport, and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other containers used for the manufacturing, holding, storage, or dispensing of pharmaceutical products.

[0246] The second container is used to hold the first container and optionally a package insert. 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 bags. The package insert may be physically attached to the outside of the first container via tape, adhesive, staples, or other attachment methods, or may be placed inside the second container without any means of physical attachment to the first container. Alternatively, the package insert is placed outside the second container. When placed outside the second container, it is preferable that the package insert be physically attached via tape, adhesive, staples, or other attachment methods. Alternatively, it may be adjacent to or in contact with the outside of the second container without being physically attached.

[0247] Package inserts are labels, tags, markers, etc. They list information regarding the pharmaceutical composition contained within the first container. The information listed will typically be determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) having jurisdiction over the region where the manufactured article is sold. In one embodiment, the package insert specifically lists an indication that the pharmaceutical composition has been approved. The package insert may be made of any material in which a person can read the information contained therein or on it. For example, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-back paper, or plastic, etc.) on which the intended information is formed (e.g., printed or applied).

[0248] manufacturing method

[0249] The compounds of the present invention can be prepared in a number of ways widely known to those skilled in the art of organic synthesis. The compounds of the present invention may be synthesized using the methods described below, or modifications thereof as recognized by those skilled in the art, in combination with synthesis methods known in the art of synthetic organic chemistry. Preferred methods include, but are not limited to, the methods described below. All references cited herein are incorporated herein by reference in their entirety.

[0250] The compounds of the present invention may be prepared using the reactions and techniques described in this section. The reactions are carried out in a solvent suitable for the reagents and materials used and suitable for carrying out the transformation. Furthermore, in the description of the synthesis method described below, all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, duration of experiment, and post-processing procedure, are selected to be standard conditions for the reaction, and it should be understood that this should be readily recognized by a person skilled in the art. It is understood by a person skilled in the art of organic synthesis that functional groups present in 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 a person skilled in the art, and therefore alternative methods must be used. This may sometimes require judgment regarding modifying the order of synthesis steps to obtain the target compound of the present invention, or selecting one specific process reaction scheme for another process reaction scheme. In addition, it will be recognized that another major consideration in planning any synthetic route in this field is the careful selection of a protecting group used to protect the reactive functional groups present in the compounds described in this invention. An authoritative description describing many alternatives to those skilled in the art is [Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999)].

[0251] Examples

[0252] The compound of Formula I and the intermediate used in the preparation of the compound of Formula I can be prepared using the procedures and related procedures presented in the following examples. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are intended not to be limiting, but to demonstrate how the compound of Formula I can be prepared. The starting materials and reagents used in these examples, if not prepared by the procedures described herein, are generally commercially available, or are reported in the chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0253] abbreviation

[0254] ACN Acetonitrile

[0255] AcOH acetic acid

[0256] DIPEA Diisopropylethylamine

[0257] Boc tert- Butoxycarbonyl

[0258] DCE dichloroethane

[0259] DCM dichloromethane

[0260] TEA Triethylamine

[0261] DMAP Dimethylaminopyridine

[0262] DMF dimethylformamide

[0263] NaHCO3 sodium bicarbonate

[0264] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphyl

[0265] EtOAc ethyl acetate

[0266] H or H2 hydrogen

[0267] h, hr, or hrs time

[0268] HATU O-(7-azabezotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0269] HCl hydrochloric acid

[0270] NaH sodium hydride

[0271] CO carbon monoxide

[0272] HOAc acetic acid

[0273] HPLC High Pressure Liquid Chromatography

[0274] MTBE methyl tert-butyl ether

[0275] LC liquid chromatography

[0276] M Mall

[0277] M +1 (M+H) +

[0278] NIS n-iodosuccinimide

[0279] MeOH methanol

[0280] MHz megahertz

[0281] min. minutes

[0282] mM millimoles

[0283] MS Mass Spectrometry

[0284] n or N normal

[0285] NBS n-bromosuccinimide

[0286] nm nanometer

[0287] nM nanomoles

[0288] NMP N-methylpyrrolidin

[0289] Pd(PPh3)4-tetrakis(triphenylphosphine)palladium

[0290] Pd / C carbon phase palladium

[0291] PdCl2(dppf) [1,1'- 비스( diphenylphosphino)ferrocene]dichloropalladium(II)

[0292] PET ether petroleum ether

[0293] Ret time stay time

[0294] sat. saturated

[0295] SFC Supercritical Fluid Chromatography

[0296] TFA trifluoroacetic acid

[0297] THF Tetrahydrofuran

[0298] 2nd generation Xphos precatalyst: (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0299] HPLC conditions for analysis and purification:

[0300] Method A (SCP): Column: XBridge BEH XP C18 (50 x 2.1) 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 220 nm.

[0301] Method B (SCP): Column: Xbridge BEH XP C18 (50 x 2.1) 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 220 nm.

[0302] (C): Kinetex XB-C18 (75 x 3 mm) 2.6 micrometers; Solvent A: 10 mM ammonium formate in water:acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Temperature: 50°C; Gradient: 0-100% B over 5 min; Flow rate: 1.1 mL / min; Detection: UV 220 nm.

[0303] (D): Column: Ascentis Express C18 (50 x 2.1) 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℃; Gradient: 0-100% B over 3 minutes; Flow rate: 1.1 mL / min.

[0304] (E) Waters Acquity SDS Mobile phase: A: Water B: ACN; 5%-95% B within 1 min; Gradient range: 50%-98% B (0-0.5 min); 98% B (0.5-1 min); 98%-2% B (1-1.1 min); Run time: 1.2 min; Flow rate: 0.7 mL / min; Analysis time: 1.7 min; Detector: Detector 1: UV 220 nm; Detector 2: MS (ES + ).

[0305] (F) Aquiti UPLC BEH C18 (3.0 x 50 mm) 1.7 μm. Buffer: 5 mM ammonium acetate

[0306] 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; Detector: Detector 1: UV 220 nm; Detector 2: MS (ES + ).

[0307] (G) Column - Luna 3.0 C18 (2) 100 Å LC column (20 X 4.0 mm) Mercury MS™ Mobile phase A: Milli-Q 0.1% TFA in water; Mobile phase B: 0.1% TFA in ACN, flow rate: 1.5 mL / min.

[0308] (H): Column: Asentis Express C18 (50 x 2.1) 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℃; Gradient: 0-100%B over 3 minutes; Flow rate: 1.1 mL / min.

[0309] (I) LCMS for purification: Waters Exbridge C18, 19 x 150 mm, 5-μm particles; Mobile phase A: 10-mM ammonium acetate; Mobile phase B: methanol; Gradient: 10-45% B over 20 minutes, followed by holding at 100% B for 5 minutes; Flow rate: 20 mL / min.

[0310] Example 1

[0311] 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0312]

[0313] Intermediate 1A: 2-bromothiazole-5-carboxylic acid

[0314]

[0315] 10% NaOH (300 mL, 450 mmol) was added to a solution of methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol) in methanol (1500 mL) at 0°C. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under vacuum to remove the solvent, the solid was dissolved in water (200 mL), acidified to a pH of ~4-5 using cold 1.5 N HCl, the resulting precipitate was filtered and dried to obtain 2-bromothiazole-5-carboxylic acid (81 g, 389 mmol, 86% yield) as a white solid product.

[0316] LCMS residence time 0.35 min [C]. MS (E - ) m / z: 208.0 (M+2H).

[0317] Intermediate 1B: tert-butyl (2-bromothiazole-5-yl)carbamate

[0318]

[0319] Diphenylphosphoryl azide (111 mL, 506 mmol) was added dropwise to a solution of 2-bromothiazole-5-carboxylic acid (81 g, 389 mmol) in t-BuOH (1000 mL) at room temperature, followed by TEA (65.1 mL, 467 mmol), and the resulting solution was heated at 80°C for 12 hours. The reaction mixture was concentrated under vacuum, diluted with water (500 mL) and a brine solution (300 mL), and extracted with ethyl acetate (3 x 500 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude material was purified by combiflash using a 120 g silica column while eluting the compound with 15% EtOAc in petroleum ether. The fraction was collected and concentrated to obtain tert-butyl (2-bromothiazole-5-yl)carbamate (52 g, 186 mmol, 47.8% yield) as a grayish-white solid.

[0320] LCMS residence time 1.57 min [G]. MS (E - ) m / z: 281.1 (M+2H).

[0321] Intermediate 1C: tert-butyl 4-(5-((tert-butoxycarbonyl)amino)thiazole-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0322]

[0323] Potassium tribasic phosphate (34.2 g, 161 mmol) was added to a solution of tert-butyl (2-bromothiazole-4-yl)carbamate (15 g, 53.7 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19.94 g, 64.5 mmol) in dioxane (300 mL) and water (34 mL). The resulting solution was degassed with N2 for 10 minutes, then PdCl2(dppf)-CH2Cl2 adduct (4.39 g, 5.37 mmol) was added, and the solution was degassed for an additional 5 minutes. The resulting mixture was heated at 90°C for 12 hours. 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 obtain the crude product. The crude material was purified by combiflash using a 120 g silica column while eluting the compound with 45% EtOAc in petroleum ether. The fraction was collected and concentrated to obtain tert-butyl 4-(4-((tert-butoxycarbonyl)amino)thiazole-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19 g, 49.3 mmol, 92% yield) as a pale yellow solid.

[0324] LCMS dwell time 3.38 min [C]. MS (E - ) m / z: 382.1 (M+H).

[0325] Intermediate 1D: Tert-butyl 4-(5-((tert-butoxycarbonyl)amino)thiazole-2-yl)piperidine-1-carboxylate

[0326]

[0327] Nitrogen (N2) was purged from a solution (500 mL) of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)thiazole-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19 g, 49.8 mmol) and EtOAc, followed by the addition of Pd / C (9.54 g, 8.96 mmol), and the reaction mixture was purged three more times with N2. Hydrogen gas was introduced into the mixture through a balloon; the mixture was then stirred at room temperature for 8 hours. The suspension was filtered through a Celite layer, the filtrate was collected and concentrated to obtain tert-butyl 4-(4-((tert-butoxycarbonyl)amino)thiazole-2-yl)piperidine-1-carboxylate (18 g, 46.0 mmol, 92% yield) as a pale yellow solid.

[0328] LCMS dwell time 3.24 min [C]. MS (E - ) m / z: 384.1 (M+H).

[0329] Intermediate 1E: tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-yl)piperidine-1-carboxylate

[0330]

[0331] NIS (9.97 g, 44.3 mmol) in acetonitrile (250 mL) was added dropwise at 0°C to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)thiazole-2-yl)piperidine-1-carboxylate (17 g, 44.3 mmol) in acetonitrile (700 mL). The resulting solution was stirred at the same temperature for 10 minutes. The reaction mixture was quenched with an aqueous sodium thiosulfate solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude material was purified by combiflash using a 120 g silica column while eluting the compound with 16% EtOAc in petroleum ether. The fraction was collected and concentrated to obtain tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-yl)piperidine-1-carboxylate (17 g, 33.0 mmol, 74.5% yield) as a pale yellow solid.

[0332] LCMS dwell time 3.40 min [C]. MS (E - ) m / z: 510.1 (M+H).

[0333] Intermediate 1F: tert-butyl 4-(5-((tert-butoxycarbonyl)(3-methylbut-2-en-1-yl)amino)-4-iodothiazole-2-yl)piperidine-1-carboxylate

[0334]

[0335] NaH (1.335 g, 33.4 mmol) was added at 0°C to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-yl)piperidine-1-carboxylate (17 g, 33.4 mmol) in DMF (250 mL), and the mixture was stirred for 10 minutes at the same temperature. Subsequently, 1-bromo-3-methylbut-2-ene (4.27 mL, 36.7 mmol) was added dropwise, and the mixture was stirred for 10 minutes 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 layer was dried over sodium sulfate, filtered, and concentrated to extract tert-butyl 4-(5-((tert-butoxycarbonyl)(3-methylbut-2-en-1-yl)amino)-4-iodothiazole-2-yl)piperidine-1-carboxylate (17.2 g, 28.3 mmol, 85% yield) was obtained as a pale yellow oil.

[0336] LCMS dwell time 4.13 min [C]. MS (E - ) m / z: 578.1 (M+H).

[0337] Intermediate 1G: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0338]

[0339] Tetrabutylammonium bromide (1.675 g, 5.19 mmol) was added to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)(3-methylbut-2-en-1-yl)amino)-4-iodothiazole-2-yl)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 minutes, Pd(OAc)2 (0.035 g, 0.156 mmol) was added, the mixture was degassed again for an additional 5 minutes, and the resulting reaction mixture was heated at 100°C for 12 hours. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL), and the filtrate was concentrated to obtain the crude material. The crude material was purified by combi-flash using a 40 g silica column while eluting the compound with 18%-45% EtOAc in petroleum ether. The fraction was collected and concentrated to obtain tert-butyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (510 mg, 0.245 mmol, 27.71% yield) as a pale yellow solid.

[0340] LCMS dwell time 4.29 min [C]. MS (E - ) m / z: 450.1 (M+2).

[0341] Intermediate 1H: tert-butyl 5-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0342]

[0343] NBS (269 mg, 1.511 mmol) dissolved in DCE (10 mL) was added dropwise at 0°C to a solution of tert-butyl 4-(6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-carboxylate (480 mg, 1.373 mmol) in DCE (10 mL). The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude material was purified by combiflash using a 24 g silica column while eluting the compound with 8% EtOAc in petroleum ether. The fraction was collected and concentrated to obtain tert-butyl 4-(5-bromo-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-carboxylate (100 mg, 0.233 mmol, 17.00% yield) as a white solid.

[0344] LCMS dwell time 4.29 min [C]. MS (E - ) m / z: 528.1 (M+H).

[0345] Intermediate 1I: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0346]

[0347] Tribasic potassium phosphate (148 mg, 0.851 mmol) was added to a solution of tert-butyl 5-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (150 mg, 0.284 mmol) and 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (94 mg, 0.341 mmol) in dioxane (5 mL) and water (0.556 mL); the resulting solution was degassed with N2 for 10 minutes; and PdCl2(dppf)-CH2Cl2 adduct (11.59 mg, 0.014 mmol) was added, and degassing was performed again for 5 minutes. The resulting mixture was heated at 85°C for 3 hours. 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 obtain the crude product. The crude material was purified by combiflash using a 24 g silica column while eluting the compound with 48% EtOAc in petroleum ether. The fraction was collected and concentrated to obtain 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]thiazole-4-carboxylate (130 mg, 0.302 mmol, 76% yield) as a brown solid.

[0348] LCMS dwell time 1.43 min [C]. MS (E - ) m / z: 597.1 (M+H).

[0349] Example 1

[0350] 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0351] Hydrochloric acid (1 ml, 32.9 mmol) in dioxane was added to a solution of 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]thiazole-4-carboxylate (95 mg, 0.159 mmol) in DCM (1 mL), and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum to remove volatile substances, washed with diethyl ether (2 x 5) ml, the ether layer was separated by slicing, and the solid was dried to obtain 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (62 mg, 0.156 mmol, 98% yield) as a yellow solid.

[0352] LCMS dwell time 0.93 min [A]. MS (E - ) m / z: 397.1 (M+H).

[0353] 1 H NMR (400MHz, DMSO-d6) δ 11.63 (s, 1H), 8.48 (s, 2H), 7.11 (d, J=1.2 Hz, 1H), 4.09-3.98 (m, 3H), 3.23-3.19 (m, 2H), 2.92-2.84 (m, 3H), 2.13 (d, J=10.0 Hz, 2H), 1.90 (s, 1H), 1.88 -1.73 (m, 2H), 1.43 (d, J=6.8 Hz, 6H).

[0354] The following examples were prepared according to the general procedure described in Example 1.

[0355] Table 1

[0356]

[0357] Example 6

[0358] 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethane-1-one

[0359]

[0360] 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), HATU (16.88 mg, 0.044 mmol) was added following TEA (0.011 mL, 0.081 mmol). The resulting reaction mixture was stirred at 25°C for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 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)ethane-1-one (4.4 mg, 9.14 μmol, 22.64% yield) as a pale yellow solid.

[0361] LCMS dwell time 1.14 min [A]. MS (E - ) m / z: 482.2 (M+H).

[0362] 1H NMR (400MHz, DMSO-d6) δ 11.62 (s, 1H), 8.55-8.37 (m, 2H), 7.10 (s, 1H), 4.39 (d,J=13.0 Hz, 1H), 4.10-3.98 (m, 3H), 3.36-3.27 (m, 4H), 3.21-3.13 (m, 3H), 2.88-2.78 (m, 1 H), 2.31 (s, 4H), 2.07 (d, J=15.4 Hz, 3H), 1.73 (d, J=10.3 Hz, 1H), 1.64-1.50 (m, 1H), 1.42 (d, J=6.8 Hz, 6H).

[0363] Example 7

[0364] 2-(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)-N,N-dimethylacetamide

[0365]

[0366] 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 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(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)-N,N-dimethylacetamide (9.5 mg, 0.019 mmol, 46.3% yield) as a pale yellow solid.

[0367] LCMS dwell time 1.29 min [A]. MS (E - ) m / z: 482.2 (M+H).

[0368] 1 H NMR (400MHz, DMSO-d6) δ 11.60 (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), 2.92 (d, J=11.0 Hz, 2H), 2.82 (s, 3H), 2.23 (t, J=10.6 Hz, 2H), 2.10-1.99 (m, 2H), 1.90 (s, 2H), 1.83-1.67 (m, 2H), 1.42 (d, J=6.8 Hz, 6H).

[0369] The following examples were prepared according to the general procedure described in Example 7.

[0370] Table 2

[0371]

[0372] Example 10

[0373] 6-isopropyl-2-(1-isopropylpiperidine-4-yl)-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole

[0374]

[0375] To a solution of 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (18 mg, 0.045 mmol) in MeOH (2 mL), TEA (0.013 mL, 0.091 mmol) and propan-2-one (5.80 mg, 0.050 mmol) were added dropwise at 0°C. The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (5.71 mg, 0.091 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification. After LCMS purification, the fractions containing the product were combined and dried using a Zinbaek centrifugal evaporator to obtain 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 (4.14 mg, 0.09 mmol, 20.3% yield) as a pale yellow solid.

[0376] LCMS residence time 1.15 minutes [A]. MS (E -) m / z: 439.2 (M+H).

[0377] 1 H NMR (400MHz, DMSO-d6) δ 11.68 (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, 6.6 Hz, 2H), 2.31 (br. s., 2H), 2.13 -2.00 (m, 2H), 1.44 (d, J=6.8 Hz, 2H), 1.28 (d, J=6.6 Hz, 5H), 1.16 (t, J=7.2 Hz, 6H).

[0378] The following examples were prepared according to the general procedure described in Example 10.

[0379] Table 3

[0380]

[0381] Example 15

[0382] 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-2-methylpropan-2-ol

[0383]

[0384] 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-methylpropan-2-ol (4.93 mg, 0.045 mmol) in DMF (2 mL). The resulting solution was heated at 85°C for 12 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 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-methylpropan-2-ol (5.4 mg, 0.012 mmol, 25.4% yield) as a pale yellow solid.

[0385] LCMS 1.37 min [A]. MS (E - ) m / z: 469.2 (M+H).

[0386] 1 H NMR (400MHz, DMSO-d6) δ 11.66 (s, 1H), 8.46 (d, J=1.5 Hz, 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=6.8 Hz,6H), 1.26 (s, 6H).

[0387] Example 16

[0388] 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0389]

[0390] 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-(methylsulfonyl)ethane (9.78 mg, 0.069 mmol) in DMF (1 mL). The resulting solution was heated at 85°C for 12 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a cinnabar centrifugal evaporator to obtain 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (7.7 mg, 0.015 mmol, 38% yield) as a pale yellow solid.

[0391] LCMS 1.35 min [A]. MS (E - ) m / z: 503.2 (M+H).

[0392] 1H NMR (400MHz, DMSO-d6) δ 11.60 (s, 1H), 8.46 (s, 2H), 7.11 (s, 1H), 4.05 (s, 3H), 3.31 (d,J=6.1 Hz, 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=8.3 Hz, 2H), 1.82-1.65 (m, 2H), 1.43 (d, J=6.8 Hz, 6H).

[0393] Example 17

[0394] 2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide

[0395]

[0396] To a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (16 mg, 0.042 mmol) in DMF (2 mL) solvent, TEA (0.018 mL, 0.126 mmol) was added, followed by 2-chloro-N,N-dimethylacetamide (7.36 μl, 0.071 mmol) at room temperature. The resulting reaction mixture was then stirred at the same temperature for 12 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a cinnabar centrifugal evaporator to obtain 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 (4.1 mg, 8.37 μmol, 19.89% yield) as a pale yellow solid.

[0397] LCMS 1.33 min [A]. MS (E - ) m / z: 466.2 (M+H).

[0398] 1 H NMR (400MHz, DMSO-d6) δ 11.62 (s, 1H), 8.71 (s, 1H), 8.50 (s, 1H), 7.55 (s, 1H), 4.26 (s, 3H), 3.18-3.08 (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=6.6 Hz, 6H)

[0399] Example 18

[0400] 1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-2-methylpropan-2-ol

[0401]

[0402] Potassium carbonate (19.61 mg, 0.142 mmol) was 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 (18 mg, 0.047 mmol) in DMF (2 mL), followed by 1-chloro-2-methylpropan-2-ol (5.14 mg, 0.047 mmol), and the resulting pale yellow solution was heated at 85°C for 6 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 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)-2-methylpropan-2-ol (2.6 mg, 5.51 μmol, 11.66% yield) as a pale yellow solid.

[0403] LCMS 1.41 min [A]. MS (E - ) m / z: 453.2 (M+H).

[0404] 1H NMR (400 MHz, DMSO-d6) δ 11.69-11.54 (m, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 7.55 (s, 1H), 5.24 (br. s., 1H), 3.72 (d, J=10.5 Hz, 2H), 3.22 (br. s., 2H), 3.17 (s, 3H), 3.12 (br. s., 3H), 2.93 (dd, J=12.1, 7.0 Hz, 2H), 2.62 (s, 3H), 2.24 (br. s., 3H), 2.19 (s, 3H), 1.42 (d, J=6.8 Hz, 6H).

[0405] Example 19

[0406] 2-(dimethylamino)-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)ethane-1-one

[0407]

[0408] To a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-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), HATU (17.59 mg, 0.046 mmol) was added following TEA (0.012 mL, 0.084 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(dimethylamino)-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)ethane-1-one (1 mg, 2.083 μmol, 4.95% yield) as a pale yellow solid.

[0409] LCMS dwell time 1.19 min [A]. MS (E - ) m / z: 466.2 (M+H).

[0410] 1 H NMR (400MHz, DMSO-d6) δ 11.58 (br. s., 1H), 8.71 (s, 1H), 8.50 (s, 1H), 7.55 (s, 1H), 4.39 (d, J=13.0 Hz, 1H), 4.12 (d, J=13.7 Hz, 1H), 3.14-3.06 (m, 6H), 2.84-2.71 (m, 2H), 2.61 (s, 3 H), 2.19 (s, 4H), 2.15-2.02 (m, 2H), 1.80-1.63 (m, 2H), 1.41 (d, J=6.8 Hz, 6H).

[0411] Example 20

[0412] 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0413]

[0414] To a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (10 mg, 0.026 mmol) in MeOH (2 mL), TEA (7.33 μL, 0.053 mmol), oxetan-3-one (2.083 mg, 0.029 mmol), and acetic acid (0.150 μL, 2.63 μmol) were added dropwise at 0°C. The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (3.30 mg, 0.053 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 method I using LCMS for purification to obtain 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (1 mg, 2.268 μmol, 8.63% yield) as a pale yellow solid.

[0415] LCMS dwell time 1.43 min [A]. MS (E - ) m / z: 437.2 (M+H).

[0416] 1H NMR (400MHz, DMSO-d6) δ 8.71 (s, 1H), 8.50 (s, 2H), 7.55 (s, 1H), 4.55 (t, J=6.5 Hz, 2H), 4.48-4.40 (m, 2H), 3.16-3.10 (m, 2H), 3.04 (d, J=2.9 Hz, 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=6.6 Hz, 6H).

[0417] The following examples were prepared according to the general procedure described in Example 20.

[0418] Table 4

[0419]

[0420] Example 24

[0421] 2-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide

[0422]

[0423] To a solution of 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.056 mmol) in DMF (2 mL), TEA (0.024 mL, 0.169 mmol) and 2-chloro-N,N-dimethylacetamide (9.88 μL, 0.096 mmol) were added at room temperature. The resulting reaction mixture was then stirred at the same temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (5.4 mg, 0.012 mmol, 21.12% yield) as a pale yellow solid.

[0424] LCMS residence time 1.50 minutes [A]. MS (E - ) m / z: 440.2 (M+H).

[0425] 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.08 (s, 2H), 3.27 (d, J=6.8 Hz, 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=6.8 Hz, 6H), 1.15 (s, 6H).

[0426] Example 25

[0427] 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(1-isopropylpiperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0428]

[0429] To a solution of 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.056 mmol) in MeOH (2 mL), TEA (0.016 mL, 0.113 mmol) and propan-2-one (3.60 mg, 0.062 mmol) were added dropwise at 0°C, followed by acetic acid (0.323 μL, 5.64 μmol). The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (7.09 mg, 0.113 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification. After LCMS purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 5-(2,6-dimethylpyridine-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.

[0430] LCMS dwell time 1.38 min [A]. MS (E - ) m / z: 397.2 (M+H).

[0431] 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.72 (d, J=9.8 Hz, 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, 6.6 Hz, 2H), 2.31 (br. s., 2H), 2.13-2.00 (m, 3H), 1.44 (d, J=6.8 Hz, 4H), 1.28 (d, J=6.6 Hz, 5H), 1.16 (t, J=7.2 Hz, 6H).

[0432] The following examples were prepared according to the general procedure described in Example 25.

[0433] Table 5

[0434]

[0435] Example 28

[0436] 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)ethane-1-one

[0437]

[0438] To a solution of 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(piperidine-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), HATU (23.60 mg, 0.062 mmol) was added following TEA (0.016 mL, 0.113 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(dimethylamino)-1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethane-1-one (7.9 mg, 0.018 mmol, 31.9% yield) as a pale yellow solid.

[0439] LCMS dwell time 1.36 min [A]. MS (E - ) m / z: 440.2 (M+H).

[0440] 1 H NMR (400MHz, DMSO-d6) δ 11.57 (s, 1H),,7.72 (d, J=9.8 Hz, 1H), 7.43-7.32 (m, 1H), 4.43 (d, J=13.7 Hz, 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=11.7 Hz, 1H), 2.83 (s, 6H), 2.65 (s, 6H), 2.22-2.09 (m, 2H),1.83 (d, J=9.5 Hz, 1H), 1.64 (d, J=8.6 Hz, 1H), 1.46 (d, J=6.8 Hz, 6H).

[0441] Example 29

[0442] 1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-2-methylpropan-2-ol

[0443]

[0444] Potassium carbonate (23.39 mg, 0.169 mmol) was added to a solution of 5-(2,6-dimethylpyridine-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 1-chloro-2-methylpropan-2-ol (6.12 mg, 0.056 mmol), and the resulting pale yellow solution was heated at 80°C for 6 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-2-methylpropan-2-ol (2.8 mg, 6.56 μmol, 11.63% yield) as a pale yellow solid.

[0445] LCMS 1.61 min [A]. MS (E - ) m / z: 427.2 (M+H).

[0446] 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H),,7.72 (d, J=9.8 Hz, 1H), 7.43-7.32 (m, 1H), 5.24 (br. s., 1H), 3.72 (d, J=10.5 Hz, 2H), 3.22 (br. s., 3H), 3.17 (s, 3H), 3.12 (br. s., 4H), 2.93(dd, J=12.1, 7.0 Hz, 2H), 2.62 (s, 3H), 2.24 (br. s., 3H), 2.19 (s, 3H), 1.42 (d, J=6.8 Hz, 6H).

[0447] Example 30

[0448] 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide

[0449]

[0450] TEA (0.013 mL, 0.092 mmol) and 2-chloro-N,N-dimethylacetamide (45 mg, 0.370 mmol) were added at room temperature 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). The resulting reaction mixture was then stirred at the same temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (7.0 mg, 0.014 mmol, 14.95% yield) as a pale yellow solid.

[0451] LCMS dwell time 1.56 min [A]. MS (E - ) m / z: 465.2 (M+H).

[0452] 1H NMR (400MHz, DMSO-d6) δ 11.16 (s, 1H), 8.34 (dd, J=4.5, 1.6 Hz, 1H), 7.99 (dd, J=7.8,1.5 Hz, 1H), 7.60 (s, 1H), 7.17 (dd, J=7.9, 4.5 Hz, 1H), 3.91 (d, J=4.6 Hz, 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=15.2 Hz, 3H), 1.87-1.64 (m, 3H), 1.38 (d, J=6.8 Hz, 6H).

[0453] The following examples were prepared according to the general procedure described in Example 30.

[0454] Table 6

[0455]

[0456] Example 32

[0457] 2-(dimethylamino)-1-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethane-1-one

[0458]

[0459] 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 dimethyl glycine (45 mg, 0.436 mmol) in DMF (2 mL), HATU (35.1 mg, 0.092 mmol) was added, followed by TEA (0.013 mL, 0.092 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(dimethylamino)-1-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethane-1-one (12 mg, 0.024 mmol, 26.2% yield) as a pale yellow solid.

[0460] LCMS dwell time 1.44 min [A]. MS (E - ) m / z: 465.2 (M+H).

[0461] 1H NMR (400MHz, DMSO-d6) δ 11.17 (s, 1H), 8.34 (dd, J=4.6, 1.5 Hz, 1H), 7.99 (dd, J=7.8,1.5 Hz, 1H), 7.60 (s, 1H), 7.18 (dd, J=8.1, 4.6 Hz, 1H), 4.41 (d, J=12.7 Hz, 1H), 4.13 (d, J=13.7Hz, 1H), 3.93-3.86 (m, 4H), 3.22-3.04 (m, 3H), 2.79 (t, J=11.6 Hz, 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=6.8 Hz,6H).

[0462] Example 33

[0463] 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0464]

[0465] 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-(methylsulfonyl)ethane (9.39 mg, 0.066 mmol) in DMF (1 mL). The resulting solution was heated at 90°C for 12 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methylsulfonyl) ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (4.4 mg, 8.82 μmol, 13.40% yield) as a pale yellow solid.

[0466] LCMS 1.63 min [A]. MS (E - ) m / z: 486.2 (M+H).

[0467] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.33 (dd, J=4.6, 1.5 Hz, 1H), 7.99 (dd, J=7.9,1.6 Hz, 1H), 7.60 (s, 1H), 7.17 (dd, J=7.9, 4.5 Hz, 1H), 3.91 (d, J=4.9 Hz, 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=7.6 Hz, 2H), 1.75 (d, J=9.5 Hz,2H), 1.38 (d, J=6.8 Hz, 6H).

[0468] Example 34

[0469] 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0470]

[0471] 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), TEA (0.018 mL, 0.132 mmol) and oxetan-3-one (5.22 mg, 0.072 mmol) were added dropwise at 0°C, followed by acetic acid (0.377 μL, 6.59 μmol). The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (8.28 mg, 0.132 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification. After LCMS purification, the fractions containing the product were combined and dried using a Zinbaek centrifugal evaporator to obtain 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole as a pale yellow solid.

[0472] LCMS dwell time 1.65 minutes [A]. MS (E - ) m / z: 436.2 (M+H).

[0473] 1H NMR (400MHz, DMSO-d6) δ 11.15 (s, 1H), 8.34 (dd, J=4.6, 1.5 Hz, 1H), 7.99 (dd, J=7.8,1.5 Hz, 1H), 7.69-7.46 (m, 2H), 7.18 (dd, J=7.9, 4.5 Hz, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 3.99-3.86 (m, 2H), 3.42 (d, J=4.9 Hz, 1H), 3.18 (d, J=5.1 Hz, 1H), 3.12-2.93(m, 2H), 2.79 (d, J=10.3 Hz, 2H), 2.07 (d, J=8.1 Hz, 2H), 1.94 (t, J=11.0 Hz, 2H), 1.86-1.70(m, 2H), 1.38 (d, J=7.1 Hz, 6H).

[0474] The following examples were prepared according to the general procedure described in Example 34.

[0475] Table 7

[0476]

[0477] Example 37

[0478] 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile

[0479]

[0480] To a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (25 mg, 0.062 mmol) in MeOH (2 mL), oxetan-3-one (4.49 mg, 0.062 mmol), TEA (8.68 μL, 0.062 mmol), and then acetic acid (0.356 μL, 6.23 μmol) were added dropwise at 0°C. The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (7.83 mg, 0.125 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification. After LCMS purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (9.1 mg, 0.020 mmol, 31.4% yield) as a pale yellow solid.

[0481] LCMS dwell time 1.74 min [A]. MS (E - ) m / z: 458.2 (M+H).

[0482] 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 9.13 (dd, J=4.2, 1.7 Hz, 1H), 8.45 (d, J=7.6 Hz,1H), 8.40 (dd, J=8.6, 1.7 Hz, 1H), 7.75 (dd, J=8.7, 4.3 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.47 (t, J=6.1 Hz, 2H), 3.91 (s, 2H), 3.44 (br. s., 1H), 2.90 -2.71 (m, 2H), 2.10 (d, J=12.2 Hz, 2H), 1.97 (br. s., 2H), 1.88-1.69 (m, 2H), 1.34 (d, J=6.8 Hz,6H).

[0483] The following examples were prepared according to the general procedure described in Example 37.

[0484] Table 8

[0485]

[0486] Example 39

[0487] 5-(2-(1-(dimethylglycyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile

[0488]

[0489] To a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (20 mg, 0.050 mmol) and dimethylglycine (5.14 mg, 0.050 mmol) in DMF (2 mL), HATU (18.94 mg, 0.050 mmol) was added, followed by TEA (0.014 mL, 0.100 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 5-(2-(1-(dimethylglycyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (10.5 mg, 0.020 mmol, 40.2% yield) as a pale yellow solid.

[0490] LCMS residence time 1.50 minutes [A]. MS (E - ) m / z: 487.2 (M+H).

[0491] 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 9.13 (dd, J=4.2, 1.5 Hz, 1H), 8.49-8.42 (m, 1 H), 8.39 (dd, J=8.7, 1.6 Hz, 1H), 7.83-7.64 (m, 2H), 4.43 (d, J=12.2 Hz, 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=6.8 Hz, 6H).

[0492] Example 40

[0493] 2-(4-(5-(8-cyanoquinoline-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide

[0494]

[0495] To a solution of 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (20 mg, 0.050 mmol) in DMF (2 mL), 2-chloro-N,N-dimethylacetamide (6.06 mg, 0.050 mmol) was added dropwise with TEA (0.014 mL, 0.100 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(4-(5-(8-cyanoquinoline-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (7.2 mg, 0.015 mmol, 29.7% yield) as a pale yellow solid.

[0496] LCMS dwell time 1.64 min [A]. MS (E - ) m / z: 487.2 (M+H).

[0497] 1H NMR (400MHz, DMSO-d6) δ 11.70 (s, 1H), 9.13 (d, J=4.2 Hz, 1H), 8.45 (d, J=7.3 Hz, 1H),8.40 (d, J=8.6 Hz, 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=6.8 Hz, 6H).

[0498] Example 41

[0499] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0500]

[0501] Intermediate 41A: tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)thiazole-2-yl)piperidine-1-carboxylate

[0502]

[0503] Copper(I) iodide (0.075 g, 0.393 mmol) and triphenylphosphine (0.103 g, 0.393 mmol) were added while purging with argon to a solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-yl)piperidine-1-carboxylate (2 g, 3.93 mmol) in a mixture of toluene (40 mL) and diisopropylamine (10 mL), bis(triphenylphosphine)palladium(II) dichloride (0.138 g, 0.196 mmol) was added, the reaction mixture was stirred for 5 minutes, 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (1.008 g, 5.89 mmol) was added, and in a sealed tube The product was heated at 45°C for 3 hours. The reaction mixture was diluted with DCM, filtered through Celite, washed with water and brine, dried under Na2SO4, concentrated, and purified by 60% elution with EtOAc in petroleum ether on silica gel to obtain tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)thiazole-2-yl)piperidine-1-carboxylate as a pale yellow solid.

[0504] LCMS dwell time 2.07 min [F]. MS (E - ) m / z: 553.5 (M+H).

[0505] Intermediate 41B: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0506]

[0507] Silver acetic acid (0.574 g, 3.44 mmol) was added to a stirred solution of tert-butyl 4-(5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)thiazole-2-yl)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 minutes. The reaction mixture was filtered through Celite, concentrated, and purified by eluting with 0 to 70% EtOAc in petroleum ether on a 40 g silica column to obtain 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]thiazole-4-carboxylate (1.8 g, 3.26 mmol, 95% yield) as a grayish-white solid.

[0508] LCMS dwell time 2.12 min [F]. MS (E - ) m / z: 553.6 (M+H).

[0509] Intermediate 41C: tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0510]

[0511] A solution of NBS (0.725 g, 4.07 mmol) in DMF (5 mL) was added to a solution of 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]thiazole-4-carboxylate (1.5 g, 2.71 mmol) in DMF (30 mL) at 0°C, and then stirred overnight at room temperature. Next, water (40 mL) was added to the reaction mixture and stirred for 20 minutes at room temperature. The obtained solid was collected by filtration and then dried under vacuum to obtain 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]thiazole-4-carboxylate (1.4 g, 2.217 mmol, 82% yield) as a grayish-white solid.

[0512] LCMS dwell time 1.16 min [F]. MS (E - ) m / z: 633.4 (M+2H).

[0513] Intermediate 41D: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0514]

[0515] Tripotassium phosphate (1.512 g, 7.12 mmol) was added to a solution of 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]thiazole-4-carboxylate (1.5 g, 2.375 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.596 g, 9.50 mmol) in 1,4-dioxane (30 mL) and water (3 mL), and then purged with nitrogen for 5 minutes. PdCl2(dppf)-CH2Cl2 adduct (0.194 g, 0.237 mmol) was added, and the reaction mixture was purged again for 2 minutes. The reaction mixture was heated in a sealed tube at 90°C for 4 hours. The reaction mixture was filtered through Celite, concentrated, and purified by eluting with 50% EtOAc in petroleum ether on silica gel to obtain 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]thiazole-4-carboxylate (1.3 g, 2.193 mmol, 92% yield).

[0516] LCMS residence time 1.4 min [F]. MS (E - ) m / z: 593.4 (M+H).

[0517] Intermediate 41E: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0518]

[0519] 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]thiazole-4-carboxylate (1.3 g, 2.193 mmol) was added to ethyl acetate (30 mL). The flask was purged with N2, and Pd-C (0.233 g, 2.193 mmol) was added. After purging with nitrogen gas, hydrogen gas was introduced through a balloon. The reaction mixture was stirred at ambient temperature for 4 hours. The flask was evacuated and filled with N2. The suspension was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by eluting it on silica gel with 50% EtOAc in petroleum ether to obtain 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]thiazole-4-carboxylate (0.95 g, 1.597 mmol, 72.8% yield).

[0520] LCMS dwell time 1.57 min [F]. MS (E - ) m / z: 595.5 (M+H).

[0521] Example 41

[0522] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0523] TFA (2.91 mL, 37.8 mmol) was added to a stirred solution 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-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.45 g, 0.757 mmol) in DCM (5 mL) at 0°C, and then the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, 12 mL of MTBE was added to the residue and stirred at room temperature for 5 minutes, and the obtained solid was collected by filtration to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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.

[0524] LCMS dwell time 1.127 min [A]. MS (E - ) m / z: 395.2 (M+H).

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 11.37-11.30 (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 = 6.8 Hz, 6H).

[0526] The following intermediate was prepared according to the general procedure described in intermediate 41.

[0527] Table 9

[0528]

[0529] Example 43

[0530] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0531]

[0532] 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 oxetan-3-one (18.27 mg, 0.253 mmol) in methanol (2 mL), stirred overnight at room temperature, then sodium cyanoborohydride (6.37 mg, 0.101 mmol) was added to the reaction mixture at 0°C and stirred for 2 hours at room temperature. The reaction mixture was diluted with water (2 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 using Method I by LCMS for purification. After LCMS purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (12.1 mg, 0.026 mmol, 52.1% yield).

[0533] LCMS duration 1.443 min [A]. MS (E - ) m / z: 451.3 (M+H).

[0534] 1H NMR (400MHz, DMSO-d6) δ 11.31 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 4.65-4.51 (m, 2H), 4.46 (t, J=6.2 Hz, 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=17.9 Hz, 2H), 1.85-1.71 (m, 2H), 1.31 (d, J=6.8 Hz, 6H).

[0535] The following examples were prepared according to the general procedure described in Example 43.

[0536] Table 10

[0537]

[0538]

[0539] Example 55

[0540] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole

[0541]

[0542] TEA (7.07 μL, 0.051 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole (20 mg, 0.051 mmol) and 1-chloro-2-(methylsulfonyl)ethane (7.23 mg, 0.051 mmol) in a mixture of THF (1.5 mL) and DMF (0.5 mL), and 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 layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a cinnabar centrifugal evaporator to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (7.4 mg, 0.015 mmol, 29.2% yield).

[0543] LCMS dwell time 0.974 min [B]. MS (E - ) m / z: 501.3 (M+H).

[0544] 1 H NMR (400MHz, DMSO-d6) δ 11.31 (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=11.5 Hz, 2H), 1.31 (d, J=6.8 Hz, 6H).

[0545] The following examples were prepared according to the general procedure described in Example 55.

[0546] Table 11

[0547]

[0548] Example 59

[0549] 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethane-1-one

[0550]

[0551] 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]pyridine-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 then stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a cinnabar centrifugal evaporator to obtain 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)piperidin-1-yl)ethane-1-one (15.5 mg, 0.035 mmol, 54.5% yield).

[0552] LCMS duration 1.387 min [A]. MS (E - ) m / z: 437.2 (M+H).

[0553] 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 4.44 (d, J=12.7 Hz, 1H), 3.99-3.89 (m, 1H), 3.27-3.17 (m, 1H), 2.90 (s, 1H), 2.80-2.62 (m, 5H), 2.58 (s, 3H), 2.19 (s, 3H), 2.15-1.95 (m, 2H), 1.74 (dd, J=12.3, 3.5 Hz, 1H), 1.57 (dd, J=12.3, 3.8 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H).

[0554] Example 60

[0555] 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one

[0556]

[0557] 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]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (40 mg, 0.104 mmol) and oxetan-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 reaction mixture at 0°C, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (2 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 using Method I by LCMS for purification. After LCMS purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (17 mg, 0.037 mmol, 35.9% yield) as a white solid.

[0558] LCMS duration 1.925 min [C]. MS (E - ) m / z: 441.2 (M+H).

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1 H) 7.53 (s, 1 H) 4.52-4.58 (m, 2 H) 4.45 (t, J=6.02 Hz, 2 H) 3.46 (s, 3 H) 3.40-3.44 (m, 1 H) 3.37 (s, 1 H) 2.95-3.05 (m, 2 H) 2.66-2.81 (m, 3 H) 2.54-2.63 (m, 1 H) 2.31-2.36 (m, 2 H) 2.04 (s, 3 H) 1.88-1.98 (m, 2 H) 1.70-1.83 (m, 2 H) 1.29 (d, J=7.03 Hz, 6 H).

[0560] Example 61

[0561] 5-(6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one

[0562]

[0563] 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]thiazole-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (40 mg, 0.104 mmol) and 1-chloro-2-(methylsulfonyl)ethane (14.83 mg, 0.104 mmol) in a mixture of THF (1.5 mL) and DMF (0.5 mL), and 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 layer was dried over sodium sulfate, filtered, and concentrated. The crude sample was purified using Method I by LCMS for purification. After purification with LCMS for purification, the fractions containing the product were combined and dried using a cinnabar centrifugal evaporator to obtain 5-(6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridin-2(1H)-one (16 mg, 0.032 mmol, 30.5% yield).

[0564] LCMS dwell time 1.949 min [C]. MS (E - ) m / z: 491.2 (M+H).

[0565] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 1 H) 7.53 (s, 1 H) 3.46 (s, 3 H) 3.05 (s, 3 H) 2.98 (d, J=11.55 Hz, 3 H) 2.63-2.79 (m, 5 H) 2.10-2.34 (m, 3 H) 2.04 (s, 5 H) 1.65-1.82 (m, 4 H) 1.29 (d, J=7.03 Hz, 6 H).

[0566] The following examples were prepared according to the general procedure described in Example 61.

[0567] Table 12

[0568]

[0569] Examples 65 and 66

[0570] N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine

[0571]

[0572] Intermediate 65A: tert-butyl (2-(1,4-dioxaspiro[4.5]des-7-en-8-yl)thiazole-5-yl)carbamate

[0573]

[0574] To a solution of tert-butyl (2-bromothiazole-5-yl)carbamate (70 g, 251 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]des-7-en-8-yl)-1,3,2-dioxaborolane (100 g, 376 mmol) in dioxane (1500 mL), tribasic potassium phosphate (160 g, 752 mmol) dissolved in 375 mL of water was added. The reaction mixture was degassed with argon for 20 minutes, and then PdCl2(dppf)-CH2Cl2 adduct (20.48 g, 25.08 mmol) was added. The reaction mixture was degassed again for 5 minutes, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with EtOAc (3000 mL), poured into a separating funnel, washed with water (2 x 1500 mL) and brine (1500 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude material was purified by silica gel chromatography by eluting with 30% ethyl acetate in hexane, the fractions were collected and concentrated to obtain tert-butyl (2-(1,4-dioxaspiro[4.5]des-7-en-8-yl)thiazole-5-yl)carbamate (75 g, 84% yield) as a yellow solid.

[0575] LCMS dwell time 2.44 min [C]. MS (E - ) m / z: 339.2 (M+H).

[0576] Intermediate 65B: tert-butyl (2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate

[0577]

[0578] To a solution of tert-butyl (2-(1,4-dioxaspiro[4.5]des-7-en-8-yl)thiazole-5-yl)carbamate (75 g, 222 mmol) in MeOH (1000 mL) and ethyl acetate (1000 mL), Pd / C (23.58 g, 222 mmol) was added after purging with N2. After pumping / purging with N23x, H2 gas was introduced through a balloon. The reaction mixture was stirred at ambient temperature for 12 hours. The flask was evacuated and filled with N2. The suspension was filtered, and the filtrate was concentrated to obtain the crude product. The crude sample was purified by eluting with 30% EtOAc in petroleum ether by silica gel chromatography, the fraction was collected and concentrated to obtain tert-butyl (2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (70 g, 88% yield) as a white solid.

[0579] LCMS duration of stay 2.36 minutes [C],

[0580] MS (E - ) m / z: 341 (M+H).

[0581] Intermediate 65C: tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl) carbamate

[0582]

[0583] NIS (36.3 g, 162 mmol) dissolved in acetonitrile (2000 mL) was added dropwise to a solution of tert-butyl (2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (50 g, 147 mmol) in acetonitrile (2000 mL), and the reaction mixture was stirred at 0°C for 30 minutes. 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 material was purified by silica gel chromatography while eluting with 30% EtOAc in petroleum ether, the fraction was collected and concentrated to obtain tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (45 g, 66% yield) as a yellow solid.

[0584] LCMS dwell time 3.05 min [C]. MS (E - ) m / z: 467.2 (M+H).

[0585] Intermediate 65D: tert-butyl (4-iodo-2-(1,4-dioxaspiro [4.5]decane-8-yl)thiazole-5-yl)(3-methylbut-2-en-1-yl)carbamate

[0586]

[0587] NaH (5.15 g, 129 mmol) was slowly added dropwise to a solution of tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (30 g, 64.3 mmol) in DMF (100 mL). 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 minutes. The reaction mixture was quenched with ice-cold water, diluted with EtOAc (1000 mL), poured into a separating funnel, poured in brine (1000 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude material was purified by eluting with 30% EtOAc in petroleum ether using silica gel chromatography, the fraction was collected and concentrated to obtain tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (28 g, 81% yield) as a white solid.

[0588] LCMS residence time 2.5 minutes [C]. MS (E - ) m / z: 535.2 (M+H).

[0589] Intermediate 65E: tert-butyl 6-isopropyl-2-(1,4-dioxaspiro [4.5]decane-8-yl)-4H-pyrrolo [3, 2-d]thiazole-4-carboxylate

[0590]

[0591] Potassium carbonate (14.48 g, 105 mmol) was added to a solution of tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)(3-methylbut-2-en-1-yl)carbamate (28 g, 52.4 mmol) in DMF (600 mL), tetrabutylammonium bromide (50.7 g, 157 mmol) was degassed with argon for 10 minutes, and PdOAc2 (1.176 g, 5.24 mmol) was added. The reaction mixture was heated at 90°C for 12 hours. The reaction mixture was diluted with EtOAc and passed through a Celite pad. The combined organic extract was concentrated to obtain the crude product. The crude material was purified by eluting with 10% EtOAc in petroleum ether using silica gel chromatography, the fraction was collected and concentrated to obtain tert-butyl 6-isopropyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (9.5 g, 40% yield) as a pale yellow solid.

[0592] LCMS residence time 2.5 minutes [C]. MS (E - ) m / z: 535.2 (M+H).

[0593] Intermediate 65F: tert-butyl 5-bromo-6-isopropyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0594]

[0595] NBS (3.74 g, 21.03 mmol) in DCE (100 mL) was added dropwise to tert-butyl 6-isopropyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (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 minutes. The reaction mixture was quenched with saturated sodium sulfite (50 mL), diluted with DCM (500 mL), poured into a separating funnel, poured in brine (500 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude material was purified by eluting with 30% EtOAc in petroleum ether using silica gel chromatography, the fraction was collected and concentrated to obtain tert-butyl 5-bromo-6-isopropyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (6.2 g, 54% yield) as a pale yellow solid.

[0596] LCMS residence time 2.3 minutes [C]. MS (E - ) m / z: 485.2(M+H).

[0597] Intermediate 65G: tert-butyl 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0598]

[0599] To a solution of tert-butyl 5-bromo-6-isopropyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (5.5 g, 11.33 mmol) in dioxane (150 mL) and water (20 mL), tribasic potassium phosphate (7.21 g, 34.0 mmol) and 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 minutes, and a PdCl2(dppf)-CH2Cl2 adduct (0.925 g, 1.133 mmol) was added. The reaction mixture was heated at 75°C for 4 hours. The reaction mixture was diluted with EtOAc (3000 mL), poured into a separating funnel, washed with water (2 x 500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude material was purified by silica gel chromatography while eluting with 40% EtOAc in petroleum ether, the fraction was collected and concentrated to obtain tert-butyl(2-(1,4-dioxaspiro[4.5]des-7-en-8-yl)thiazole-5-yl)carbamate (3.7 g, 60% yield) as a yellow solid.

[0600] LCMS dwell time 3.58 min [C]. MS (E - ) m / z: 554.2 (M+H).

[0601] Intermediate 65H: 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-one

[0602]

[0603] TFA (55 mL) was added to a solution of tert-butyl 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (3.5 g, 6.32 mmol) in DCM (55.0 mL), and stirred at ambient temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was softened with n-hexane to obtain 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (2.5 g, 92%) as a pale solid.

[0604] LCMS dwell time 2.82 min [C]. MS (E - ) m / z: 410.2 (M+H).

[0605] 1 H NMR (400MHz, DMSO-d6) δ 11.63 (s, 1H), 8.57-8.38 (m, 2H), 7.13 (d, J=1.0 Hz, 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=6.8 Hz, 6H).

[0606] The following intermediate was prepared according to the general procedure described in intermediate 65H.

[0607] Table 13

[0608]

[0609] Examples 65 and 66: N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine

[0610] 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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (2.6 g, 6.35 mmol) in THF (20 mL) and DMF (20.00 mL), and stirred at ambient temperature for 12 hours. The reaction mixture was concentrated to remove DMF and THF, the resulting residue was dissolved 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 one pot. The reaction was continued at the same temperature (-78°C) for 3 hours and cooled to 0°C within 1 hour. The reaction mixture was quenched with 10 mL of ice-cold water, and the reaction mixture was concentrated. The residue was extracted with 10% methanol in DCM (100 mL x 2). The organic layer was concentrated, and the obtained crude product was purified by purification LCMS using Method I. The fractions corresponding to peak 1 (Isomer 1) and peak 2 (Isomer 2) were collected and concentrated. This was further softened with anhydrous ethanol (100 mL x 2), the obtained white solid was dissolved in deionized water (150 mL), and freeze-dried for 2 days. NMR indicated the presence of ethanol. The freeze-dried compound was further dissolved in deionized water (150 mL), and freeze-drying was repeated for an additional 2 days.

[0611] Example 65 (Isomer 1):

[0612] LCMS dwell time 1.62 min [C]. MS (E - ) m / z: 467.3 (M+H).

[0613] 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.56-8.37 (m, 2H), 7.10 (s, 1H), 4.64 (t, J=6.6 Hz, 2H), 4.33 (t, J=6.4 Hz, 2H), 4.05 (s, 3H), 3.98 (t, J=6.7 Hz, 1H), 3.23-3.12 (m, 1H), 2.99 -2.89 (m, 1H), 2.43 (t, J=11.0 Hz, 1H), 2.17-2.04 (m, 2H), 1.85 (d, J=10.5 Hz, 2H), 1.59-1.46 (m, 2H), 1.42 (d, J=6.6 Hz, 6H), 1.28-1.10 (m, 2H).

[0614] Example 66 (Isomer 2):

[0615] LCMS dwell time 2.82 min [C]. MS (E - ) m / z: 467.3 (M+H).

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.56-8.38 (m, 2H), 7.12 (s, 1H), 4.63 (t, J=6.6 Hz, 2H), 4.35 (t, J=6.4 Hz, 2H), 4.17 (d, J=4.9 Hz, 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=7.8 Hz, 1H), 1.44 (d, J=6.8 Hz, 6H), 1.24 (s, 2H).

[0617] The following examples were prepared according to the general procedure described in Examples 65 and 66.

[0618] Table 14

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628] Example 126

[0629] 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide

[0630]

[0631] 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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (20 mg, 0.049 mmol) in DMF (5 mL). The reaction mixture was stirred at ambient temperature for 12 hours, 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 obtained crude product was purified by purification LCMS using Method I. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide (4.6 mg, 18% yield) as a pale white solid.

[0632] LCMS dwell time 1.42 min [C]. MS (E - ) m / z: 496.2 (M+H).

[0633] 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.55-8.38 (m, 2H), 7.75-7.63 (m, 1H), 7.12 (d, J=1.2 Hz, 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=6.8 Hz, 6H).

[0634] Example 127

[0635] N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)methanesulfonamide

[0636]

[0637] 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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (20 mg, 0.049 mmol) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was quenched with 1 mL of ice-cold water, and the reaction mixture was concentrated. The residue was extracted with 10% methanol (5 mL x 2) in DCM. The organic layer was concentrated, and the obtained crude product was purified by purification LCMS using Method I. After purification with LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)methanesulfonamide (3.6 mg, 15% yield) as a pale white solid.

[0638] LCMS dwell time 1.42 min [C]. MS (E - ) m / z: 489.2 (M+H).

[0639] 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.52-8.44 (m, 2H), 7.12 (d, J=1.2 Hz, 1H), 7.08 (d, J=7.3 Hz, 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=6.8 Hz, 7H).

[0640] Example 128

[0641] trans 2-(ethyl(methyl)amino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide

[0642]

[0643] 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]thiazole-2-yl)cyclohexyl)acetamide

[0644]

[0645] 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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (100 mg, 0.244 mmol) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with DCM, washed with water, and concentrated to obtain 2-chloro-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide (80 mg, 0.164 mmol, 68%) as a colorless liquid.

[0646] LCMS residence time 1.26 min [C]. MS (E - ) m / z: 488.1 (M+H).

[0647] Example 128:

[0648] TEA (5.72 μL, 0.041 mmol) and N-methyl ethanolamine (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]thiazole-2-yl)cyclohexyl)acetamide (10 mg, 0.021 mmol) in DCM (5 mL), and the mixture was stirred at ambient temperature for 12 hours. The reaction mixture was quenched with 1 mL of ice-cold water, and the reaction mixture was concentrated. The residue was extracted with 10% methanol (5 mL x 2) in DCM. The organic layer was concentrated, and the obtained crude product was purified by purification using LCMS according to Method I. After purification with LCMS for purification, the fractions containing the product were combined and dried using centrifugation to obtain 2-(ethyl(methyl)amino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide (6.3 mg, 60% yield) as a pale white solid.

[0649] LCMS dwell time 1.58 min [C]. MS (E - ) m / z: 510.1 (M+H).

[0650] 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.55-8.41 (m, 2H), 7.75-7.54 (m, 1H), 7.12 (d, J=1.2 Hz, 1H), 4.06 (s, 3H), 3.75-3.62 (m, 1H), 3.18 (td, J=6.9, 13.6 Hz, 1H), 3.09-2.92 (m, 3H), 2.29 (s, 3H), 2.19-2.10 (m, 2H), 1.97-1.81 (m, 3H), 1.69-1.54 (m, 2H), 1.44 (d, J=6.8 Hz, 6H), 1.04 (t, J=7.1 Hz, 3H).

[0651] The following examples were prepared according to the general procedure described in Example 128.

[0652] Table 15

[0653]

[0654] Examples 130 and 131

[0655] N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine

[0656]

[0657] N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine was prepared as described in Examples 65 and 66 using 4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (0.1 g, 0.254 mmol) as a starting intermediate.

[0658] Example 130 (Isomer 1): After purification with LCMS for purification, the fraction containing issomer 1 was collected and evaporated to obtain a pale white solid (0.0016, 1.4% yield).

[0659] LCMS dwell time 1.42 min [C]. MS (E - ) m / z: 451.3 (M+H).

[0660] 1H NMR (400MHz, DMSO-d6) δ 11.56 (s, 1H), 8.69 (s, 1H), 8.49 (s, 1H), 7.54 (s, 1H), 4.75 (t, J=7.2 Hz, 2H), 4.56 (t, J=6.6 Hz, 2H), 3.19-3.07 (m, 4H), 2.61 (s, 3H), 2.17 (d, J=12.2 Hz, 2H), 1.98 (br. s., 2H), 1.59 (d, J=12.5 Hz, 2H), 1.40 (d, J=6.8 Hz, 8H).

[0661] Example 131 (Isomer 2): After purification with LCMS for purification, the fraction containing isomer 2 was collected and evaporated to obtain a pale white solid (0.0074 6.4% yield).

[0662] LCMS dwell time 1.58 min [C]. MS (E - ) m / z: 451.3 (M+H).

[0663] 1 H NMR (400MHz, DMSO-d6) δ 11.55 (s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.56 (s, 1H), 4.63 (t, J=6.6 Hz, 2H), 4.35 (t, J=6.2 Hz, 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=13.4 Hz, 2H), 1.65-1.48 (m, 4H), 1.42 (d, J=6.8 Hz, 6H).

[0664] The following examples were prepared according to the general procedure described in Examples 130 and 131.

[0665] Table 16

[0666]

[0667]

[0668] Examples 144 and 145

[0669] N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-methyloxetane-3-amine

[0670]

[0671] Intermediate 144A: tert-butyl (4-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate

[0672]

[0673] Triphenylphosphine (0.225 g, 0.858 mmol) and copper(I) iodide (0.163 g, 0.858 mmol) were added to a solution of tert-butyl (4-iodo-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl) carbamate (4.0 g, 8.58 mmol) in toluene (50 mL) and DIPEA (10.00 mL), and degassed with argon for 10 minutes. Next, 6-ethynyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (1.753 g, 11.15 mmol) was added, followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.33 g, 0.429 mmol), and degassing was performed again for 5 minutes. The resulting reaction mixture was heated at 45°C for 3 hours. The reactant was filtered, washed with 100 ml of ethyl acetate, and the filtrate was concentrated to obtain the crude product. The crude material was purified by eluting with 60% EtOAc / petroleum ether using a 40 g silica column by combiflash. After concentrating the fraction, tert-butyl (4-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethynyl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (2.0 g, 4.04 mmol, 47.0% yield) was collected as a pale yellow solid.

[0674] LCMS dwell time 3.01 min [E]. MS (E - ) m / z: 496.2 (M+H).

[0675] Intermediate 144B: tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0676]

[0677] Silver acetic acid (1.179 g, 7.06 mmol) was added to a solution of tert-butyl (4-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)thiazole-5-yl)carbamate (3.5 g, 7.06 mmol) in toluene (50 mL). The resulting solution was heated at 100°C for 45 minutes. The reaction mixture was filtered through Celite, washed with EtOAc (10 mL), and the filtrate was concentrated to obtain tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (2.0 g, 4.04 mmol, 57.1% yield) as a pale yellow solid.

[0678] LCMS dwell time 2.91 min [E]. MS (E - ) m / z: 496.2.1 (M+H).

[0679] Intermediate 144C: ​​tert-butyl 6-bromo-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0680]

[0681] NBS (0.790 g, 4.44 mmol) in DMF (20 mL) was added dropwise at 0°C to a solution of tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (2.0 g, 4.04 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with 70 ml of ice water and stirred for 10 minutes, the resulting precipitate was filtered and dried to obtain tert-butyl 6-bromo-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (1.6 g, 2.79 mmol, 69.0% yield) as a pale yellow solid.

[0682] LCMS dwell time 3.24 min [E]. MS (E - ) m / z: 576.2 (M+2H).

[0683] Intermediate 144D: tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0684]

[0685] Tribasic potassium phosphate (0.970 g, 5.57 mmol) was added to a solution of tert-butyl 6-bromo-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (1.6 g, 2.79 mmol) in dioxane (15 mL) and water (1.667 mL). The solution was degassed for 10 minutes, PdCl2(dppf)-CH2Cl2 adduct (0.227 g, 0.279 mmol) was added, the reaction mixture was degassed again for 5 minutes, and then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.63 mL, 13.93 mmol) was added. The resulting reaction mixture was heated at 70°C for 4 hours. The reaction product was concentrated, diluted with water (100 mL), and extracted with DCM (3X 100 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by eluting with 80% EtOAc / petroleum ether using a 40 g silica column by combiflash. After concentrating the fraction, tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (1.1 g, 2.054 mmol, 73.7% yield) was collected as a pale yellow solid.

[0686] LCMS dwell time 3.59 minutes [E]. MS (E - ) m / z: 536.2 (M+H).

[0687] Intermediate 144E: tert-butyl 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0688]

[0689] A solution of tert-butyl 5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (1.1 g, 2.054 mmol) in methanol (75 mL) and DCM (25 mL) was purged with nitrogen gas, and Pd / C (0.874 g, 4.11 mmol) was added. The system was evacuated under vacuum, purged with hydrogen gas, and stirred for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through the plug of a Celite pad. The Celite pad was rinsed with additional methanol, and the filtrate was concentrated and dried to obtain tert-butyl 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.85 g, 92%) as a white solid.

[0690] LCMS dwell time 2.22 min [F]. MS (E - ) m / z: 538.2 (M+H).

[0691] Intermediate 144F: 4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one

[0692]

[0693] TFA (10 mL, 130 mmol) was added dropwise to a solution of tert-butyl 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (1.1 g, 2.046 mmol) in DCM (20 mL) and stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (20 mL) and washed with 10% NaHCO3 (20 mL). The reaction mixture was concentrated, co-vaporized with DCM and petroleum ether (3 x 20 mL), and dried under vacuum to obtain 4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (0.8 g, 2.033 mmol, 99% yield) as a yellow solid.

[0694] LCMS dwell time 1.34 min [F]. MS (E - ) m / z: 394.2 (M+H).

[0695] The following intermediates were prepared in a manner similar to intermediates 144 and 145:

[0696] Table 17

[0697]

[0698] Examples 144 and 145: N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-methyloxetane-3-amine

[0699] To a solution of 4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (75 mg, 0.191 mmol) in THF (5 mL) and DMF (5 mL), 3-methyloxetane-3-amine (16.60 mg, 0.191 mmol) was added, followed by TEA (0.027 mL, 0.191 mmol), and the resulting pale yellow solution was stirred under nitrogen at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (23.95 mg, 0.381 mmol) was added at 0°C and stirring was continued at room temperature for 2 hours. The reaction mixture was concentrated to remove volatile substances, the crude material was diluted with DCM (30 mL), and washed with water (25 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified using Method I by LCMS for purification. After LCMS purification, fractions containing isomers 1 and 2 were collected and dried individually using a cinnabar centrifugal evaporator to obtain isomers 1 and 2.

[0700] Example 144 (Isomer 1) was obtained as a pale yellow solid (23 mg, 0.048 mmol, 24.93% yield).

[0701] LCMS dwell time 1.38 min [A]. MS (E - ) m / z: 465.3.

[0702] 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1 H) 8.84 (s, 1 H) 8.49 (s, 1 H) 7.80 (s, 1 H) 4.41 (d, J=5.38 Hz, 2 H) 4.21 (d, J=5.62 Hz, 2 H) 2.91-2.98 (m, 1 H) 2.68-2.77 (m, 2 H) 2.57-2.65 (m, 2 H) 2.28 (s, 3 H) 2.06-2.15 (m, 2 H) 1.73-1.81 (m, 2 H) 1.58 (qd, J=12.76, 2.81 Hz, 2 H) 1.44 (s, 3 H) 1.31(d, J=6.85 Hz, 6 H).

[0703] Example 145 (isomer 2) was obtained as a pale yellow solid.

[0704] LCMS dwell time 1.58 min [A]. MS (E - ) m / z: 465.3.

[0705] 1 H NMR (400 MHz, DMSO-d6) δ 11.31-11.38 (m, 1 H) 8.86 (s, 1 H) 8.49 (s, 1 H) 7.81 (s, 1 H) 4.42 (d, J=5.62 Hz, 2 H) 4.18 (d, J=5.62 Hz, 2 H) 3.13- 3.18 (m, 1 H) 2.79-2.86 (m, 1 H) 2.71-2.78 (m, 1 H) 2.29 (s, 3 H) 2.03-2.14 (m, 2 H) 1.78-1.88 (m, 2 H) 1.54-1.64 (m, 2 H) 1.49 (br d, J=3.18 Hz, 2H) 1.42 (s, 3 H) 1.33 (d, J=6.85 Hz, 6 H).

[0706] The following examples were prepared according to the general procedure described in Examples 144 and 145.

[0707] Table 18

[0708]

[0709]

[0710]

[0711] Examples 162 and 163

[0712] 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide

[0713]

[0714] Intermediate 162A: 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine

[0715]

[0716] To a solution of 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-one (200 mg, 0.488 mmol) in THF (5 mL) and DMF (5 mL), acetic acid (2.80 μl, 0.049 mmol) was added dropwise after methanolamine (4.88 mL, 9.77 mmol) in THF, and the resulting pale yellow solution was stirred under nitrogen at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (61.4 mg, 0.977 mmol) was added at 0°C, and stirring was continued at room temperature for 2 hours. The reaction mixture was concentrated to remove volatile substances, the crude material was diluted with DCM (30 mL), washed with water (25 mL), the separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (250 mg, 0.353 mmol, 72.3% yield) as a yellow solid.

[0717] LCMS residence time 1.6 min [C]. MS (E - ) m / z: 425.3.

[0718] Examples 162 and 163: 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide

[0719] To a solution of 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (70 mg, 0.165 mmol) in THF (2 mL) and DMF (1 mL), TEA (0.046 mL, 0.330 mmol) was followed by 2-chloro-N,N-dimethylacetamide (20.04 mg, 0.165 mmol). The resulting solution was stirred at room temperature for 12 hours. 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 using Method I by LCMS for purification. After purification with LCMS for purification, fractions containing isomers 1 and 2 were collected and dried individually using a centrifugal evaporator to obtain isomers 1 and 2.

[0720] Example 162 (isomer 1) was obtained as a pale yellow solid (19.8 mg, 0.036 mmol, 22.01% yield).

[0721] LCMS duration 1.30 min [A]. MS (E - ) m / z: 510.2 (M+H).

[0722] 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.57-8.43 (m, 2H), 7.12 (s, 1H), 4.12-3.99 (m, 3H), 3.24-3.14 (m, 2H), 3.01 (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=6.8 Hz, 6H).

[0723] Example 163 (isomer 2) was obtained as a pale yellow solid (4.1 mg, 7.32 μmol, 4.44% yield).

[0724] LCMS dwell time 1.44 min [A]. MS (E - ) m / z: 510.2 (M+H).

[0725] 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.55-8.42 (m, 2H), 7.14 (d, J=1.2 Hz, 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=9.0 Hz, 3H), 1.64 (br. s., 2H), 1.52 -1.37 (m, 6H).

[0726] The following examples were prepared according to the general procedure described in Examples 162 and 163.

[0727] Table 19

[0728]

[0729] The following examples were prepared according to the general procedure described in intermediates 144 and 145.

[0730] Table 20

[0731]

[0732]

[0733] Examples 172 and 173

[0734] 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexane-1-amine

[0735]

[0736] To a solution of 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-one (75 mg, 0.191 mmol) in THF (3 mL) and DMF (2 mL), (3-methyloxetane-3-yl)methaneamine (19.33 mg, 0.191 mmol) was added dropwise at 0°C, followed by acetic acid (1.094 μL, 0.019 mmol), and the resulting pale yellow solution was stirred under nitrogen at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (24.01 mg, 0.382 mmol) was added at 0°C, and stirring was continued at room temperature for 2 hours. 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 using Method I by LCMS for purification. After LCMS purification, fractions containing isomers 1 and 2 were collected and dried individually using a cinnabar centrifugal evaporator.

[0737] Example 172 (Isomer 1) was obtained as a pale yellow solid (2.7 mg, 5.42 μmol, 2.84% yield).

[0738] LCMS dwell time 1.48 min [A]. MS (E - ) m / z: 478.3 (M+H).

[0739] 1 H NMR (400MHz, DMSO-d6) δ 11.16 (s, 1H), 8.39-8.28 (m, 1H), 8.00-7.97 (m, 1H), 7.60(s, 1H), 7.18 (dd, J=8.1, 4.6 Hz, 1H), 4.43 (d, J=6.4 Hz, 2H), 4.28 (d, J=6.4 Hz,2H), 3.91 (d, J=3.4 Hz, 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).

[0740] Example 173 (isomer 2) was obtained as a pale yellow solid (3.0 mg, 5.69 μmol, 2.98% yield).

[0741] LCMS dwell time 1.53 min [A]. MS (E - ) m / z: 478.3 (M+H).

[0742] 1 H NMR (400MHz, DMSO-d6) δ 11.17 (s, 1H), 8.34 (d, J=4.4 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H),7.60 (s, 2H), 7.18 (dd, J=7.7, 4.5 Hz, 1H), 4.38 (d, J=6.1 Hz, 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=12.0 Hz, 2H), 1.40 (d,J=6.8 Hz, 6H).

[0743] The following examples were prepared according to the general procedure described in Examples 172 and 173.

[0744] Table 21

[0745]

[0746]

[0747]

[0748] Examples 184 and 185

[0749] N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine

[0750]

[0751] 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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-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 for 2 hours at room temperature. 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 using Method I by a purification LCMS. After purification by the purification LCMS, fractions containing isomers 1 and 2 were collected and dried individually using a cinnabar centrifugal evaporator.

[0752] Example 184 (Isomer 1): (9.9 mg, 0.021 mmol, 17.19% yield).

[0753] LCMS duration of stay 1.348 min [A]. MS (E - ) m / z: 465.3 (M+H).

[0754] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.72 (s, 1H), 8.46 (s, 1H), 4.65 (t, J=6.7 Hz, 2H), 4.35 (t, J=6.1 Hz, 2H), 4.07-3.96 (m, 1H), 2.95 (tt, J=11.9, 3.6 Hz, 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=11.0 Hz, 2H), 1.63-1.42 (m, 2H), 1.41-1.12 (m, 7H), 1.12-0.97 (m, 1H).

[0755] 실시예 185 (이성질체 2): (9.1 mg, 0.018 mmol, 14.64% 수율).

[0756] LCMS 체류 시간 1.514분 [A]. MS (E - ) m / z: 465.3 (M+H).

[0757] 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.72 (d, J=8.8 Hz, 1H), 8.47 (d, J=0.7 Hz, 1H), 4.68-4.59 (m, 2H), 4.55 (d, J=4.9 Hz, 2H), 3.63 (qd, J=11.5, 5.4 Hz, 1H), 3.25-3.18 (m, 1H), 2.97-2.86 (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=9.3 Hz, 1H), 1.93-1.82 (m, 3H), 1.82-1.59 (m, 2H), 1.34 (d, J=6.8 Hz, 6H), 1.17 (t, J=7.2 Hz, 2H).

[0758] The following examples were prepared according to the general procedure described in Examples 184 and 185.

[0759] Table 22A

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768] Table 22B

[0769] The following examples were prepared according to the general procedure described in intermediate 162.

[0770]

[0771]

[0772] Examples 241 and 242

[0773] 5-(6-isopropyl-2-(4-(oxetane-3-ylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one

[0774]

[0775] AcOH (7.20 μL, 0.126 mmol) was added to a solution of 5-(6-isopropyl-2-(4-oxocyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-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 for 2 hours at room temperature. 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 using Method I by LCMS for purification. After LCMS purification, fractions containing isomers 1 and 2 were collected and dried individually using a cinnabar centrifugal evaporator.

[0776] Example 241 (Isomer 1): (13.6 mg, 0.028 mmol, 22.29% yield).

[0777] LCMS duration 1.523 min [A]. MS (E - ) m / z: 455.3 (M+H).

[0778] 1 H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 7.52 (s, 1H), 4.64 (t, J=6.6 Hz, 2H), 4.34 (t, J=6.4 Hz, 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=10.3 Hz, 2H), 1.61-1.45 (m, 2H), 1.36-1.08 (m, 8H).

[0779] Example 242 (Isomer 2): (7.8 mg, 0.016 mmol, 12.89% yield).

[0780] LCMS duration 1.702 min [A]. MS (E - ) m / z: 455.3 (M+H).

[0781] 1 H NMR (400MHz, DMSO-d6) δ 11.03 (s, 1H), 7.53 (s, 1H), 4.64 (t, J=6.6 Hz, 2H), 4.35 (t, J=6.2 Hz, 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=4.6 Hz, 4H), 1.37-1.24 (m, 6H).

[0782] The following examples were prepared according to the general procedure described in Examples 241 and 242.

[0783] Table 23

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] Examples 269 and 270

[0790] 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane

[0791]

[0792] Intermediate 269A: tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-6-vinyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0793]

[0794] Vinylboronic acid (34.8 mg, 0.484 mmol) and tribasic potassium phosphate (237 mg, 1.118 mmol) were added to a solution of tert-butyl 6-bromo-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (220 mg, 0.373 mmol) in dioxane (10 mL) and water (2.500 mL). The solution was degassed with argon for 10 minutes, and PdCl2(dppf)-CH2Cl2 adduct (30.4 mg, 0.037 mmol) was added. The resulting reaction mixture was heated at 90°C for 12 hours. 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 material was purified by eluting with 40% EtOAc / petroleum ether using a 40 g silica column by Combiflash. After concentrating the fraction, tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-6-vinyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.18 g, 90% yield) was collected as a pale yellow solid.

[0795] LCMS dwell time 3.35 minutes [C]. MS (E - ) m / z: 538.2 (M+H).

[0796] Intermediate 269B: tert-butyl 6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0797]

[0798] A solution of tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-6-vinyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.18 g, 0.335 mmol) in THF (10 mL) and methanol (2.5 mL) was purged with nitrogen gas, and Pd-C (0.036 g, 0.335 mmol) was added. The system was evacuated under vacuum, purged with hydrogen gas, and stirred for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through the plug of a Celite pad to obtain tert-butyl 6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.15 g, 83%) as a yellow solid.

[0799] LCMS dwell time 1.48 min [C]. MS (E - ) m / z: 540.2 (M+H).

[0800] Intermediate 269C: 4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one

[0801]

[0802] TFA (5 mL) was added to a solution of tert-butyl 6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (120 mg, 0.222 mmol) in DCM (5.00 mL), and stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain 4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (80 mg, 91%) as a yellow solid.

[0803] LCMS dwell time 2.31 min [C]. MS (E - ) m / z: 396.2 (M+H).

[0804] Examples 269 and 270: 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane

[0805] To a solution of 4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-one (100 mg, 0.253 mmol) in THF (5 mL) and DMF (5.00 mL), acetic acid (0.014 mL, 0.253 mmol) was followed by the addition of 2-oxa-6-azaspiro[3.3]heptane (376 mg, 3.79 mmol), and the mixture was stirred at ambient temperature for 12 hours. The reaction mixture was concentrated to remove DMF and THF, the resulting residue was dissolved in 3 mL of dry methanol, and cooled to -78°C under a nitrogen atmosphere. NaCNBH4 (79 mg, 1.264 mmol) was added at once. The reaction was continued at the same temperature (-78°C) for 3 hours, followed by cooling to 0°C over 1 hour. The reaction mixture 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 obtained crude product was purified using Method I via LCMS for purification. After LCMS purification, fractions containing isomers 1 and 2 were collected and dried individually using a Zinbaek centrifugal evaporator.

[0806] Example 269 (Isomer 1) was obtained as a pale yellow solid (3 mg, 2.3%).

[0807] LCMS residence time 1.12 min [A]. MS (E - ) m / z: 479.2 (M+H).

[0808] 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.50-8.44 (m, 1H), 7.17 (d, J=1.2 Hz, 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).

[0809] Example 270 (isomer 2) was obtained as a pale yellow solid (2.5 mg, 1.9%).

[0810] LCMS dwell time 1.02 min [A]. MS (E - ) m / z: 479.2 (M+H).

[0811] 1 H NMR (400MHz, DMSO-d6) δ 11.69 (s, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.47 (s, 1H), 7.18 (d, J=1.2 Hz, 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).

[0812] The following examples were prepared according to the general procedure described in Examples 269 and 270.

[0813] Table 24

[0814]

[0815] Example 273

[0816] N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine

[0817]

[0818] Intermediate 273A: tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[0819]

[0820] Methylboronic acid (304 mg, 5.08 mmol) and tribasic potassium phosphate (702 mg, 3.05 mmol) were added to a solution of tert-butyl 6-bromo-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (600 mg, 1.016 mmol) in THF (30 mL) and water (7.5 mL). The solution was degassed with argon for 10 minutes, 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 hours. The reaction product was concentrated, diluted with water (100 mL), and extracted with DCM (3X 100 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by eluting with 40% EtOAc / petroleum ether using a 40 g silica column by combiflash. After concentrating the fraction, tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.35 g, 65% yield) was collected as a pale yellow solid.

[0821] LCMS dwell time 2.78 min [C]. MS (E - ) m / z: 526.2 (M+H).

[0822] Intermediate 273B: 4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one

[0823]

[0824] TFA (10 mL) was added to a solution of tert-butyl 5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-2-(1,4-dioxaspiro[4.5]decane-8-yl)-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (350 mg, 1.142 mmol) in DCM (10.00 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain 4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (250 mg, 58%) as a yellow solid.

[0825] LCMS residence time 1.64 min [C]. MS (E - ) m / z: 382.2 (M+H).

[0826] Example 273

[0827] N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine

[0828] 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]pyridine-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexan-1-one (80 mg, 0.210 mmol) in THF (2 mL) and DMF (2.00 mL), followed by oxetane-3-amine (0.012 mL, 0.210 mmol), and the solution was stirred at ambient temperature for 12 hours. NaCNBH3 (13.18 mg, 0.210 mmol) was added, and the reaction mixture was continued at room temperature for 1 hour. The reaction mixture was quenched with 10 mL of water and extracted with 10% methanol in DCM (10 mL x 2). The organic layer was concentrated. The obtained crude product was purified using Method I by LCMS for purification. After LCMS purification, fractions containing isomers 1 and 2 were collected and dried individually using a cinnabar centrifugal evaporator to obtain Example 273 as a pale yellow solid (isomer 1: 3.5 mg, 3.7%) and Example 273 as a pale yellow solid (isomer 2: 3.5 mg, 3.7%).

[0829] Example 273 (Isomer 1):

[0830] LCMS dwell time 1.20 min [A]. MS (E - ) m / z: 439.2 (M+H).

[0831] 1H NMR (400MHz, DMSO-d6) δ 11.72 (s, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.46 (s, 1H), 7.23 (d, J=1.2 Hz, 1H), 4.64 (t, J=6.5 Hz, 2H), 4.32 (t, J=6.2 Hz, 2H), 4.07 (s, 3H), 3.98 (quin, J=6.8 Hz, 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).

[0832] The following examples were prepared according to the general procedure described in Example 273.

[0833] Table 25

[0834]

[0835] Intermediate 277B

[0836] 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0837]

[0838] Intermediate 277A: 7,8-dimethyl-6-((trimethylsilyl)ethynyl)-[1,2,4]triazolo[1,5-a]pyridine

[0839]

[0840] Copper(I) iodide (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 degassed with argon for 10 minutes. Then, bis(triphenylphosphine)palladium(II) dichloride (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 hours. The reaction mixture was filtered through a Celite layer 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 obtain 7,8-dimethyl-6-((trimethylsilyl)ethinyl)-[1,2,4]triazolo[1,5-a]pyridine (16 g, 55.9 mmol, 84% yield) as a brown oil.

[0841] LCMS 1.90 min [F]. MS (E - ) m / z: 244.2 (M+H).

[0842] Intermediate 277B: 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0843] 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 stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with water (150 mL), and extracted with DCM (3 x 250 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by eluting with 75% EtOAc / petroleum ether using a 120 g silica column by combiflash. After concentrating the fraction, 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.

[0844] LCMS 1.81 min [C]. MS (E - ) m / z: 172.2 (M+H).

[0845] The following intermediate was prepared according to the general procedure described in intermediate 277B.

[0846] Table 26

[0847]

[0848] Example 278

[0849] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0850]

[0851] Intermediate 278A: Methyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate

[0852]

[0853] DPPF (3.97 g, 7.16 mmol) and PdOAc2 (0.804 g, 3.58 mmol) were added to a solution of tert-butyl (2-bromothiazole-5-yl)carbamate (10 g, 35.8 mmol) in methanol (75 mL) and DMF (75 mL). The solution was degassed with argon for 10 minutes. The reactants were saturated with CO2 gas, then TEA (19.97 mL, 143 mmol) was added, and the mixture was heated at 80°C at 10 kg / cm² in the presence of CO2. 2 The mixture was stirred under pressure for 7 hours. The reaction mixture was concentrated, the residue was dissolved in DCM (100 mL), washed with water (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude material was purified by eluting the compound with 35% ethyl acetate in petroleum ether using an ISCO with a 120 g silica column, the fraction was collected and concentrated to obtain methyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate (7.5 g, 29.0 mmol, 81% yield) as a grayish-white solid.

[0854] LCMS residence time 2.10 min [C]. MS (E - ) m / z: 259.1 (M+H).

[0855] Intermediate 278B: Methyl 5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-carboxylate

[0856]

[0857] NIS (6.53 g, 29.0 mmol) in acetonitrile (50 mL) was added dropwise at 0°C to a solution of methyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate (7.5 g, 29.0 mmol) in acetonitrile (150 mL), and stirred for 10 minutes at the same temperature. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (3 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude material was purified by eluting with 31% EtOAc / petroleum ether using an 80 g silica column by combiflash. After concentrating the fraction, 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.

[0858] LCMS dwell time 1.64 min [F]. MS (E - ) m / z: 384.1 (M+H).

[0859] Intermediate 278C: Methyl 5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)thiazole-2-carboxylate

[0860]

[0861] Triphenylphosphine (0.137 g, 0.521 mmol) and copper(I) iodide (0.099 g, 0.521 mmol) were added to a solution of methyl 5-((tert-butoxycarbonyl)amino)-4-iodothiazole-2-carboxylate (2.0 g, 5.21 mmol) in toluene (50 mL) and DIPEA (10.00 mL), and degassed with argon for 10 minutes. Then, 6-ethynyl-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (1.159 g, 6.77 mmol) was added, followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.183 g, 0.260 mmol), and degassed again for 5 minutes. The resulting reaction mixture was heated at 45°C for 3 hours. The reaction mixture was filtered, washed with ethyl acetate (100 mL), and the filtrate was concentrated to obtain the crude product. The crude product was purified by combiflash using a 40 g silica column with 4% MeOH / CHCl3 elution. After concentrating the fraction, methyl 5-((tert-butoxycarbonyl)amino)-4-((7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)ethinyl)thiazole-2-carboxylate (1.4 g, 3.28 mmol, 62.9% yield) was collected as a pale yellow solid.

[0862] LCMS dwell time 2.71 min [C]. MS (E - ) m / z: 428.2.1 (M+H).

[0863] Intermediate 278D: 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate

[0864]

[0865] Silver acetic acid (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]pyridine-6-yl)ethinyl)thiazole-2-carboxylate (1.3 g, 3.04 mmol) in toluene (15 mL), and the resulting solution was heated at 100°C for 45 minutes. The reaction mixture was filtered through Celite, washed with ethyl acetate (10 mL), and the filtrate was concentrated to obtain 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.3 g, 2.80 mmol, 92% yield) as a pale yellow solid.

[0866] LCMS dwell time 2.71 min [C]. MS (E - ) m / z: 428.2.1 (M+H).

[0867] Intermediate 278E: 4-(tert-butyl) 2-methyl 6-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate

[0868]

[0869] NBS (0.541 g, 3.04 mmol) in DMF (5 mL) was added dropwise at 0°C to a solution of 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, 3.04 mmol) in DMF (15 mL) and stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water (70 mL), stirred for 10 minutes, the resulting precipitate was filtered and dried to obtain 4-(tert-butyl) 2-methyl 6-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (0.9 g, 1.777 mmol, 58.4% yield) as a pale yellow solid.

[0870] LCMS dwell time 3.01 min [C]. MS (E - ) m / z: 508.2 (M+2H).

[0871] Intermediate 278F: 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate

[0872]

[0873] To a solution of 4-(tert-butyl) 2-methyl 6-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (2.1 g, 4.15 mmol) in THF (15 mL) and water (1.667 mL), tribasic potassium phosphate (1.445 g, 8.29 mmol) was added and degassed for 10 minutes, then chloro(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 for 5 minutes, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.48 g, 20.74 mmol) was added. The reaction mixture was heated at 70°C for 4 hours. 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 material was purified by eluting with 41% EtOAc / petroleum ether using a 24 g silica column by combiflash. After concentrating the fraction, 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.3 g, 2.78 mmol, 67.0% yield) was collected as a pale yellow solid.

[0874] LCMS dwell time 1.86 min [F]. MS (E - ) m / z: 468.2 (M+H).

[0875] Intermediate 278G: 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate

[0876]

[0877] A solution of 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-(prop-1-en-2-yl)-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.3 g, 2.78 mmol) in methanol (75 mL) was purged with nitrogen gas, and Pd / C (0.444 g, 0.417 mmol) was added. The system was evacuated under vacuum, purged with hydrogen gas, and stirred for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through the plug of a Celite pad. The Celite pad was rinsed with additional methanol, and the filtrate was concentrated and dried to obtain 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.15 g, 2.449 mmol, 88% yield) as a white solid.

[0878] LCMS dwell time 1.92 min [F]. MS (E - ) m / z: 470.2 (M+H).

[0879] Intermediate 278H: Methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylate

[0880]

[0881] TFA (1.805 mL, 23.43 mmol) was added dropwise to a solution of 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.1 g, 2.343 mmol) in DCM (10 mL) and stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (20 mL) and washed with 10% NaHCO3 (20 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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.

[0882] LCMS dwell time 2.39 min [C]. MS (E - ) m / z: 370.2 (M+H).

[0883] Intermediate 278I: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylic acid

[0884]

[0885] 10% sodium hydroxide (5 mL, 2.328 mmol) was added dropwise to a solution of methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylate (0.86 g, 2.328 mmol) in methanol (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, the aqueous layer was acidified to a pH of ~4-5, the resulting precipitate was filtered and dried to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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.

[0886] LCMS residence time 0.94 min [C]. MS (E - ) m / z: 355.2 (M+H).

[0887] The following intermediate was prepared according to the general procedure described in intermediate 278I.

[0888] Table 27

[0889]

[0890] Intermediate 278K: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0891]

[0892] A solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxylic acid (400 mg, 1.125 mmol) in THF (10 mL) was heated at 70°C for 1 hour. The reaction mixture was concentrated to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (340 mg, 1.092 mmol, 97% yield) as a pale yellow solid.

[0893] LCMS dwell time 1.26 min [F]. MS (E - ) m / z: 3122 (M+H).

[0894] Intermediate 278L: 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0895]

[0896] A solution of NBS (194 mg, 1.092 mmol) in DMF (3 mL) was added dropwise to 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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 hours. The reaction mixture was quenched with water (50 mL), stirred for 10 minutes, the resulting precipitate was filtered and dried to obtain 2-bromo-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (275 mg, 0.705 mmol, 64.5% yield) as a grayish-white solid.

[0897] LCMS residence time 1.52 min [G]. MS (E - ) m / z: 390.2 (M+H).

[0898] The following intermediate was prepared according to the general procedure described in Intermediate 278L.

[0899] Table 28

[0900]

[0901] Intermediate 278N: tert-butyl 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-carboxylate

[0902]

[0903] 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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (250 mg, 0.641 mmol) and tert-butylpiperazine-1-carboxylate (179 mg, 0.961 mmol) in toluene (7 mL). The resulting solution was degassed with N2 for 10 minutes, Pd2(dba)3 (58.7 mg, 0.064 mmol) was added, followed by BINAP (399 mg, 0.641 mmol), at which point the solution was degassed again for 5 minutes. The resulting mixture was heated at 90°C for 12 hours. 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 obtain the crude product. The crude material was purified by combiflash using a 24 g silica column while eluting the compound with 75% ethyl acetate in petroleum ether. The fraction was collected and concentrated to obtain tert-butyl 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-carboxylate (210 mg, 0.424 mmol, 66.1% yield) as a pale yellow solid.

[0904] LCMS dwell time 3.48 min [C]. MS (E - ) m / z: 496.2 (M+H).

[0905] Example 278

[0906] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0907] HCl (2 mL, 8.00 mmol) in dioxane was added dropwise to a solution of tert-butyl 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-carboxylate (210 mg, 0.424 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with 10% NaHCO3 (20 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (170 mg, 100% yield) as a pale yellow solid.

[0908] LCMS dwell time 1.62 min [C]. MS (E - ) m / z: 396.2 (M+H).

[0909] The following examples were prepared according to the general procedure described in Example 278.

[0910] Table 29

[0911]

[0912] Example 280

[0913] 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-2-(dimethylamino)ethane-1-one

[0914]

[0915] To a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-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), HATU (65.4 mg, 0.172 mmol) was followed by TEA (0.024 mL, 0.172 mmol). The resulting solution was stirred at room temperature for 12 hours. 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.

[0916] LCMS dwell time 1.76 min [C]. MS (E - ) m / z: 481.2 (M+H).

[0917] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 4.17 (s, 4H), 3.91 (s, 4 H), 3.37 (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=6.8 Hz, 6H).

[0918] Example 281

[0919] 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-2-methylpropan-2-ol

[0920]

[0921] 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]pyridine-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.063 mmol) and 1-chloro-2-methylpropan-2-ol (6.86 mg, 0.063 mmol) in DMF (1 mL). The resulting solution was heated at 80°C for 12 hours. 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 reaction mixture was purified by LCMS for purification using Method I, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-2-methylpropan-2-ol (16.7 mg, 0.035 mmol, 55.9% yield) as a pale yellow solid.

[0922] LCMS dwell time 2.01 min [A]. MS (E - ) m / z: 468.2 (M+H).

[0923] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 4.17 (s, 1H), 3.91 (s, 1 H), 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=6.8 Hz, 6H), 1.13 (s, 6H).

[0924] Example 282

[0925] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0926]

[0927] TEA (8.81 μL, 0.063 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (25 mg, 0.063 mmol) and 1-chloro-2-(methylsulfonyl)ethane (9.01 mg, 0.063 mmol) in DMF (1 mL). The resulting solution was heated at 90°C for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole as a pale yellow solid.

[0928] LCMS duration 1.70 min [A]. MS (E - ) m / z: 502.3 (M+H).

[0929] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (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).

[0930] Example 283

[0931] 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazol-2-yl)piperazine-1-yl)-N,N-dimethylacetamide

[0932]

[0933] TEA (8.81 μL, 0.063 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-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 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-N,N-dimethylacetamide (19.5 mg, 0.039 mmol, 62.3% yield) as a pale yellow solid.

[0934] LCMS dwell time 1.72 min [A]. MS (E - ) m / z: 481.2 (M+H).

[0935] 1H NMR (400 MHz, DMSO-d6) δ 10.98 (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).

[0936] The following examples were prepared according to the general procedure described in Example 283.

[0937]

[0938] Example 286

[0939] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole

[0940]

[0941] Acetic acid (9.41 μL, 0.164 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (65 mg, 0.164 mmol) and oxetan-3-one (11.84 mg, 0.164 mmol) in methanol (2 mL) at 0°C. The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (10.33 mg, 0.164 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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.

[0942] LCMS residence time 2.16 min [C]. MS (E -) m / z: 452.2 (M+H).

[0943] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (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=6.8 Hz, 6H).

[0944] The following examples were prepared according to the general procedure described in Example 286.

[0945]

[0946] Example 290

[0947] 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(3-methyloxetane-3-yl)piperidine-4-amine

[0948]

[0949] Intermediate 290A: 8-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane

[0950]

[0951] 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]pyridine-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 minutes, 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 minutes and heated at 90°C for 16 hours. The reaction mixture was diluted with water (100 mL), and Extraction was performed with ethyl acetate (2 x 100 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude material was purified by eluting with 45% ethyl acetate / DCM using a 24 g silica column by Combiflash. After concentrating the fraction, 8-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (490 mg, 1.083 mmol, 85% yield) was collected as a pale yellow solid.

[0952] LCMS dwell time 1.54 min [F]. MS (E - ) m / z: 453.2 (M+H).

[0953] Intermediate 290B: 1-(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-4-one

[0954]

[0955] 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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-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 hours. The reaction mixture was concentrated to obtain 1-(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-4-one (400 mg, 0.979 mmol, 98% yield) as a yellow oil.

[0956] LCMS dwell time 1.36 min [F]. MS (E - ) m / z: 409.2 (M+H).

[0957] Example 290

[0958] 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(3-methyloxetane-3-yl)piperidine-4-amine

[0959] Acetic acid (3.50 μL, 0.061 mmol) was added at 0°C 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]thiazole-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). The resulting solution was stirred at room temperature for 12 hours, 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 hours. The reaction product was concentrated, 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 reaction product was purified using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifugal evaporator to obtain 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(3-methyloxetane-3-yl)piperidine-4-amine (14.1 mg, 48%) as a pale yellow solid.

[0960] LCMS dwell time 1.75 minutes [A]. MS (E - ) m / z: 480.2 (M+H).

[0961] 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 4.42 (d, J=5.1 Hz,2H), 4.21 (d, J=5.4 Hz, 2H), 3.91 (s, 1H), 3.82 (d, J=12.2 Hz, 2H), 3.01 (t, J=11.6 Hz, 2H), 2.81(br. s., 1H), 2.63 (dt, J=13.6, 6.8 Hz, 1H), 2.59-2.53 (m, 2H), 2.18 (s, 3H), 1.70 (d, J=12.5 Hz,2H), 1.46 (s, 2H), 1.37 (d, J=11.2 Hz, 2H), 1.26 (d, J=6.8 Hz, 6H).

[0962] The following examples were prepared according to the general procedure described in Example 290.

[0963] Table 30

[0964]

[0965]

[0966] Example 300

[0967] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3,3]heptane-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0968]

[0969] Intermediate 300A: tert-butyl 6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0970]

[0971] 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]pyridine-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 minutes, then Pd2(dba)3 (0.199 g, 0.218 mmol) was added, followed by the addition of BINAP (0.136 g, 0.218 mmol), and the solution was degassed again for 5 minutes. The resulting reaction mixture was heated at 90°C for 16 hours. 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 material was purified by eluting with 45% ethyl acetate / DCM using a 24 g silica column by Combiflash. After concentrating the fraction, tert-butyl 6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (550 mg, 1.083 mmol, 49.7% yield) was collected as a yellow solid.

[0972] LCMS duration 1.80 min [F]. MS (E - ) m / z: 508.2 (M+H).

[0973] Intermediate 300B: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole

[0974]

[0975] TFA (3 mL, 38.9 mmol) was added dropwise to a solution of tert-butyl 6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 0.788 mmol) in DCM (10 mL), and the solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (400 mg, 0.979 mmol, 98% yield) as a yellow solid.

[0976] LCMS dwell time 1.32 min [A]. MS (E - ) m / z: 408.2 (M+H).

[0977] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (d, J=4.2 Hz, 1H), 8.67 (s, 1H), 8.44 (d, J=2.0 Hz, 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=2.4 Hz, 3H), 1.91 (s, 1H), 1.76 (s, 1H), 1.25 (d, J=7.1 Hz, 6H).

[0978] Example 300

[0979] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3,3]heptane-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[0980] Acetic acid (7.02 μL, 0.123 mmol) was added at 0°C to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3,3]heptane-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). The resulting solution was stirred at room temperature for 12 hours, 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 hours. The reaction mixture was concentrated, 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 reaction mixture was purified using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifugal evaporator to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3,3]heptane-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (18.9 mg, 0.039 mmol, 31.9% yield) as a pale yellow solid.

[0981] LCMS dwell time 1.52 min [A]. MS (E - ) m / z: 464.2 (M+H).

[0982] The following examples were prepared according to the general procedure described in Example 300.

[0983] Table 31

[0984]

[0985] Example 303

[0986] 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-methylpropan-2-ol

[0987]

[0988] 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]pyridine-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3,3]heptan-2-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.123 mmol) and 1-chloro-2-methylpropan-2-ol (13.32 mg, 0.123 mmol) in DMF (1 mL). The resulting solution was heated at 80°C for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined and dried using a centrifugal evaporator to obtain 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3,3]heptan-2-yl)-2-methylpropan-2-ol (5.6 mg, 0.011 mmol, 9.04% yield) as a pale yellow solid.

[0989] LCMS dwell time 1.28 min [A]. MS (E - ) m / z: 480.2 (M+H).

[0990] 1H NMR (400MHz, DMSO-d6) δ 11.00-10.95 (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=6.8 Hz, 5H), 1.15-1.00 (m, 6H).

[0991] Example 304

[0992] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole

[0993]

[0994] TEA (0.034 mL, 0.245 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (100 mg, 0.245 mmol) and 1-chloro-2-(methylsulfonyl)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 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (23 mg, 0.044 mmol, 18.02% yield) as a pale yellow solid.

[0995] LCMS dwell time 1.81 min [C]. MS (E - ) m / z: 514.2 (M+H).

[0996] Example 305

[0997] 5-(6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one

[0998]

[0999] TEA (8.77 μL, 0.063 mmol) was added to a solution of 5-(6-isopropyl-2-(2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (25 mg, 0.063 mmol) and 1-chloro-2-(methylsulfonyl)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 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 5-(6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (13.3 mg, 0.026 mmol, 41.6% yield) as a pale yellow solid.

[1000] LCMS dwell time 1.24 min [A]. MS (E - ) m / z: 504.2 (M+H).

[1001] Example 306

[1002] 5-(6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one

[1003]

[1004] Acetic acid (4.32 μL, 0.075 mmol) was added to a solution of 5-(6-isopropyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (30 mg, 0.075 mmol) and oxetan-3-one (5.44 mg, 0.075 mmol) in methanol (1 mL) at 0°C, followed by TEA (10.52 μL, 0.075 mmol). The resulting solution was stirred at room temperature for 12 hours, 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 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifuge to obtain 5-(6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (1.0 mg, 2.205 μmol, 2.92% yield) as a pale yellow solid.

[1005] LCMS dwell time 1.27 min [A]. MS (E - ) m / z: 454.2 (M+H).

[1006] The following examples were prepared according to the general procedure described in Example 306.

[1007] Table 32

[1008]

[1009] Example 308

[1010] (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl

[1011]

[1012] Intermediate 308A: tert-butyl (R)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-carboxylate

[1013]

[1014] 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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (2.0 g, 5.12 mmol) and tert-butyl(R)-3-methylpiperazine-1-carboxylate (1.539 g, 7.69 mmol) in dioxane (60 mL). The solution was degassed for 10 minutes, then XPhos Pd G2 (0.403 g, 0.512 mmol) was added, and the reaction mixture was degassed again for 5 minutes. The resulting reaction mixture was heated at 110°C for 16 hours. 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 material was purified by eluting with 65% ethyl acetate / DCM using a 40 g silica column by Combiflash. After concentrating the fraction, tert-butyl (R)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-carboxylate (2.2 g, 4.32 mmol, 84% yield) was collected as a yellow solid.

[1015] LCMS dwell time 3.62 min [C]. MS (E - ) m / z: 508.2 (MH).

[1016] The following intermediate was prepared according to the general procedure described in intermediate 308A.

[1017] Table 33

[1018]

[1019] Example 308

[1020] (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl

[1021] 4 M hydrochloric acid (10 mL, 329 mmol) in dioxane was added dropwise to a solution of tert-butyl (R)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-carboxylate (2.2 g, 4.32 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl (1.9 g, 4.18 mmol, 97% yield) as a pale yellow solid.

[1022] LCMS dwell time 1.31 min [A]. MS (E - ) m / z: 410.2 (M+H).

[1023] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1 H) 8.65 (s, 1 H) 8.43 (s, 1 H) 3.92 (br dd, J=5.14, 2.69 Hz, 1 H) 3.45-3.49 (m, 1 H) 2.93-2.98 (m, 1 H) 2.85-2.91 (m, 1 H) 2.74-2.80 (m, 1 H) 2.60-2.71 (m, 1 H) 2.56 (s, 3 H) 2.19 (s, 3 H) 1.26 (d, J=6.85 Hz, 9 H).

[1024] The following examples were prepared according to the general procedure described in Example 308.

[1025] Table 34

[1026]

[1027] Example 312

[1028] (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N,N-dimethylacetamide

[1029]

[1030] 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]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-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 hours. 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 the LCMS method I for purification to obtain (R)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N,N-dimethylacetamide (27 mg, 0.054 mmol, 44.3% yield) as a pale yellow solid.

[1031] LCMS dwell time 1.71 min [A]. MS (E - ) m / z: 495.3 (M+H).

[1032] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1 H) 8.66 (s, 1 H) 8.43 (s, 1 H) 3.99-4.10 (m, 1 H) 3.51-3.62 (m, 1 H) 3.12-3.28 (m, 3 H) 3.08 (s, 3 H) 2.89 (br d, J=11.49 Hz, 1 H) 2.84 (s, 3 H) 2.74 (br d, J=11.00 Hz, 1 H) 2.63 (dt, J=13.63, 6.76 Hz, 1 H) 2.56 (s, 3 H) 2.39 (dd, J=11.25, 3.42 Hz, 1 H) 2.19 -2.29 (m, 1 H) 2.19 (s, 2 H) 1.24-1.31 (m, 9 H).

[1033] The following examples were prepared according to the general procedure described in Example 312.

[1034] Table 35

[1035]

[1036] Example 316

[1037] (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole

[1038]

[1039] TEA (0.017 mL, 0.122 mmol) was added at 0°C to a solution of (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.122 mmol) and oxetan-3-one (8.80 mg, 0.122 mmol) in methanol (1 mL). The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (15.34 mg, 0.244 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction product was concentrated, 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifugal evaporator to obtain (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (22 mg, 0.043 mmol, 35.6% yield) as a pale yellow solid.

[1040] LCMS dwell time 1.78 min [A]. MS (E - ) m / z: 466.2 (M+H).

[1041] The following examples were prepared according to the general procedure described in Example 316.

[1042] Table 36

[1043]

[1044]

[1045] Example 325

[1046] (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-methylpropan-2-ol

[1047]

[1048] 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]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.122 mmol) and 1-chloro-2-methylpropan-2-ol (13.25 mg, 0.122 mmol) in DMF (1 mL). The resulting solution was heated at 80°C for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-methylpropan-2-ol (14.9 mg, 0.030 mmol, 24.83% yield) as a pale yellow solid.

[1049] LCMS dwell time 2.03 min [A]. MS (E - ) m / z: 482.2 (M+H).

[1050] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1 H) 8.66 (s, 1 H) 8.43 (s, 1 H) 4.16 (s, 1 H) 3.95-4.04 (m, 1 H) 3.52 (br d, J=12.23 Hz, 1 H) 3.27 (td, J=12.10, 2.93 Hz, 1 H) 3.18 (d, J=5.14 Hz, 1 H) 2.99 (br d, J=11.00 Hz, 1 H) 2.90 (br d, J=11.00 Hz, 2 H) 2.59-2.67 (m, 1 H) 2.56 (s, 2 H) 2.43 (dd, J=11.37, 3.30 Hz, 1 H) 2.16-2.32 (m, 4 H) 2.08 (s, 2 H) 1.24-1.36 (m, 6 H) 1.14 (d, J=6.11 Hz, 6 H).

[1051] Example 326

[1052] (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(methylamino)ethane-1-one

[1053]

[1054] Intermediate 326A: tert-butyl (R)-(2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-oxoethyl)(methyl) carbamate

[1055]

[1056] To a solution of (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-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), HATU (46.4 mg, 0.122 mmol) was followed by TEA (0.017 mL, 0.122 mmol). The resulting solution was stirred at room temperature for 12 hours. 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 obtain tert-butyl (R)-(2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-oxoethyl)(methyl)carbamate (50 mg, 0.086 mmol, 70.5% yield) as a yellow solid.

[1057] LCMS dwell time 1.88 min [F]. MS (E - ) m / z: 581.2.

[1058] Example 326

[1059] (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(methylamino)ethane-1-one

[1060] 4 M hydrochloric acid (1 mL, 32.9 mmol) in dioxane was added dropwise to solution tert-butyl (R)-(2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-oxoethyl)(methyl)carbamate (50 mg, 0.086 mmol) in DCM (2 mL), and stirred at room temperature for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(methylamino)ethane-1-one (27 mg, 0.053 mmol, 61.3% yield) as a pale yellow solid.

[1061] LCMS dwell time 1.29 min [A]. MS (E - ) m / z: 481.2 (M+H).

[1062] 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.96-11.03 (m, 1 H) 8.64-8.84 (m, 3 H) 8.45 (s, 1 H) 6.96-7.27 (m, 1 H) 3.96-4.44 (m, 5 H) 3.65-3.80 (m, 3) H) 3.33 (br d, J=9.54 Hz, 1 H) 3.09-3.25 (m, 2 H) 2.80-3.05 (m, 1 H) 2.54-2.69 (m, 6 H) 2.18 (s, 3 H) 1.21-1.30 (m, 6 H).

[1063] The following examples were prepared according to the general procedure described in Example 326:

[1064]

[1065] Example 328

[1066] 2-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole

[1067]

[1068] Acetic acid (6.76 μL, 0.118 mmol) was added at 0°C to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-2,5-dimethylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.118 mmol) and oxetan-3-one (8.51 mg, 0.118 mmol) in methanol (1 mL). The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (14.84 mg, 0.236 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifugal evaporator to obtain 2-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole) as a pale yellow solid.

[1069] LCMS dwell time 1.88 min [A]. MS (E - ) m / z: 480.2 (M+H).

[1070] The following examples were prepared according to the general procedure described in Example 328.

[1071] Table 37

[1072]

[1073] Example 335

[1074] 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-N,N-dimethylacetamide

[1075]

[1076] TEA (0.016 mL, 0.118 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-2,5-dimethylpiperazine-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 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-N,N-dimethylacetamide (19 mg, 0.037 mmol, 31.3% yield) as a pale yellow solid.

[1077] LCMS dwell time 1.79 min [A]. MS (E - ) m / z: 509.2 (M+H).

[1078] The following examples were prepared according to the general procedure described in Example 335.

[1079] Table 38

[1080]

[1081] Example 339

[1082] 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-methylpropan-2-ol

[1083]

[1084] 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]pyridine-6-yl)-2-((2S,5R)-2,5-dimethylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.118 mmol) and 1-chloro-2-methylpropan-2-ol (12.82 mg, 0.118 mmol) in DMF (1 mL). The resulting solution was heated at 80°C for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-methylpropan-2-ol (14 mg, 0.027 mmol, 22.97% yield) as a pale yellow solid.

[1085] LCMS dwell time 2.13 min [A]. MS (E -) m / z: 496.2 (M+H).

[1086] Example 340

[1087] 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(methylamino)ethane-1-one

[1088]

[1089] Intermediate 340A: tert-butyl (2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-oxoethyl)(methyl)carbamate

[1090]

[1091] To a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-2,5-dimethylpiperazine-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), HATU (44.9 mg, 0.118 mmol) was followed by TEA (0.016 mL, 0.118 mmol). The resulting solution was stirred at room temperature for 12 hours. 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 obtain tert-butyl (2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-oxoethyl)(methyl)carbamate (45 mg, 0.076 mmol, 64.1% yield) as a yellow solid.

[1092] LCMS dwell time 2.09 min [F]. MS (E - ) m / z: 595.2.

[1093] Example 340

[1094] 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(methylamino)ethane-1-one

[1095] To a solution of tert-butyl (2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-oxoethyl)(methyl)carbamate (45 mg, 0.076 mmol) in DCM (2 mL), 4 M hydrochloric acid (1 mL, 32.9 mmol) in dioxane was added dropwise and stirred at room temperature for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 1-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(methylamino)ethane-1-one (22 mg, 0.044 mmol, 58.2% yield) as a pale yellow solid.

[1096] LCMS dwell time 1.34 min [A]. MS (E - ) m / z: 495.2 (M+H).

[1097] The following examples were prepared according to the general procedure described in Example 340.

[1098] Table 39

[1099]

[1100] Example 342

[1101] (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N-methylacetamide

[1102]

[1103] 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]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-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 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (S)-2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N-methylacetamide (8 mg, 0.017 mmol, 22.72% yield) as a pale yellow solid.

[1104] LCMS residence time 1.60 min [A]. MS (E - ) m / z: 481.2 (M+H).

[1105] The following examples were prepared according to the general procedure described in Example 342.

[1106] Table 40

[1107]

[1108] Example 345

[1109] (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-methylpropan-2-ol

[1110]

[1111] 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]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and 1-chloro-2-methylpropan-2-ol (11.21 mg, 0.073 mmol) in DMF (1 mL). The resulting solution was heated at 80°C for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-methylpropan-2-ol (4.1 mg, 8.51 μmol, 11.62% yield) as a pale yellow solid.

[1112] LCMS dwell time 2.09 min [A]. MS (E - ) m / z: 482.2 (M+H).

[1113] Example 346

[1114] (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(dimethylamino)ethane-1-one

[1115]

[1116] 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]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and dimethyl glycine (7.55 mg, 0.073 mmol) in DMF (1 mL). The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 X 10 mL). The crude sample was purified using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (S)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(dimethylamino)ethane-1-one (17 mg, 0.032 mmol, 44.1% yield) as a pale yellow solid.

[1117] LCMS residence time 1.50 minutes [A]. MS (E - ) m / z: 495.2 (M+H).

[1118] The following examples were prepared according to the general procedure described in Example 346.

[1119] Table 41

[1120]

[1121] Example 348

[1122] (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole

[1123]

[1124] TEA (10.21 μL, 0.073 mmol) was added at 0°C to a solution of (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (30 mg, 0.073 mmol) and oxetan-3-one (5.28 mg, 0.073 mmol) in methanol (1 mL). The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (9.21 mg, 0.147 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction product was concentrated, 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifugal evaporator to obtain (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (15 mg, 0.032 mmol, 44.0% yield) as a pale yellow solid.

[1125] LCMS dwell time 1.78 min [A]. MS (E - ) m / z: 466.2 (M+H).

[1126] The following examples were prepared according to the general procedure described in Example 348.

[1127] Table 42

[1128]

[1129] Example 353

[1130] (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N-methylacetamide

[1131]

[1132] 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]pyridine-6-yl)-2-(2-methylpiperazine-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 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (R)-2-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-N-methylacetamide (24 mg, 0.047 mmol, 37.5% yield) as a pale yellow solid.

[1133] LCMS dwell time 1.45 min [A]. MS (E - ) m / z: 467.2 (M+H).

[1134] The following examples were prepared according to the general procedure described in Example 353.

[1135] Table 43

[1136]

[1137] Example 359

[1138] (R)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-methylpropan-2-ol

[1139]

[1140] 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]pyridine-6-yl)-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (50 mg, 0.126 mmol) and 1-chloro-2-methylpropan-2-ol (13.72 mg, 0.126 mmol) in DMF (1 mL). The resulting solution was heated at 80°C for 12 hours. 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (R)-1-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-methylpropan-2-ol (4.2 mg, 8.98 μmol, 7.10% yield) as a pale yellow solid.

[1141] LCMS dwell time 1.68 min [A]. MS (E - ) m / z: 468.2 (M+H).

[1142] Example 360

[1143] (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]thiazole-2-yl)-3-methylpiperazine-1-yl)ethane-1-one

[1144]

[1145] 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]pyridine-6-yl)-2-(2-methylpiperazine-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 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The crude sample was purified using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain (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]thiazole-2-yl)-3-methylpiperazine-1-yl)ethane-1-one (18 mg, 0.037 mmol, 29.3% yield) as a pale yellow solid.

[1146] LCMS dwell time 1.27 min [A]. MS (E - ) m / z: 481.2 (M+H).

[1147] Example 361

[1148] (R)-2-(4-isobutyl-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole

[1149]

[1150] TEA (0.018 mL, 0.126 mmol) was added at 0°C to a solution of (R)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(2-methylpiperazine-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). The resulting solution was stirred at room temperature for 12 hours. Subsequently, sodium cyanoborohydride (15.89 mg, 0.253 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated, 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 using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a Zinbaek centrifugal evaporator to obtain (R)-2-(4-isobutyl-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (27 mg, 0.060 mmol, 47.3% yield) as a pale yellow solid.

[1151] LCMS dwell time 1.27 min [B]. MS (E - ) m / z: 452.2 (M+H).

[1152] The following examples were prepared according to the general procedure described in Example 361.

[1153] Table 44

[1154]

[1155] Examples 368 and 369

[1156] 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-N-(4-(dimethylamino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carboxamide

[1157]

[1158] DIPEA (9.83 μL, 0.056 mmol) was added to a solution of 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-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 hours. The reaction mixture was concentrated to obtain the crude product. The crude sample was purified using Method I by LCMS for purification. After purification with LCMS for purification, fractions containing isomers 1 and 2 were collected and dried individually using a cinnabar centrifugal evaporator to obtain Example 368A (isomer 1) as a pale yellow solid (7.0 mg, 0.014 mmol, 25.7% yield) and Example 368B (isomer 2) as a pale yellow solid (6.1 mg, 0.013 mmol, 22.60% yield).

[1159] Example 368, Isomer 1:

[1160] LCMS dwell time 1.26 min [A]. MS (E - ) m / z: 480.2 (M+H).

[1161] 1 H NMR (400MHz, DMSO-d6) δ 11.66 (s, 1H), 8.83 (s, 1H), 8.53-8.42 (m, 1H), 8.12 (d, J=7.8Hz, 1H), 3.94 (d, J=3.7 Hz, 1H), 2.86-2.71 (m, 1H), 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=11.5 Hz, 4H), 1.37 (d, J=6.8 Hz, 5H).

[1162] Example 369, Isomer 2:

[1163] LCMS dwell time 1.29 min [A]. MS (E - ) m / z: 480.2 (M+H).

[1164] 1 H NMR (400MHz, DMSO-d6) δ 11.66 (s, 1H), 8.83 (s, 1H), 8.47 (s, 1H), 8.23 ​​(d, J=9.3 Hz,1H), 3.91 (s, 1H), 3.78 (br. s., 2H), 2.84-2.72 (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).

[1165] The following examples were prepared according to the general procedure described in Example 368.

[1166] Table 45

[1167]

[1168]

[1169]

[1170]

[1171] Example 391

[1172] 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide

[1173]

[1174] HATU (33.4 mg, 0.088 mmol) was added to a solution of 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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). The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated to obtain the crude product. The crude sample was purified using Method I by LCMS for purification, the fractions containing the product were combined, and dried using a centrifugal evaporator to obtain 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (2.9 mg, 8.52 μmol, 9.69% yield) as a pale yellow solid.

[1175] LCMS dwell time 1.37 min [A]. MS (E - ) m / z: 341.2 (M+H).

[1176] 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (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 = 6.8 Hz, 6H).

[1177] The following examples were prepared according to the general procedure described in Example 391.

[1178] Table 46

[1179]

[1180]

[1181] Example 401

[1182] N-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-1-isopropylpiperidine-4-amine

[1183]

[1184] Intermediate 401A: tert-butyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(hydroxymethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[1185]

[1186] Diisobutyl aluminum hydride (4.44 mL, 5.32 mmol) was added dropwise at -78°C to a solution of 4-(tert-butyl) 2-methyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2,4-dicarboxylate (1.0 g, 2.130 mmol) in toluene (25 mL), and the resulting reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was quenched with 1.5 N HCl (15 mL) at -78°C. The reaction mixture was extracted with EtOAc (3 x 50 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain tert-butyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(hydroxymethyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate (0.9 g, 2.038 mmol, 96% yield) as a yellow solid.

[1187] LCMS dwell time 1.54 min [F]. MS (E - ) m / z: 442.2 (M+H).

[1188] Intermediate 401B: tert-butyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-formyl-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-4-carboxylate

[1189]

[1190] To a solution of 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]thiazole-4-carboxylate (1.0 g, 2.265 mmol) in DCM (25 mL), Celite (0.488 g, 1.310 mmol) was followed by the aliquot addition of pyridinium chlorochromate (0.488 g, 2.265 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was filtered through a layer of Celite and washed with additional DCM (60 mL). The filtrate was concentrated to obtain the crude product. The crude material was purified by eluting with 40% ethyl acetate / petroleum ether using a 24 g silica column by combiflash. After concentrating the fraction, tert-butyl 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-carboxylate (0.65 g, 1.479 mmol, 65.3% yield) was collected as a pale yellow solid.

[1191] LCMS dwell time 3.43 min [C]. MS (E - ) m / z: 44202 (M+H).

[1192] Intermediate 401C: 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carbaldehyde

[1193]

[1194] TFA (3 mL, 38.9 mmol) was added dropwise to a solution of tert-butyl 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-carboxylate (0.65 g, 1.479 mmol) in DCM (10 mL) and stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (25 mL) and washed with a cooled 10% sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-carbaldehyde (0.42 g, 1.237 mmol, 84% yield) as a pale yellow solid.

[1195] LCMS dwell time 2.41 min [C]. MS (E - ) m / z: 440.2 (M+H).

[1196] Example 401

[1197] N-((5-(7,8-dimethy...

Claims

Claim 1 Compound of the following chemical formula (I), its N-oxide, or salt: Here: X is N and Y is S; or X is S and Y is N or CH; R1 is F, Cl, -CN, C 1-4 Alkyl, C 1-3 Fluoroalkyl, -OCH3, or -S(O)2(C 1-3 alkyl) and; G is: ;(iv) 9-circle heterocyclic ring selected from the following: ; or (v) a 10-circle heterocyclic ring selected from the following: And; each R2 independently consists of halo, -CN, -OH, -NO2, C 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), -O(CH2) 1-2 OC(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(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 x S(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), -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazollyl, imidazollyl, pyrimidinyl, triazolyl, or -C(O)(thiazolyl) and;R 2a 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; and each R 2b is independently H, halo, -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), -(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) and; R 2c is R 2a or R 2b Igo;R 2d is R 2a or R 2b is; only R 2c and R 2d One of them is R 2a and R 2c and the other one of R2 is R 2b And;A is:(i) H, -NR y R y , or -CH2NHCH2C(O)NR x R x ;(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)R3, or -NR x C(O)R3; or (iii) R3 and; R3 is: (i) each of 0 to 2 R 3a and 0 to 2 R 3b C substituted with 3-5 (ii) -NR y R y , -NR x (C 1-6 hydroxyalkyl), -NR x (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 (Azetidinyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x (ethyl oxetanil), -NR x (isopropyloxetanil), -NR x (Tetrahydropyranil), -NR x (bicyclo[1.1.1]pentyl), -NR x (CH2(methyloxetanyl)), -NR x (Dioxydotetrahydrothiophenyl), -NR x CH2(hydroxymethylcyclopropyl), -NR x CH2(methylsulfonylcyclopropyl), -NR x CH2(methylcyclobutyl), -NR x HCH2C(O)(morpholinyl), azetidinyl, fluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, pyrrolidinyl, piperazinonil, morpholinyl, dioxothiomorpholinyl, oxazephanil, bicyclo[1.1.1]fentanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, deoxydothiazspiro[3.3]heptanyl, oxaazabicyclo[3.2.1]octanyl, oxazaspiro[3.5]nonanyl, or cyclohexyl substituted with diazspiro[4.4]nonanyl; or (iii) C 1-6 Alkyl, C 1-6 hydroxyalkyl, -(CH2) 1-3 S(O)2(C 1-6 Diazaspiro[3.3]heptanyl substituted with alkyl), oxetanyl, or -CH2(tetrahydropyranyl); and each R 3a is independently F, Cl, C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Fluoroalkyl, C 1-6 hydroxyalkyl, -(CH2) 1-3 O(C 1-3 alkyl), -C(O)(C 1-6 alkyl), -CH2C(O)NR y R y , -NR y R y , -NR x (C 1-4 hydroxyalkyl), -C(O)(CH2) 1-3 NR y R y , -C(O)(C 1-6 alkyl), -(CH2) 0-2 S(O)2(C 1-3 alkyl), -(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 (Oxetanil), -CH2(methyltriazolyl), C 3-6 Cycloalkyl, oxetanyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, -CH2(C 3-6 Cycloalkyl), -CH2(Oxetanil), -CH2(Methyl Oxetanil), -CH2(Tetrahydropyranil), -NR x (C 3-6 cycloalkyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x CH2(methyloxetanyl), or -C(O)(deoxydotetrahydrothiopyranyl); and each R 3b is -CH3 and 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 is and R5 is H, C 1-3 alkyl, or C 1-3 It is a fluoroalkyl; and each R x is independently H or -CH3; and each R y is independently H or C 1-6 It is alkyl; p is 0, 1, or 2. Claim 2 In paragraph 1, a compound in which X is N and Y is S, its N-oxide, or salt. Claim 3 In paragraph 1, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCH3, or -S(O)2(C 1-2 alkyl) and; G is: (iv) 9-membered heterocyclic ring selected from the following: ; or (v) a 10-circle heterocyclic ring selected from the following: And; each R2 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, and R 2a Ga 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; and each R 2b independently H, F, Cl, -CN, -NR x R x , C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 hydroxyalkyl, -(CH2) 0-2 O(C 1-2 alkyl), -(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) and; A is: (i) -CH2NHCH2C(O)NR x R x ;(ii) -CR x R x R3, -CH2NR x R3, -CH2NR x CH2R3, -C(O)NR x R3, -C(O)NR x R4, -C(O)R3, or -NR x C(O)R3; or (iii) R3 and; R3 is: (i) each of 0 to 1 R 3a and 0 to 2 R 3b (ii) -NR substituted with azetidinyl, oxetanil, cyclopropyl, pyrrolidinyl, pyrrolidinonil, piperidinyl, piperazinil, piperazinonil, morpholinil, deoxydothiomorpholinil, oxazephanil, diazaspiro[3.3]heptanil, deoxydothiaazaspiro[3.3]heptanil, oxaazaspiro[3.3]heptanil, or oxaazaspiro[3.5]nonanil; 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 (Azetidinyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x (ethyl oxetanil), -NR x (isopropyloxetanil), -NR x (Tetrahydropyranil), -NR x (bicyclo[1.1.1]pentyl), -NR x (CH2(methyloxetanyl)), -NR x (Dioxydotetrahydrothiophenyl), -NR x CH2(hydroxymethylcyclopropyl), -NR x CH2(methylsulfonylcyclopropyl), -NR x CH2(methylcyclobutyl), -NR x HCH2C(O)(morpholinyl), azetidinyl, fluoroazetidinyl, hydroxyazetidinyl, methoxyazetidinyl, hydroxy(trifluoromethyl)azetidinyl, bis(hydroxymethyl)azetidinyl, pyrrolidinyl, piperazinonil, morpholinyl, dioxothiomorpholinyl, oxazephanil, bicyclo[1.1.1]fentanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, deoxydothiazspiro[3.3]heptanyl, oxaazabicyclo[3.2.1]octanyl, oxazaspiro[3.5]nonanyl, or cyclohexyl substituted with diazspiro[4.4]nonanyl; or (iii) C 1-4 Alkyl, C 1-4 hydroxyalkyl, -(CH2) 1-2 S(O)2(C 1-3 Diazaspiro[3.3]heptanyl substituted with alkyl), oxetanyl, or -CH2(tetrahydropyranyl); and each R 3a independently F, Cl, C 1-5 Alkyl, C 1-3 Cyanoalkyl, C 1-3 Fluoroalkyl, C 1-4 hydroxyalkyl, -(CH2) 1-2 O(C 1-2 alkyl), -C(O)(C 1-3 alkyl), -CH2C(O)NR x R x , -NR y R y , -NH(C 1-4 hydroxyalkyl), -C(O)(CH2) 1-3 NR x R x , -C(O)(C 1-3 alkyl), -(CH2) 0-2 S(O)2(C 1-2 alkyl), -(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 (Oxetanil), -CH2(methyltriazolyl), cyclobutyl, oxetanil, pyrrolidinyl, morpholinil, tetrahydropyranil, -CH2(C 3-4 Cycloalkyl), -CH2(Oxetanil), -CH2(Methyl Oxetanil), -CH2(Tetrahydropyranil), -NR x (Cyclobutyl), -NR x (Oxetanil), -NR x (methyloxetanyl), -NR x A compound in which CH2(methyloxetanyl), or -C(O)(deoxydotetrahydrothiopyranyl) is; and R5 is H, -CH3, -CH2CH3, -CF3, -CH2CHF2, or -CH2CF3, its N-oxide, or salt. Claim 4 In paragraph 1, R1 is -CH3, -CH2CH3, or -CH(CH3)2; and G is and; each R2 is independently -CN, -CH3, or -OCH3 and A is: (i) -CH2NHCH2C(O)NH2; (ii) -CH2R3, -CH2NHR3, -CH2NHCH2R3, -C(O)NHR3, -C(O)NR x R4, or -C(O)R3; or (iii) 0 to 1 R each 3a Cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl, or diazaspiro[3,3]heptanyl substituted with; and R3 each having 0 to 1 R 3a and 0 to 2 R 3b Azetidinyl, oxetanil, cyclopropyl, cyclobutyl, pyrrolidinyl, pyrrolidinonil, piperidinyl, piperazinil, piperazinonil, morpholinil, deoxydothiomorpholinil, oxazepanil, diazaspiro[3.3]heptanil, deoxydothiaazaspiro[3.3]heptanil, oxaazaspiro[3.3]heptanil, or oxaazaspiro[3.5]nonanil substituted with; R 3a A 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)CH2CH2S(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(methyl oxetanyl), -CH2(tetrahydropyranyl), -C(O)(deoxydotetrahydrothiopyranyl), -NH(cyanocyclopropyl), -NH(cyclobutyl), -NH(methylcyclobutyl), -NH(oxetanyl), -NH(methyl oxetanyl), -NH(ethyl oxetanyl), -NH(isopropylpiperidinyl), -NH(tetrahydropyranyl), -NH(bicyclo[1.1.1]pentyl), -NHCH2(methyl oxetanyl), -NH(Dioxydotetrahydrothiophenyl), -NHCH2(Hydroxymethylcyclopropyl), -NHCH2(Methylsulfonylcyclopropyl), -NHCH2(Methylcyclobutyl), -NHCH2C(O)(Morfollinyl), Cyclobutyl, Azetidinyl, Fluorozetidinyl, Difluoroazetidinyl, Hydroxyazetidinyl, Methoxyazetidinyl, Hydroxy(Trifluoromethyl)azetidinyl, Bis(Hydroxymethyl)azetidinyl, Oxetanil, Pyrrolidinyl, Acetamidopyrrolidinyl, Piperazinonil, Tetrahydropyranil, Morfollinyl, Dioxothiomorpholinyl, Oxazepanil, Bicyclo[1.1.1]fentanyl, Azaspiro[3.3]heptanil, Oxazaspiro[3.3]heptanyl, Deoxydothiazspiro[3.3]heptanil, oxaazabicyclo[3.2.1]octanil, oxaazspiro[3.5] Nonanyl, or diazaspiro[4.4]nonanyl; R4 is H, -CH2CHF2, -CH2CF3, -CH2CH2N(CH3)2, -CH2R3, -CH2CR. x R x R3, or -(CH2)3R3; R5 is H or -CH2CF3; a compound in which p is 0, 1, or 2, its N-oxide, or salt. Claim 5 In paragraph 1, A is each 0 to 1 R 3a A compound that is cyclohexyl, piperidinyl, piperazinyl, methylpiperazinyl, dimethylpiperazinyl, or diazaspiro[3.3]heptanyl substituted with, its N-oxide, or salt. Claim 6 In paragraph 1, A is a compound in which A is -CH2R3, -CH2NHR3, -CH2NHCH2R3, or -CH2NHCH2C(O)NH2, its N-oxide, or salt. Claim 7 In paragraph 1, A is -C(O)NHR3 or -C(O)NR x A compound of R4, its N-oxide, or salt. Claim 8 In paragraph 1, A is a compound in which A is -C(O)R3, its N-oxide, or salt. Claim 9 In paragraph 1, a compound in which X is S and Y is N, its N-oxide, or salt. Claim 10 In paragraph 1, a compound in which X is S and Y is CH, its N-oxide, or salt. Claim 11 In claim 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 (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-dimethylpyridine-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-carbonitrile (5); 2-(dimethylamino)-1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethane-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]thiazole-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]thiazole-2-yl)piperidin-1-yl)-N-methylacetamide (8); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4-(2,2,2-trifluoroethyl)-2-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (9); 6-isopropyl-2-(1-isopropylpiperidine-4-yl)-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (10); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (11);6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (12); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-neopentylpiperidine-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-methyloxetane-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-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]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)-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]thiazole-2-yl)piperidin-1-yl)ethane-1-one (19); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (20); 6-isopropyl-2-(1-isopropylpiperidine-4-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (21);6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (22); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (23); 2-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (24); 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(1-isopropylpiperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (25); 5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (26); 5-(2,6-dimethylpyridine-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-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)ethanol-1-one (28); 1-(4-(5-(2,6-dimethylpyridine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidin-1-yl)-2-methylpropan-2-ol (29); 2-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-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]thiazole-2-yl)piperidin-1-yl)ethane-1-one (32);6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidine-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)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (34); 6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (35); 6-isopropyl-2-(1-isopropylpiperidine-4-yl)-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole (36); 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (37); 5-(6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (38); 5-(2-(1-(dimethylglycyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)quinoline-8-carbonitrile (39); 2-(4-(5-(8-cyanoquinoline-5-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (40); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (41); 5-(6-isopropyl-2-(piperidin-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (42); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-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]pyridine-6-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]pyridine-6-yl)-6-isopropyl-2-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (46); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-((3-methyloxetane-3-yl)methyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (47); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole (48); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-methylpiperidine-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)piperidine-4-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (53);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(1-(2-ethylbutyl)piperidine-4-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (54); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidine-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]thiazole-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]thiazole-2-yl)piperidin-1-yl)ethane-1-one (59); 5-(6-isopropyl-2-(1-(oxetane-3-yl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (60); 5-(6-isopropyl-2-(1-(2-(methylsulfonyl)ethyl)piperidine-4-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (61); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N,N-dimethylacetamide (62); 2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)-N-methylacetamide (63);2-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-1-yl)acetamide (64); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (65-66); (1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)azetidine-3,3-diyl)dimethanol (67); 6-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-methyloxetane-3-amine (70-71); N-ethyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (72-73); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (74-75); 2-(4-(azetidine-1-yl)cyclohexyl)-6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (76-77); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (78-79); 4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl) thiomorpholine 1,1-dioxide (82-83);1-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (84-85); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexane-1-amine (86-87); N-isopropyl-4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (88-89); (R)-3-fluoro-4-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylbutan-2-ol (90-91); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexane-1-amine (92-93); 3-ethyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (94-95); 6-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-thi-6-azaspiro[3,3]heptane 2,2-dioxide (96-97); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(pyrrolidine-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazolo-2-yl)cyclohexyl)pyrrolidine-3-yl)acetamide (100-101);4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-1,4-oxazepan (102-103); (1R,5S)-8-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)cyclopropane-1-carbonitrile (106-107); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(1-methylcyclobutyl)cyclohexane-1-amine (108-109); 2-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-7-oxa-2-azspiro[3.5]nonane (110-111); 7-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-7-azspiro[3.5]nonane (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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (114-115); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-azspiro[3.3]heptane-6-amine (116-117); 1-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-(trifluoromethyl)azetidine-3-ol (118-119);4-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazine-2-one (120-121); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(3-methoxyazetidine-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (122-123); N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-N-methyloxetane-3-amine (124-125); 2-(dimethylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-2-yl)cyclohexyl)methansulfonamide (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]thiazole-2-yl)cyclohexyl)acetamide (128); 2-(isobutylamino)-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)acetamide (129); N-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (130-131); N-ethyl-4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazolo-2-yl)-N-methylcyclohexane-1-amine (132);4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexane-1-amine (134-135); 6-(4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (140-141); (1-(((4-(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)methyl)cyclopropyl)methanol (142-143); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-methyloxetane-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]thiazole-2-yl)cyclohexyl)-1,4-oxazepan (146-147); 4-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazine-2-one (148-149); 6-isopropyl-2-(4-(3-methoxyazetidine-1-yl)cyclohexyl)-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (150-151);N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (152-153); 6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(pyrrolidine-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methylcyclohexane-1-amine (158-159); N-(4-(6-isopropyl-5-(7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (160-161); 2-((4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)(methyl)amino)-N,N-dimethylacetamide (162-163); 4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-methyl-N-(2-(methylsulfonyl)ethyl)cyclohexane-1-amine (164-165); 1-isopropyl-N-(4-(6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-N2-methylethane-1,2-diamine (170-171); 4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)cyclohexane-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]thiazole-2-yl)-N-methylcyclohexane-1-amine (174-175); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)bicyclo[1.1.1]pentan-1-amine (176-177); N-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (178-179); 6-(4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-6-azaspiro[3.3]heptane (180-181); 1-((4-(6-isopropyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (182-183); N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)oxetane-3-amine (184-185); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(2-methoxy-2-methylpropyl)cyclohexane-1-amine (186-187);5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(3-methoxyazetidine-1-yl)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole (188-189); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-ethyl-N-methylcyclohexane-1-amine (190-191); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropylcyclohexane-1-amine (194-195); 1-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-2-methylpropan-2-ol (196-197); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-neopentylcyclohexane-1-amine (198-199); N-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)tetrahydro-2H-pyran-4-amine (200-201); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((1-methylcyclobutyl)methyl)cyclohexane-1-amine (202-203); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-N,N-dimethylacetamide (204-205);2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-1-morpholinoethane-1-one (206-207); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)-N-methylacetamide (208-209); 2-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)acetamide (210-211); 4-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)morpholine (212-213); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)cyclohexane-1-amine (214-215); 2-(4-(azetidine-1-yl)cyclohexyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]thiazole-2-yl)cyclohexyl)piperazine-2-one (220-221); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropyl-N-methylcyclohexane-1-amine (222-223);1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)azetidine-3-ol (224-225); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(4-(3-fluoroazetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (226-227); 4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isobutyl-N-methylcyclohexane-1-amine (228-229); 3-((4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)amino)tetrahydrothiophene 1,1-dioxide (230-232); 6-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-thi-6-azaspiro[3,3]heptane 2,2-dioxide (233-234); 1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-3-(trifluoromethyl)azetidine-3-ol (235-236); 7-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-2-oxa-7-azspiro[3.5]nonane (237-238); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)-7-oxa-2-azspiro[3.5]nonane (239-240); 5-(6-isopropyl-2-(4-(oxetane-3-ylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (241-242);5-(6-isopropyl-2-(4-((2-methoxy-2-methylpropyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (243-244); 5-(2-(4-(2-oxa-6-azaspiro[3,3]heptane-6-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (245-246); 5-(2-(4-(ethyl(methyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (247-248); 5-(6-isopropyl-2-(4-((tetrahydro-2H-pyran-4-yl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (249-250); 5-(2-(4-((2-hydroxy-2-methylpropyl)amino)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (251-252); 5-(6-isopropyl-2-(4-(isopropylamino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (253-254); 5-(2-(4-(azetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (255-256); 5-(6-isopropyl-2-(4-(((1-(methylsulfonyl)cyclopropyl)methyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (257-258); 4-(4-(6-isopropyl-5-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl)piperazine-2-one (259-260); 5-(6-isopropyl-2-(4-(isopropyl(methyl)amino)cyclohexyl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (261-262);5-(2-(4-(3-hydroxyazetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (263-264); 5-(2-(4-(3-fluoroazetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (265-266); 5-(2-(4-(3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)cyclohexyl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (267-268); 6-(4-(6-ethyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-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]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)cyclohexyl) oxetane-3-amine (271-272); N-(4-(5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-methyl-4H-pyrrolo[3,2-d]thiazole-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]thiazole-2-yl)cyclohexyl)piperazine-2-one (275-276); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2-(piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (278); 5-(6-isopropyl-2-(piperazine-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)piperazine-1-yl)-2-(dimethylamino)ethane-1-one (280);1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-2-methylpropan-2-ol (281); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(2-(methylsulfonyl) ethyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (282); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-N,N-dimethylacetamide (283); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)-N-methylacetamide (284); 2-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperazine-1-yl)acetamide (285); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (286); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (287); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-isopropylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (288); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-((3-methyloxetane-3-yl)methyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (289);1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(3-methyloxetane-3-yl)piperidine-4-amine (290); 1-((1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-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]thiazole-2-yl)-N-isopropyl-N-methylpiperidine-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]thiazole-2-yl)piperidine-4-amine (293); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(2-methoxy-2-methylpropyl)piperidine-4-amine (294); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((3-methyloxetane-3-yl)methyl)piperidine-4-amine (295); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-(oxetane-3-yl)piperidine-4-amine (296); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-isopropylpiperidine-4-amine (297); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-ethyl-N-methylpiperidine-4-amine (298);1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)piperidine-4-amine (299); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(6-isobutyl-2,6-diazaspiro[3,3]heptane-2-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (300); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (301); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole (302); 1-(6-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,6-diazaspiro[3,3]heptan-2-yl)-2-methylpropan-2-ol (303); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3,3]heptan-2-yl)-4H-pyrrolo[3,2-d]thiazole (304); 5-(6-isopropyl-2-(6-(2-(methylsulfonyl)ethyl)-2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (305); 5-(6-isopropyl-2-(6-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (306); 5-(6-isopropyl-2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3,3]heptane-2-yl)-4H-pyrrolo[3,2-d]thiazole-5-yl)-1,3,4-trimethylpyridine-2(1H)-one (307);(R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole, HCl (308); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-2,5-dimethylpiperazine-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-methylpiperazine-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-methylpiperazine-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-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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)piperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)-N-methylacetamide (315); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (316);(R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (317); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-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-dimethylpiperazine-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-methylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (320); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (321); (R)-2-(4-cyclobutyl-2-methylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (322); (R)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(4-(1-isopropylpiperidin-4-yl)-2-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (323); (R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(methylamino)ethan-1-one (326);(R)-1-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(dimethylamino)ethane-1-one (327); 2-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (328); 2-((2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (329); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (330); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-((2S,5R)-4-ethyl-2,5-dimethylpiperazine-1-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (331); 2-((2S,5R)-4-(cyclopropylmethyl)-2,5-dimethylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (332); 2-((2S,5R)-4-cyclobutyl-2,5-dimethylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (333); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-((2S,5R)-4-isopropyl-2,5-dimethylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (334);2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-N,N-dimethylacetamide (335); 2-((2R,5S)-4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-N-methylacetamide (336); 2-((2S,5R)-2,5-dimethyl-4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-2,5-dimethylpiperazine-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-dimethylpiperazine-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]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(methylamino)ethane-1-one (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]thiazole-2-yl)-2,5-dimethylpiperazine-1-yl)-2-(dimethylamino)ethane-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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)piperazine-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-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)-2-(dimethylamino)ethan-1-one (346); (S)-(4-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-3-methylpiperazine-1-yl)(1,1-deoxydotetrahydro-2H-thiopyran-4-yl)methanone (347); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (348); S)-2-(4-cyclobutyl-2-methylpiperazine-1-yl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (349); (S)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-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-methylpiperazine-1-yl)-4H-pyrrolo[3,2-d]thiazole (351);(S)-2-(4-(cyclopropylmethyl)-2-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)acetamide (355); (R)-6-isopropyl-2-(2-methyl-4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (356); (R)-6-isopropyl-2-(4-(2-methoxyethyl)-2-methylpiperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-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]thiazolo[2-yl]-3-methylpiperazine-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]thiazolo[2-yl]-3-methylpiperazine-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]thiazole-2-yl)-3-methylpiperazine-1-yl)ethan-1-one (360);(R)-2-(4-isobutyl-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (361); (R)-2-(4-cyclobutyl-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (362); (R)-6-isopropyl-2-(2-methyl-4-(oxetane-3-yl)piperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (363); (R)-6-isopropyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (364); (R)-2-(4-(cyclopropylmethyl)-2-methylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (365); (R)-6-isopropyl-2-(4-isopropyl-2-methylpiperazine-1-yl)-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (366); (R)-2-(2,4-dimethylpiperazine-1-yl)-6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-4H-pyrrolo[3,2-d]thiazole (367); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-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]pyridine-6-yl)-6-isopropyl-N-(3-(2-oxopyrrolidine-1-yl)propyl)-4H-pyrrolo[3,2-d]thiazole-2-carboxamide (371); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)(1,1-deoxydothiomorpholino)methanone (373); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-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)piperazine-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]thiazole-2-yl)(4-(dimethylamino)piperidine-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]thiazole-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]thiazole-2-carbonyl)piperazine-2-one (378); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)(3-fluoroazetidine-1-yl)methanone (379); (5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)(4-isopropylpiperazine-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-(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-4H-pyrrolo[3,2-d]thiazole-2-yl)(3-(dimethylamino)azetidine-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]thiazole-2-yl)(4-(methylsulfonyl)piperazine-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]thiazole-2-carboxamide (385); 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-N-(morpholine-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)piperazine-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]thiazole-2-yl)(1,4-oxazepan-4-yl)methanone (394); (4-(dimethylamino)piperidine-1-yl)(6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)methanone (395); (6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrrolo[3,2-d]thiazole-2-yl)(3-methoxyazetidine-1-yl)methanone (396); 6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(oxetane-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]thiazole-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]thiazole-2-yl)methyl)amino)acetamide (402); 6-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-2-thi-6-azspiro[3.3]heptane 2,2-dioxide (403); 2-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-7-oxa-2-azspiro[3.5]nonane (404); 1-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)-N-((1-(methylsulfonyl)cyclopropyl)methyl)methaneamine (405); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)piperazine-2-one (406); 4-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)morpholine (407); 6-((5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (408); 2-((2,6-diazaspiro[3,3]heptane-2-yl)methyl)-5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-6-isopropyl-4H-pyrrolo[3,2-d]thiazole (409); 6-isopropyl-5-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-2-(piperidine-4-yl)-4H-pyrrolo[2,3-d]thiazole (410);6-isopropyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-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]pyridine-6-yl)-2-(1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-pyrrolo[2,3-d]thiazole (412); or a compound that 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), its N-oxide, or salt.; Claim 12 A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in a therapy for treating autoimmune diseases or chronic inflammatory diseases; and a pharmaceutically acceptable carrier. Claim 13 A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in a therapy for treating autoimmune diseases or chronic inflammatory diseases. Claim 14 A pharmaceutical composition according to claim 13, wherein the 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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