Triazole-substituted imidazo[1,2-a]pyrimidines as cGAS inhibitors

Abstract

The present invention relates to compounds, compositions containing same, and their use in the treatment of various disorders, particularly autoimmune, autoinflammatory, or immune-mediated conditions, such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and lupus nephritis.

Description

[Technical Field]

[0001] The present invention relates to compounds, compositions containing same, and their use in the treatment of various disorders, particularly autoimmune, autoinflammatory, or immune-mediated conditions such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis, scleroderma, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), acute kidney injury, chronic kidney disease, diabetic kidney disease or injury, APOL1 nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, idiopathic pulmonary fibrosis, interstitial lung disease, myocardial infarction, stroke, cardiac hypertrophy / heart failure, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), in particular systemic lupus erythematosus, cutaneous lupus erythematosus, and lupus nephritis. [Background technology]

[0002] Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that mediates the production of type I interferons and proinflammatory cytokines in response to dsDNA (Sun et al., Science, 33(6121), pp. 786-791, 2013; Cai et al., Mol Cell, 54(2), pp. 289-296, 2014). In the absence of DNA, cGAS exists in an autoinhibited state. Binding to DNA induces a conformational change in the active site, which catalyzes the synthesis of cyclic GMP-AMP (cGAMP) from ATP and GTP (Zhang et al., Cell Rep, 6(3), pp. 421-430, 2014; Gao et al., Cell, 153(5), pp. 1094-1107, 2013; Civril et al., Nature, 498(7454), pp. 332-337, 2013). The generated cGAMP functions as a second messenger that binds to and activates stimulator of interferon genes (STING). Activated STING recruits TANK-binding kinase 1 (TBK1), which phosphorylates STING and subsequently the transcription factor IFN regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates to the nucleus, where it functions with nuclear factor kB (NF-kB), a transcription factor also activated by STING, to activate the expression of type I IFNs and proinflammatory cytokines (Ablasser and Chen, Science, 363(6431), eaat8657, 2019).

[0003] The cGAS-STING pathway has evolved as a primary defense mechanism for detecting microbial infections, but activation of cGAS by self-DNA has been associated with several monogenic diseases (AGS, FCL, RVCL), as well as multifactorial autoimmune / inflammatory diseases. Summary of the Invention

[0004] Therapeutic targeting of the cGAS-STING pathway with small molecule cGAS inhibitors may be beneficial for a wide range of autoinflammatory, autoimmune, and immune-mediated diseases. Thus, there is a need for novel compounds capable of inhibiting the cGAS pathway.

[0005] In a first aspect, the present invention provides a compound of formula (I)

[0006] [ka]

[0007] (In the formula, R 1 is hydrogen or a prodrug moiety, R 2 is hydrogen, halo, cyano, nitro, C 1~3 Alkyl, halo(C 1~3 ) alkyl, halo(C 1~3 )alkoxy, -S(O)R 7 , -SO2R 7 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 , -CO2R 7 C 1~3 Alkyl, halo(C 1~3 ) alkyl and halo(C 1~3 ) Alkoxy is hydroxyl or -NR 7 R 8 and optionally substituted by R 3 is C 1~3 Alkyl, -C(O)R 8 or a 5- or 6-membered heteroaryl optionally substituted with a prodrug moiety; Each R 4 , R 5 and R 6 are independently -LY, Each L independently represents a bond, -(CR a R b ) n -, -O-, (CR a R b ) n O-, -O(R a R b ) n -or- (CR a R b) n O(CR a R b ) m - selected from each n or m is independently 1, 2, or 3; Each R a and R b is independently selected from hydrogen, halo, and methyl; Each Y is independently hydrogen, halo, hydroxyl, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, halo(C 2~4 ) alkenyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -S(O)R 10 , -SO2NR 9 R 10 , -N(R 10 )SO2R 10 , -CF2CH2OR 10 phenyl, 5- or 6-membered heteroaryl and 4- to 10-membered heterocycloalkyl rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; 3~7 The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are independently selected from halo, hydroxyl, —C(O)R 10 , Oxo, C 1~4 Alkyl, halo(C 1~4 ) alkyl and C 1~4 hydroxyalkyl; or R 4 and R 5are taken together with the carbon atoms to which they are attached to form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, oxo, -C(O)R 10 and -SO2R 10 and optionally substituted with 1, 2 or 3 substituents selected from R 7 and R 8 is hydrogen and C 1~4 independently selected from alkyl, R 9 are independently hydrogen, C 1~4 Alkyl, -C(O)C 1~4 Alkyl and halo(C 1~4 ) alkyl; R 10 are independently hydrogen and C 1~6 alkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0008] In a second aspect, the present invention provides a compound of formula (I)

[0009] [ka]

[0010] (In the formula, R 1 is hydrogen or a prodrug moiety, R 2 is hydrogen, halo, cyano, nitro, C 1~3 Alkyl, halo(C 1~3) alkyl, halo(C 1~3 )alkoxy, -S(O)R 7 , -SO2R 7 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 , -CO2R 7 C 1~3 Alkyl, halo(C 1~3 ) alkyl and halo(C 1~3 ) Alkoxy is hydroxyl or -NR 7 R 8 and optionally substituted by R 3 is imidazolyl or pyrazolyl, and R 3 is C 1~3 Alkyl, -C(O)R 8 or may be substituted with a prodrug moiety, Each R 4 , R 5 and R 6 are independently -LY, Each L independently represents a bond, -(CR a R b ) n -, -O-, -(CR a R b ) n O-, -O(R a R b ) n -or- (CR a R b ) n O(CR a R b ) m - selected from each n or m is independently 1, 2, or 3; Each R a and R b is independently selected from hydrogen or methyl; Each Y is independently hydrogen, halo, hydroxyl, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 2~4 Alkenyl, C1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, halo(C 2~4 ) alkenyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -S(O)R 10 , -SO2NR 9 R 10 , -N(R 10 )SO2R 10 , -CF2CH2OR 10 phenyl, 5- or 6-membered heteroaryl and 4- to 10-membered heterocycloalkyl rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; 3~7 The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are independently selected from halo, hydroxyl, —C(O)R 10 , Oxo, C 1~4 Alkyl, halo(C 1~4 ) alkyl and C 1~4 hydroxyalkyl; or R 4 and R 5 are taken together with the carbon atoms to which they are attached to form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, oxo, -C(O)R 10 and -SO2R 10 and optionally substituted with 1, 2 or 3 substituents selected from R 7 and R 8 is hydrogen and C 1~3 independently selected from alkyl, R 9are independently hydrogen, C 1~4 Alkyl, -C(O)C 1~4 Alkyl and halo(C 1~4 ) alkyl; R 10 are independently hydrogen and C 1~6 alkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0011] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0012] In a fourth aspect, the present invention provides a method of treating an autoimmune, autoinflammatory, or immune-mediated condition in a human in need thereof, comprising administering to said human a therapeutically effective amount of a compound of the invention disclosed herein.

[0013] In a fifth aspect, the present invention provides a compound of the invention disclosed herein for use in therapy.

[0014] In a sixth aspect, the present invention provides the use of a compound of the invention disclosed herein in the manufacture of a medicament for use in the treatment of an autoimmune, autoinflammatory, or immune-mediated condition. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition As used herein, the term halo refers to a chloro, fluoro, bromo or iodo substituent.

[0016] As used herein, the term cyano refers to the group -CN.

[0017] As used herein, the term nitro refers to the group —NO 2 .

[0018] As used herein, the term hydroxyl refers to an —OH group.

[0019] As used herein, the term "prodrug" refers to a compound that undergoes a rapid chemical change under physiological conditions to confer pharmacological activity to the parent compound. The term "prodrug moiety" refers to the chemical portion of a prodrug that is released under physiological conditions to form the active parent compound.

[0020] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon radical having the specified number of carbon atoms. For example, "C 1~6 The term "alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, sec-butyl, isobutyl and tert-butyl), pentyl and hexyl. 1~4 The term "alkyl" refers to an alkyl group having from 1 to 4 carbon atoms.

[0021] The term "cycloalkyl" as used herein refers to a non-aromatic saturated monocyclic hydrocarbon ring containing the specified number of carbon atoms. For example, "C 3~7 "Cycloalkyl" refers to a cycloalkyl group containing from 3 to 7 carbon atoms. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0022] As used herein, the term "alkylene" refers to a divalent radical derived from a linear or branched saturated hydrocarbon group, e.g., of 1 to 6 carbon atoms (C 1~6Exemplary groups include, but are not limited to, -CH2- (methylene), -CH2CH2- (ethylene), -CH2CH2CH2- (propylene), and -CH2CH(CH3)2- (iso-butylene).

[0023] As used herein, "C 2~4 The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing the specified number of carbon atoms and at least one double bond. For example, "C 2~4 Alkenyl" has 2 to 4 carbon atoms. Exemplary groups include, but are not limited to, ethenyl and propenyl.

[0024] The term "alkoxy" as used herein refers to an -O-alkyl group, i.e., an alkyl group attached through an oxygen linking atom, where "alkyl" is defined above. For example, "C 1~4 The term "alkoxy" refers to an alkoxy group having from 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

[0025] As used herein, the term "halo(C 1~4 "Halo(C)alkyl" is intended to mean a radical that is a straight or branched chain carbon radical, having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of the alkyl portion containing from one to four carbon atoms. Exemplary groups include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Thus, halo(C 1~2 ) The term alkyl refers to a radical having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of the alkyl portion containing 1 to 2 carbon atoms.

[0026] As used herein, "halo(C 1~4 The term "alkoxy" refers to a straight or branched chain hydrocarbon radical having at least one and up to four carbon atoms and one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms, with the radical being attached through an oxygen linking atom. Exemplary groups include, but are not limited to, -OCHF (difluoromethoxy), -OCF (trifluoromethoxy), and -OCH(CF) (hexafluoroisopropoxy).

[0027] As used herein, "C 1~4 The term "thioalkyl" refers to an -S-alkyl group, i.e., an alkyl group attached through a sulfur linking atom, where "alkyl" is defined above. For example, "C 1~4 The term "thioalkyl" refers to a thioalkyl group having from 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thio-isopropyl, and the like.

[0028] As used herein, "C 1~6 The term "hydroxyalkyl" is intended to mean a radical having one or more hydroxy groups at one or more carbon atoms of the alkyl portion containing from 1 to 6 carbon atoms, and which is a straight or branched chain carbon radical. Exemplary groups include, but are not limited to, hydroxymethyl (-CHOH), 2-hydroxyethyl (-CHCHOH), and hydroxy-isopropyl.

[0029] As used herein, "C 1~4 The term "cyanoalkyl" is intended to mean a radical having one or more cyano groups at one or more carbon atoms of the alkyl portion containing from one to four carbon atoms, and which is a straight or branched chain carbon radical.

[0030] As used herein, "halo(C 2~4 The term "alkenyl" refers to a straight or branched chain hydrocarbon radical having at least two and up to four carbon atoms and at least one double bond and one or more halogen atoms, which can be the same or different, attached to one or more carbon atoms. Exemplary groups include, but are not limited to, -CH=CHF, -CH=CF2, and -CF=CF2.

[0031] As used herein, the term "5- or 6-membered heteroaryl" refers to a group or moiety containing an aromatic monovalent monocyclic radical containing 5 or 6 ring atoms, including at least one carbon atom and at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom and optionally one, two, or three additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain one, two, or three nitrogen ring heteroatoms. Exemplary groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0032] As used herein, the term "five-membered nitrogen-containing heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic radical containing five ring atoms and containing at least one carbon atom, at least one nitrogen, and optionally at least one other heteroatom independently selected from nitrogen, oxygen, and sulfur. Exemplary groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0033] As used herein, the term "heteroarylene" refers to a group or moiety that includes an aromatic divalent monocyclic or bicyclic radical containing from 5 to 10 ring atoms, independently including at least one heteroatom selected from nitrogen, oxygen, and sulfur. For example, the term "heteroarylene" refers to a group or moiety that includes an aromatic divalent monocyclic or bicyclic radical containing from 5 to 10 ring atoms, independently including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

[0034] As used herein, the term "heterocycloalkyl" refers to a non-aromatic saturated monocyclic or bicyclic radical containing the specified number of atoms and including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. For example, the term "4- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl group having from 4 to 10 atoms.

[0035] As used herein, the term "5-8 membered monocyclic or bicyclic ring" refers to a ring which may be saturated or unsaturated and which contains from 5 to 8 ring atoms.

[0036] As used herein, the term "bicyclic ring" may refer to a bridged, fused, or spiro bicyclic group.

[0037] As used herein, the term "optionally substituted" indicates that a group can be unsubstituted or can be substituted with one or more substituents as defined herein. The term "substituted" in reference to a group indicates that a hydrogen atom attached to a member atom within the group is replaced with one of the defined substituents. In cases where a group can be selected from several alternative groups, the selected groups can be the same or different.

[0038] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0039] The term "treatment" refers to ameliorating or stabilizing a particular condition, reducing or eliminating the symptoms of a condition, slowing or eliminating the progression of a condition, and preventing or delaying the recurrence of a condition in a previously affected patient or subject.

[0040] The term "prevention" refers to the avoidance of a specified disease in a subject not suffering from the specified disease.

[0041] The term "compound(s) of the invention" refers to a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0042] The term "therapeutically effective amount" refers to the amount of a compound of the present invention that induces a desired biological response in the human body, which may vary depending on the compound, the disease and its severity, and the age and weight of the subject being treated.

[0043] Reference to a compound of formula (I) includes a reference to any one of formulae (IA), (IAA), (IB), (IBB), (IC) and (ICC).

[0044] Statement of the Invention In a first aspect, the present invention provides a compound of formula (I)

[0045] [ka]

[0046] (In the formula, R 1 is hydrogen or a prodrug moiety, R 2 is hydrogen, halo, cyano, nitro, C 1~3 Alkyl, halo(C 1~3 ) alkyl, halo(C 1~3 )alkoxy, -S(O)R 7 , -SO2R 7 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 , -CO2R 7 C 1~3 Alkyl, halo(C 1~3 ) alkyl and halo(C 1~3 ) Alkoxy is hydroxyl or -NR 7 R 8 and optionally substituted by R 3 is C 1~3 Alkyl, -C(O)R 8 or a 5- or 6-membered heteroaryl optionally substituted with a prodrug moiety; Each R 4 , R 5 and R 6 are independently -LY, Each L independently represents a bond, -(CR a R b ) n -, -O-, (CR a R b ) n O-, -O(R a R b ) n -or- (CR a R b ) n O(CR a R b ) m - selected from each n or m is independently 1, 2, or 3; Each R a and R b is independently selected from hydrogen, halo, and methyl; Each Y is independently hydrogen, halo, hydroxyl, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, halo(C 2~4 ) alkenyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -S(O)R 10 , -SO2NR 9 R 10 , -N(R 10 )SO2R 10 , -CF2CH2OR 10 phenyl, 5- or 6-membered heteroaryl and 4- to 10-membered heterocycloalkyl rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; 3~7 The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are independently selected from halo, hydroxyl, —C(O)R 10 , Oxo, C 1~4 Alkyl, halo(C 1~4 ) alkyl and C 1~4 hydroxyalkyl; or R 4 and R 5 are taken together with the carbon atoms to which they are attached to form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, oxo, -C(O)R 10 and -SO2R 10 and optionally substituted with 1, 2 or 3 substituents selected from R 7 and R 8 is hydrogen and C 1~4 independently selected from alkyl, R 9 are independently hydrogen, C 1~4 Alkyl, -C(O)C 1~4 Alkyl and halo(C 1~4 ) alkyl; R 10 are independently hydrogen and C 1~6 alkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0047] In embodiments, R 3 is C 1~3 Alkyl, -C(O)R 8 or a 5-membered heteroaryl optionally substituted with a prodrug moiety.

[0048] In embodiments, R 3 is C 1~3 Alkyl, -C(O)R 8 or a 5-membered nitrogen-containing heteroaryl optionally substituted with a prodrug moiety.

[0049] In embodiments, R 3 is a 5-membered nitrogen-containing heteroaryl optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S, and the heteroaryl is C 1~3 Alkyl, -C(O)R 8 or may be substituted by a prodrug moiety.

[0050] In embodiments, R 3 is imidazolyl or pyrazolyl, and R 3 is C 1~3 Alkyl, -C(O)R 8 or may be substituted by a prodrug moiety.

[0051] In a second aspect, the present invention provides a compound of formula (I)

[0052] [ka]

[0053] (In the formula, R 1 is hydrogen or a prodrug moiety, R 2 is hydrogen, halo, cyano, nitro, C 1~3 Alkyl, halo(C 1~3 ) alkyl, halo(C 1~3 )alkoxy, -S(O)R 7 , -SO2R 7 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 , -CO2R 7 C 1~3 Alkyl, halo(C 1~3 ) alkyl and halo(C 1~3 ) Alkoxy is hydroxyl or -NR 7 R 8 and optionally substituted by R 3 is imidazolyl or pyrazolyl, and R 3 is C 1~3 Alkyl, -C(O)R 8 or may be substituted with a prodrug moiety, Each R 4 , R 5 and R 6 are independently -LY, Each L independently represents a bond, -(CR a R b )n -, -O-, -(CR a R b ) n O-, -O(R a R b ) n -or- (CR a R b ) n O(CR a R b ) m - selected from each n or m is independently 1, 2, or 3; Each R a and R b is independently selected from hydrogen or methyl; Each Y is independently hydrogen, halo, hydroxyl, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, halo(C 2~4 ) alkenyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -S(O)R 10 , -SO2NR 9 R 10 , -N(R 10 )SO2R 10 , -CF2CH2OR 10 phenyl, 5- or 6-membered heteroaryl and 4- to 10-membered heterocycloalkyl rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; 3~7 The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are independently selected from halo, hydroxyl, —C(O)R 10 , Oxo, C1~4 Alkyl, halo(C 1~4 ) alkyl and C 1~4 hydroxyalkyl; or R 4 and R 5 are taken together with the carbon atoms to which they are attached to form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, oxo, -C(O)R 10 and -SO2R 10 and optionally substituted with 1, 2 or 3 substituents selected from R 7 and R 8 is hydrogen and C 1~3 independently selected from alkyl, R 9 are independently hydrogen, C 1~4 Alkyl, -C(O)C 1~4 Alkyl and halo(C 1~4 ) alkyl; R 10 are independently hydrogen and C 1~6 alkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0054] In embodiments, R 1 and R 3 In embodiments, only one of the prodrug moieties is R 1 Located in R 3 In another embodiment, the prodrug moiety is R3 Located in R 1 In an embodiment, R 1 is a prodrug moiety and R 3 is C 1~3 Alkyl or -C(O)R 8 In an embodiment, R 1 is a prodrug moiety and R 3 is C 1~3 Alkyl or -C(O)R 8 In an embodiment, R 1 is a prodrug moiety and R 3 is imidazolyl or pyrazolyl, and R 3 is C 1~3 Alkyl or -C(O)R 8 may be substituted by:

[0055] In embodiments, each R a and R b is independently selected from hydrogen, fluoro and methyl.

[0056] In embodiments, each R a and R b is independently selected from hydrogen and methyl.

[0057] In embodiments, R 1 is a prodrug moiety.

[0058] In embodiments, the prodrug moiety is a phosphate ester, ester or amino acid type prodrug.

[0059] In embodiments, the prodrug moiety is a phosphate ester.

[0060] In embodiments, R 1 is a phosphate ester prodrug.

[0061] In embodiments, each prodrug moiety is independently —CH(R c )OP(O)(OR d )(OR e ), -CH(R c )OC(O)-C 1~6 Alkylene-OP(O)(OR d )(OR e ), -CH(R c )OC(O)-C 1~6 Alkylene-P(O)(OR d )(OR e ), -CH(R c )OC(O)-C 1~6 Alkylene -COH, -CH(R c )OC(O)R d , -CH(R c )OC(O)OC 1~6 Alkylene -COH, -CH(R c )OC(O)-C 1~6 Alkylene-NR d R e , -CH(R c )OC(O)OC 1~6 Alkylene-NR d R e , -C(O)R d , -CH(R c )OC(O)-C 1~6 Alkylene-heterocycloalkyl, -CH(R c )OC(O)-C 1~6 Alkylene-heterocycloalkyl and -CR d R e -O-(C(O)-NR d -heteroarylene-CHO-C(O)-CH-NR d R e and R c are independently selected from hydrogen and methyl; R d and R e are each independently hydrogen or C 1~6Each heterocycloalkyl is a 4- to 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S; and each heteroarylene is a 5- or 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S.

[0062] In embodiments, R c are independently hydrogen, halo and C 1~3 alkyl.

[0063] In embodiments, R c is independently selected from hydrogen, fluoro and methyl.

[0064] In embodiments, R c is independently selected from hydrogen and methyl.

[0065] In embodiments, R c is hydrogen.

[0066] In embodiments, each prodrug moiety is independently —CH2O—P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene -COH, -CHO-C(O)R d , -CHO-C(O)OC 1~6 Alkylene -COH, -CHO-C(O)-C 1~6 Alkylene-NR d R e , -CHO-C(O)OC 1~6 Alkylene-NR d R e , -C(O)R d , -CHO-C(O)-C 1~6Alkylene-heterocycloalkyl, -CHO-C(O)-C 1~6 Alkylene-heterocycloalkyl and -CR d R e -O-(C(O)-NR d -heteroarylene-CHO-C(O)-CH-NR d R e and R d and R e are each independently hydrogen or C 1~6 Each heterocycloalkyl is a 4- to 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S; and each heteroarylene is a 5- or 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S.

[0067] In embodiments, each prodrug moiety is independently —CH2O—P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene -COH, -CHO-C(O)R d , -CHO-C(O)OC 1~6 Alkylene -COH, -CHO-C(O)-C 1~6 Alkylene-NR d R e , -CHO-C(O)OC 1~6 Alkylene-NR d R e and -C(O)R d is selected from the group consisting of:

[0068] In embodiments, each prodrug moiety is independently —CH2O—P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene -CO2H, -CHO-C(O)OC 1~6 Alkylene -COH, -CHO-C(O)-C 1~6 Alkylene-NR d R e and -CHO-C(O)OC 1~6 Alkylene-NR d R e is selected from the group consisting of:

[0069] In embodiments, each prodrug moiety is independently —CH2O—P(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene -COH, -CHO-C(O)R d , -CHO-C(O)OC 1~3 Alkylene -COH, -CHO-C(O)-C 1~3 Alkylene-NR d R e , -CHO-C(O)OC 1~3 Alkylene-NR d R e , -C(O)R d , -CHO-C(O)-C 1~3 Alkylene-heterocycloalkyl, -CHO-C(O)-C 1~3 Alkylene-heterocycloalkyl and -CR d R e -O-(C(O)-NR d -heteroarylene-CHO-C(O)-CH-NR d Re and R d and R e are each independently hydrogen or C 1~6 Each heterocycloalkyl is a 4- to 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S; and each heteroarylene is a 5- or 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S.

[0070] In embodiments, each prodrug moiety is independently —CH2O—P(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene -COH, -CHO-C(O)R d , -CHO-C(O)OC 1~3 Alkylene -COH, -CHO-C(O)-C 1~3 Alkylene-NR d R e , -CHO-C(O)OC 1~3 Alkylene-NR d R e and -C(O)R d is selected from the group consisting of:

[0071] In embodiments, each prodrug moiety is independently —CH2O—P(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~3 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~3Alkylene -CO2H, -CHO-C(O)O-, C 1~3 Alkylene -COH, -CHO-C(O)-C 1~3 Alkylene-NR d R e and -CHO-C(O)OC 1~3 Alkylene-NR d R e is selected from the group consisting of:

[0072] In embodiments, each prodrug moiety is independently:

[0073] [ka]

[0074] is selected from. In embodiments, each prodrug moiety is independently:

[0075] [ka]

[0076] is selected from. In embodiments, each prodrug moiety is —CH2O—P(O)(OR d )(OR e ) and R d and R e is as defined above.

[0077] In embodiments, each prodrug moiety is:

[0078] [ka]

[0079] is. In embodiments, R 1 is a prodrug moiety as defined in accordance with any one of the above embodiments. 1are independently -CH2O-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-OP(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene-P(O)(OR d )(OR e ), -CHO-C(O)-C 1~6 Alkylene -COH, -CHO-C(O)R d , -CHO-C(O)OC 1~6 Alkylene -COH, -CHO-C(O)-C 1~6 Alkylene-NR d R e , -CHO-C(O)OC 1~6 Alkylene-NR d R e , -C(O)R d , -CHO-C(O)-C 1~6 Alkylene-heterocycloalkyl, -CHO-C(O)-C 1~6 Alkylene-heterocycloalkyl and -CR d R e -O-(C(O)-NR d -heteroarylene-CHO-C(O)-CH-NR d R e and R d and R e are each independently hydrogen or C 1~6 Each heterocycloalkyl is a 4- to 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S; and each heteroarylene is a 5- or 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O, and S.

[0080] In embodiments, R 1 is, independently,

[0081] [ka]

[0082] is selected from. In embodiments, R 1 is -CH2O-P(O)(OR d )(OR e ) and R d and R e is as defined above.

[0083] In embodiments, R 1 teeth,

[0084] [ka]

[0085] is. In an embodiment, the compound of formula (I) has the formula (IA)

[0086] [ka]

[0087] (In the formula, R 2 , R 3 , R 4 , R 5 and R 6 is as defined herein with respect to formula (I)) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0088] In embodiments, R 1 is hydrogen.

[0089] In an embodiment, the compound of formula (I) has the formula (IAA)

[0090] [ka]

[0091] (In the formula, R 2 , R 3 , R4 , R 5 and R 6 is as defined herein with respect to formula (I)) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0092] In embodiments, R 2 is halo, cyano, halo (C 1~3 ) alkyl, halo(C 1~3 )alkoxy, -S(O)R 7 , -C(O)NR 7 R 8 and CO2R 7 and halo(C 1~3 ) alkyl and halo(C 1~3 ) Alkoxy is hydroxyl or -NR 7 R 8 may be substituted by:

[0093] In embodiments, R 2 are halo, cyano, -C(O)NH2, halo(C 1~4 ) alkoxy, halo(C 1~2 ) selected from the group consisting of alkyl, —CF2CH2NH2, —CF2CH2OH, and —S(O)CH3.

[0094] In embodiments, R 2 is selected from the group consisting of Br, cyano, —C(O)NH2, —CF2CH2NH2, —CF2CH2OH, —CH2F, —CHF2, —CF3, —CF2CF3, —CF2CH3, —CF2CHF2, —OCHF2, and —S(O)CH3.

[0095] In embodiments, R 2 is hydrogen, halo, C 1~3 Alkyl, halo(C 1~3 ) alkyl and halo(C 1~3 ) alkoxy.

[0096] In embodiments, R 2is selected from hydrogen, Br, —CF3, —CHF2, —CH3 and —OCHF2.

[0097] In embodiments, R 2 is CF3.

[0098] In an embodiment, the compound of formula (I) has formula (IB) or formula (IBB)

[0099] [ka]

[0100] (In the formula, R 3 , R 4 , R 5 and R 6 is as defined herein with respect to formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0101] In embodiments, R 3 is imidazolyl or pyrazolyl. In an embodiment, R 3 For the avoidance of doubt, in embodiments, R 3 is unsubstituted imidazolyl.

[0102] In embodiments, R 3 is an imidazolyl or pyrazolyl linked through the carbon, i.e., a C-linked imidazolyl or a C-linked pyrazolyl. 3 is a C-linked imidazolyl. 3 is imidazol-4-yl or imidazol-5-yl. In an embodiment, R 3 is imidazol-5-yl.

[0103] In embodiments, R 1 is a prodrug moiety and R 3 is imidazolyl, particularly C-linked imidazolyl.

[0104] In embodiments, R 1 is H and R 3 is substituted with a prodrug moiety.

[0105] In embodiments, R 1 teeth,

[0106] [ka]

[0107] and R 3 is imidazolyl, particularly C-linked imidazolyl. In an alternative embodiment, R 1 is hydrogen and R 3 is imidazolyl, particularly C-linked imidazolyl.

[0108] In an embodiment, the compound of formula (I) has formula (IC) or formula (ICC)

[0109] [ka]

[0110] (In the formula, R 4 , R 5 and R 6 is as defined above for formula (I)) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0111] In embodiments, each R 4 , R 5 and R 6 is independently -LY and each L is a bond.

[0112] In embodiments, each L is a bond and each Y is independently hydrogen, halo, hydroxyl, cyano, C 1~4 Alkyl, C 3~7Cycloalkyl, C 1~4 Alkoxy, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -CF2CH2OR 10 , phenyl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl rings containing 1 or 2 heteroatoms independently selected from N, O, and S, wherein heterocycloalkyl is independently selected from halo, hydroxyl, —C(O)R 10 and C 1~4 alkyl, or R 4 and R 5 together with the carbon atoms to which they are attached form a 5-8 membered monocyclic heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, oxo, -C(O)R 10 and -SO2R 10 It may be substituted with up to three substituents selected from:

[0113] In embodiments, each L is a bond, -(CR a R b ) n -, -O-, -(CR a R b ) n O-, -O(CH2) n -or- (CR a R b ) n O(CR a R b ) m -, and each Y is independently selected from hydrogen, halo, hydroxyl, cyano, C1~4 Alkyl, C 3~7 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -CF2CH2OR 10 phenyl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl rings containing 1 or 2 heteroatoms independently selected from N, O and S; C 3~7 Cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are independently selected from halo, hydroxyl, —C(O)R 10 and C 1~4 It may be substituted with 1, 2 or 3 substituents selected from alkyl.

[0114] In embodiments, each L is independently a bond, —(CH) n -, -O-, -(CH2) n O-, -O(CH2) n - and -(CH2) n O(CH2) m -, each Y is independently selected from hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, -NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -CF2CH2OR 10and a 4-10 membered heterocycloalkyl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S; 3~7 Cycloalkyl is independently halo, hydroxyl, -C(O)R 10 , Oxo, C 1~4 Alkyl, halo(C 1~4 ) alkyl and C 1~4 It may be substituted with 1, 2 or 3 substituents selected from hydroxyalkyl.

[0115] In embodiments, each L is a bond and each Y is independently hydrogen, halo, hydroxyl, cyano, C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, C 1~4 Cyanoalkyl, halo(C 1~4 ) alkyl, -NR 9 R 10 , -C(O)NR 9 R 10 , -CO2R 10 , -C(O)R 10 , -SO2R 10 , -OSO2R 10 , -CF2CH2OR 10 phenyl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl rings containing 1 or 2 heteroatoms independently selected from N, O and S; C 3~7 Cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are independently selected from halo, hydroxyl, —C(O)R 10 and C 1~4 In an embodiment, R 4 , R 5 and R 6 are hydrogen, halogens, CO2R 10 and halo(C 1~4 ) alkyl.

[0116] In embodiments, R 6 is hydrogen.

[0117] In embodiments, R 4 and R 5 are hydrogen, halogens, CO2R 10 and halo(C 1~4 ) alkyl; R 6 is hydrogen.

[0118] In embodiments, R 4 and R 6 is hydrogen.

[0119] In embodiments, R 4 , R 5 and R 6 is hydrogen.

[0120] In embodiments, R 4 and R 6 is hydrogen and R 5 is a halo.

[0121] In embodiments, R 4 and R 6 is hydrogen and R 5 is fluoro.

[0122] In embodiments, R a and R b is hydrogen.

[0123] In embodiments, R 4 and R 5 are taken together with the carbon atoms to which they are attached to form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, oxo, -C(O)R 8 and -SO2R 8 It may be substituted with up to three substituents selected from:

[0124] In embodiments, R 4 and R 5 taken together with the carbon atoms to which they are attached form a five-membered monocyclic ring. 4 and R 5 are taken together with the carbon atoms to which they are attached to form a 5-membered monocyclic ring containing one heteroatom selected from N and O. In an embodiment, R 4 and R 5 taken together with the carbon atoms to which they are attached form a 6-membered monocyclic ring. 4 and R 5 taken together with the carbon atoms to which they are attached form a 6-membered monocyclic ring containing one heteroatom selected from N and O.

[0125] In embodiments, each L is independently a bond, —(CH) n - and -(CH2) n O-.

[0126] In embodiments, each Y is independently hydrogen, halogen, COR 10 and halo(C 1~4 ) alkyl.

[0127] In an embodiment, the present invention provides a compound of formula (I)

[0128] [ka]

[0129] (In the formula, R 1 is hydrogen or a prodrug moiety, R 2 is hydrogen, halo, C 1~3 Alkyl and halo(C 1~3 ) alkyl; R 3 is imidazolyl or pyrazolyl, and R 3is optionally substituted with a prodrug moiety; Each R 4 , R 5 and R 6 are independently -LY, Each L independently represents a bond, -(CR a R b ) n - or -O-; each n is independently 1, 2, or 3; Each R a and R b is independently selected from hydrogen or methyl; Each Y is independently hydrogen, halo, C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~4 Thioalkyl, C 1~6 Hydroxyalkyl, halo(C 1~4 )Alkyl, -CO2R 10 , -COR 10 , -SO2R 10 , -OSO2R 10 , -CF2CH2OR 10 or R 4 and R 5 are taken together with the carbon atoms to which they are attached to form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C 1~4 Alkyl, -C(O)R 10 and -SO2R 10 and optionally substituted with 1, 2 or 3 substituents selected from R 10 are independently hydrogen and C 1~6 In an embodiment, the compound of formula (I) is selected from the group consisting of: 5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyramidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-chloro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(difluoromethyl)-1H-1,2,4-triazole; 3-(Difluoromethyl)-5-[6-fluoro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[7-chloro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 3-(Difluoromethyl)-5-[7-(difluoromethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; {4-oxo-4-[(4-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methoxy]butoxy}phosphonic acid, {4-oxo-4-[(5-{3-[1-({[4-(phosphonooxy)butanoyl]oxy}methyl)-1H-imidazol-4-yl]imidazo[1,2-a]pyrimidin-2-yl}-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy]butoxy}phosphonic acid; ({5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl}methoxy)phosphonic acid; Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate; Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate; 3-Bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[6-fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-chloro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 3-(Difluoromethyl)-5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-bromo-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 3-(Difluoromethyl)-5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 3-Bromo-5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-pyrazol-4-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[7-(difluoromethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-methyl-1H-1,2,4-triazole; Methyl 3-(1H-imidazol-4-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidine-7-carboxylate; 3-(1H-imidazol-4-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidine-7-carboxylic acid; 3-(Difluoromethoxy)-5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[6-(difluoromethyl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-fluoro-3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-chloro-3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(2-methyl-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; and 3-bromo-5-[6-fluoro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0130] In an embodiment, the compound of formula (I) is

[0131] [ka]

[0132] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In an embodiment, the compound of formula (I) is R 3 is imidazolyl, R 2 is CF3, the following structures depict the available tautomers

[0133] [ka]

[0134] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In an embodiment, the compound of formula (I) is R3 is imidazolyl, R 2 is CF3, one of the following structures depicting the available tautomers

[0135] [ka]

[0136] or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (I) is

[0137] [ka]

[0138] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In an embodiment, the compound of formula (I) is

[0139] [ka]

[0140] (In the formula, R 1 is a prodrug moiety or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof).

[0141] In an embodiment, the compound of formula (I) is

[0142] [ka]

[0143] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In an embodiment, the compound of formula (I) is R 3When is imidazolyl, the following structures depict the available tautomers:

[0144] [ka]

[0145] or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (I) is in the form of a free base. In one embodiment, the compound of formula (I) in the form of a free base is any one of the compounds of Examples 1 to 165.

[0146] In an embodiment, the compound of formula (I) is in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) in the form of a pharmaceutically acceptable salt is any one of the compounds of Examples 1 to 165.

[0147] Compounds of formula (I) or tautomers thereof may contain acidic or basic functional groups and thus, one of skill in the art will recognize that pharmaceutically acceptable salts of compounds of formula (I) may be prepared.

[0148] Pharmaceutically acceptable salts include, inter alia, those described in Berge, J. Pharm. Sci., 1977, 66, pp. 1-19, or those listed in P.H. Stahl and C.G. Wermuth, eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2nd ed., Stahl / Wermuth: Wiley- VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0149] Suitable pharmaceutically acceptable salts may include acid or base addition salts.

[0150] Such base addition salts can be formed by reacting a compound of Formula (I) (e.g., containing a carboxylic acid or other acidic functional group) with a suitable base, optionally in a suitable solvent, e.g., an organic solvent, to give a salt.

[0151] Such acid addition salts can be formed by reacting a compound of formula (I) (e.g., containing a basic amine or other basic functional group) with an appropriate acid, optionally in a suitable solvent, e.g., an organic solvent, to give a salt.

[0152] Salts can be prepared in situ during the final isolation and purification of compounds of formula (I). When a basic compound of formula (I) is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic base. Similarly, when a compound of formula (I) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic acid.

[0153] It is understood that when a compound of formula (I) contains two or more basic moieties, the salt formation stoichiometry may include one, two or more equivalents of acid, and such salts may contain one, two or more acid counterions, e.g., dihydrochloride.

[0154] Pharmaceutically acceptable salts of the compounds of formula (I) in their stoichiometric and non-stoichiometric forms, including sub-stoichiometric salts, are included within the scope of the present invention.

[0155] Representative pharmaceutically acceptable acid addition salts include 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), and ethanesulfonate (esylate). , formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,Examples of suitable salts include, but are not limited to, 5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate salts.

[0156] Representative pharmaceutically acceptable base addition salts include aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (tris, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazoline), and methylbenzimidazoline. amine, cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

[0157] The compounds of the present invention can exist in tautomeric forms, and it should be understood that any reference to a named or structurally depicted compound is intended to encompass all tautomeric forms of such compound.

[0158] For example, R 1 When is hydrogen, the following tautomers exist:

[0159] [ka]

[0160] For example, R 1 is the prodrug moiety and R 3 When is imidazolyl (attached via the carbon), the following tautomers exist:

[0161] [ka]

[0162] In embodiments, R 1 is hydrogen and R 3 When is imidazolyl (attached through C), the following tautomers exist:

[0163] [ka]

[0164] The present invention also includes all suitable isotopic variations of the compounds of the present invention. An isotopic variation of a compound of the present invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.

[0165] Examples of isotopes that may be incorporated into compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine isotopes, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 18F, and 36Cl, respectively. Certain isotopic variations of a compound of formula (I) or a salt or solvate thereof, such as those incorporating a radioactive isotope, such as 3H or 14C, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for ease of preparation and detectability. Furthermore, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. Accordingly, in one embodiment, the present invention includes compounds of the present invention in which one or more hydrogen atoms attached to a carbon atom are replaced by deuterium. Isotopic variations of the compounds of the present invention can generally be prepared by conventional procedures, for example, by the exemplified methods or by the preparations described in the Examples below, using appropriate isotopic variations of suitable reagents.

[0166] In an embodiment, the present invention provides a method for producing a pharmaceutical composition comprising:

[0167] [ka]

[0168] wherein one or more hydrogen atoms attached to a carbon atom are replaced by deuterium.

[0169] Representative compounds of formula (I) are listed in Table 1 below.

[0170] [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

[0171] Statement of Use Therapeutic targeting of the cGAS-STING pathway with small molecule cGAS inhibitors may be beneficial for a wide range of autoinflammatory, autoimmune, and immune-mediated diseases.

[0172] In embodiments, "treating" refers to ameliorating or stabilizing a particular condition, reducing or eliminating the symptoms of a condition, and slowing or eliminating the progression of a condition.

[0173] The compounds of the invention may be useful in preventing conditions in which cGAS or downstream components of its pathway may play a known or suspected role, such as immune conditions, inflammatory conditions, autoimmune conditions, autoinflammatory conditions, type I interferonopathies, allergies, infectious conditions, organ damage, tissue injury, and other cGAS-dependent or related conditions.

[0174] The compounds of the invention are useful in treating conditions in which cGAS or downstream components of its pathway may play a known or suspected role. The compounds of the invention may therefore be useful in treating a number of immune conditions, inflammatory conditions, autoimmune conditions, autoinflammatory conditions, type I interferonopathies, allergies, infectious conditions, organ damage, tissue injury, and other cGAS-dependent or related conditions.

[0175] The compounds of the present invention are useful for treating cGAS-related diseases or disorders.

[0176] The compounds of the present invention are useful for preventing cGAS-related diseases or disorders.

[0177] The compounds of the present invention are useful in treating infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutières syndrome (AGS), familial lupus pernio, ataxia-telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with cerebral leukoencephalopathy (RVCL), systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis (LN), psoriasis, diabetes including insulin-dependent diabetes mellitus (IDDM), dermatomyositis, human immunodeficiency virus (HIV), AIDS, polymyositis, systemic sclerosis (scleroderma) and Sjogren's syndrome (SS), rheumatoid arthritis (RA), It may be useful for the treatment of an autoimmune disease selected from, but not limited to, psoriatic arthritis, polyarthritis, myasthenia gravis, polyarteritis nodosa, vasculitis, cutaneous vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Henoch-Schonlein purpura, autoimmune hepatitis, primary sclerosing cholangitis, Wegener's granulomatosis, microscopic polyangiitis, Behcet's disease, spondylitis, giant cell arteritis, polymyalgia rheumatica, Raynaud's phenomenon, primary biliary cirrhosis, primary central nervous system vasculitis, microscopic polyangiitis, neuromyelitis optica, and mixed connective tissue disease.

[0178] The compounds of the present invention may be useful in treating acute or chronic inflammation of any tissue or organ of the human body and the resulting tissue and organ injury, including, but not limited to, musculoskeletal inflammation, vascular inflammation, cardiovascular inflammation, neuroinflammation, gastrointestinal inflammation, respiratory inflammation, renal inflammation, reproductive system inflammation, ocular inflammation, periodontal inflammation and other inflammations exemplified below.

[0179] The compounds of the present invention can be useful for treating musculoskeletal inflammation (i.e., any inflammatory condition of the musculoskeletal system), including but not limited to, conditions that affect skeletal joints, including the joints of the hand, wrist, elbow, shoulder, mandible, spine, neck, hip, knee, ankle and foot, and conditions that affect the connective tissue between muscle and bone, such as tendon.The examples of musculoskeletal inflammation that can be treated with the compounds of the present invention include arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibromyalgia, epicondylitis, myositis and osteitis (including, for example, Paget's disease, osteitis pubis and osteitis fibrosa cystica).

[0180] The compounds of the present invention may be useful in treating inflammation of the vascular or lymphatic system, including, but not limited to, atherosclerosis, arthritis, phlebitis, vasculitis and lymphangitis.

[0181] The compounds of the present invention may be useful in the treatment of cardiovascular conditions and cardiomyopathies, including, but not limited to, heart failure, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, endomyocardial fibrosis, and aortic aneurysm and dissection (AAD).

[0182] The compounds of the present invention may be useful in treating inflammation of the nervous system, including, but not limited to, encephalitis, sepsis-associated encephalopathy (SAE), cerebral ischemic stroke, traumatic brain injury (TBI), ataxia-telangiectasia, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, CNS vasculitis, and schizophrenia.

[0183] The compounds of the invention may be useful in treating inflammatory conditions of the digestive system, including, but not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), ileitis, proctitis, and colorectal cancer.

[0184] The compounds of the present invention may be useful in treating respiratory inflammation, including, but not limited to, pulmonary inflammation, chronic pulmonary inflammation, cystic fibrosis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), silicosis, asthma, and COVID-19. The compounds of the present invention may be used to ameliorate pulmonary inflammation, endothelial and vascular injury, and skin lesions resulting from COVID-19 infection.

[0185] The compounds of the present invention may be useful in treating inflammatory conditions and diseases of the liver and kidney, including, but not limited to, cirrhosis, liver fibrosis, viral hepatitis, non-alcoholic fatty liver disease (NAFLD), steatosis, non-alcoholic steatohepatitis (NASH), alcohol-related liver disease (ALD), primary hepatocellular carcinoma (HCC), hepatic ischemia-reperfusion injury (IRI), acute kidney injury (AKI), chronic kidney disease (CKD), and renal fibrosis.

[0186] The compounds of the present invention may be useful in the treatment of metabolic disorders including, but not limited to, diabetes melitus, obesity, insulin resistance and glucose intolerance.

[0187] The compounds of the invention may be useful in the treatment of inflammatory conditions of the reproductive system, including, but not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0188] The compound of the present invention can be useful for treating ocular inflammation, including but not limited to the inflammation of any structure of the eye, including eyelid.The examples of ocular inflammation that can be treated with the compound of the present invention include blepharitis, cutis laxa, conjunctivitis, dacryoadenitis, keratitis, fungal keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis and uveitis.In addition, other eye-related disorders can be treated, including age-related macular degeneration (AMD).

[0189] The compounds of the present invention may be useful in the treatment of inflammatory periodontal diseases (also known as gum disease), including, but not limited to, gingivitis, odontoblastic inflammation, chronic periodontitis, aggressive periodontitis, necrotizing ulcerative gingivitis / periodontitis and combined periodontal-endodontic lesions.

[0190] The compounds of the present invention are effective in treating acute disseminated alopecia universalis, Behcet's disease, Chagas' disease, infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutières syndrome (AGS), lupus pernio, ataxia-telangiectasia (also known as Louis-Barr syndrome), retinal vasculopathy with cerebral leukoencephalopathy (RCVL), ANCA-associated vasculitis (ANCA)-associated vasculitis, chronic fatigue syndrome, autonomic dysfunction, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, severe urinary tract infections, and urinary tract infections. The present invention may be useful in the treatment of autoimmune conditions with an inflammatory component, including, but not limited to, myasthenia gravis, opsoclonus-myoclonus ataxia, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia nodosa, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0191] The compounds of the present invention may be useful in treating T-cell mediated allergic disorders with an inflammatory component, including, but not limited to, contact hypersensitivity, contact dermatitis (including that caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0192] The compounds of the invention are useful in treating appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, suppurative hidradenitis, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis and stomatitis, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g. islet cells), bone marrow, cornea, small intestine, skin allografts, skin allografts and heart valve xenografts, serum sickness and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory syndrome, Sézary syndrome, congenital adrenal hyperplasia, non-suppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliation It may be useful in the treatment of other inflammatory conditions including, but not limited to, dermatitis deformans, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia of childhood, regional enterocolitis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis.

[0193] The compounds of the invention may be useful in treating humans suffering from one or more diseases characterized by cell proliferation in the areas of disorders associated with angiogenesis and / or vascular permeability, including vascular proliferative disorders, including arthritis (rheumatoid arthritis) and restenosis; fibrotic disorders, including cirrhosis of the liver and atherosclerosis; mesangial cell proliferative disorders, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, proliferative retinopathies, organ transplant rejection and glomerulopathies; and other disorders, including psoriasis, diabetes, and chronic wound healing.

[0194] The compounds of the present invention are useful for the treatment of neurodegenerative conditions, including, but not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).

[0195] The compounds of the present invention may be useful for treating inflammatory conditions resulting from infectious diseases, which are any disease caused by or coincident with infection with a pathogen. A pathogen can be broadly defined as any species or organism foreign to the environment of human tissue. Common disease-causing pathogens include bacteria (many such as TB), viruses (many such as HBV, HIV, and influenza), and parasitic protozoa (such as P. falciparum, which causes malaria). The compounds of the present invention may be used to treat infectious diseases resulting from bacteria, such as TB infection (Mycobacterium tuberculosis), chlamydia, tularemia infection (Franciseiia tuiarensis), plasmodium infection, or DNA or RNA virus infection. The compounds of the present invention may be used to treat infectious diseases resulting from the DNA virus family: Herpesviridae (herpes simplex virus-1, Kaposi's sarcoma-associated virus, and Epstein-Barr virus), Papillomaviridae (human papillomavirus), adenovirus, and Hepadnaviridae (hepatitis B virus). Examples of RNA virus families include Retroviridae (human immunodeficiency viruses), Flaviviridae (dengue virus, Zika virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronaviruses, MERS, SARS, and SARS-CoV2 coronaviruses).

[0196] The compounds of the invention may be useful in ameliorating organ damage or injury sustained as a result of a cGAS-mediated disease or disorder, such as acute kidney injury, liver injury, lung injury, cardiac injury, and the like.

[0197] The compounds of the invention may be particularly useful in the treatment of systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis and scleroderma, especially systemic lupus erythematosus and lupus nephritis.

[0198] The compounds of the invention may be particularly useful in the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), acute kidney injury, chronic kidney disease, diabetic kidney disease or injury, myocardial infarction, stroke, cardiac hypertrophy / heart failure, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0199] Aicardi-Goutières syndrome (AGS) is an early-onset disorder manifested by progressive encephalopathy and chilblain-like skin lesions, demonstrating features of both autoinflammatory and autoimmune diseases characterized biochemically by elevated type I interferon levels (Stetson et al., Cell 134(4), pp. 587-598, 2008; Crow et al., Nat Rev Immunol 15(7), pp. 429-440, 2015; Uggenti et al., Annu Rev Immunol 37:247-267, 2019). Many AGS patients exhibit features of systemic autoimmunity, such as antinuclear and anti-DNA autoantibodies, similar to SLE. More than 75% of AGS patients harbor mutations in Trex1 or RNase H2, which result in the accumulation of cytoplasmic DNA due to insufficient DNA clearance (Trex1) or DNA damage-promoted micronucleus formation (RNase H2). Importantly, knockout of these nucleases and / or knockin of inactivating AGS mutations causes fatal autoimmune disease in mice, which can be rescued by cGAS or STING deficiency (Gray et al., 2015 J Immunol 195(5), pp. 1939-1943, 2015; Gao et al., PNAS USA 112(42), E5699-E5705, 2015; Pokatayevet et al., J Exp Med 213(3), pp. 329-336, 2016; Mackenzie et al., EMBO J 35(8), pp. 831-844, 2016). In addition to AGS, Trex1 mutations have been associated with familial lupus pernio (FCL), the cutaneous form of systemic lupus erythematosus, and retinal vasculopathy with cerebral leukoencephalopathy (RVCL) (Rice et al., J Clin Immunol 35(3), pp. 235-243, 2015). Recently, biallelic mutations in the LSM11 and RNU7-1 genes, which encode components of the histone pre-mRNA processing complex, were identified in genetically uncharacterized AGS patients and associated with excessive cGAS signaling (Uggenti et al., Nat Genet 52(12), pp. 1364-1372, 2020).

[0200] Direct evidence that STING activation causes inflammatory disease came from the identification of gain-of-function mutations in the TMEM173 gene, encoding STING, in patients presenting with early-onset vasculopathy and pulmonary inflammation (Liu et al., N Engl J Med 371(6), pp. 507-518, 2014). Disease caused by such mutations, here classified as SAVI (STING-associated vasculopathy with infancy-onset), is characterized by relapsing fever, ulcerative skin lesions, vasculitis, and interstitial lung disease. SAVI-associated STING mutations are thought to cause spontaneous STING dimerization and activation without cGAMP (Ergun et al., Cell 178(2), pp. 290-301, 2019).

[0201] COPA syndrome, named for defects in the COPa protein, which is involved in Golgi-to-ER transport, is also associated with abnormal cGAS-STING signaling. COPA-mutant STING spends proportionally more time in an active state in the Golgi apparatus, which is thought to result in constitutive signaling (Lepelley et al., J Exp Med 217(11), e20200600, 2020; Mukai et al., Nat Commun 12(1), 61, 2021). All COPA patients present with pulmonary disease, although a smaller subset of patients develop arthritis and kidney disease.

[0202] DNAse II (ceII) deficiency was first described in humans in 2017. Affected patients demonstrate severe neonatal anemia, membranoproliferative glomerulonephritis, osteoarthritis, and elevated levels of anti-dsDNA antibodies (Rodero et al., Nature Communications 8(1), 2176, 2017). Although DNase II is an endosomal nuclease, accumulation of dsDNA in endolysosomes is thought to eventually result in their rupture, exposing DNA to cGAS. DNase II-deficient mice die during embryonic development due to severe anemia and develop chronic polyarthritis when crossed with IFNAR null mice (Kawane et al., Science 292(5521), 1546-1549, 2001; Yoshida et al., Nat Immunol 6(1), 49-56, 2005). Interestingly, deletion of cGAS or STING completely rescues DNase II-deficient mice from both embryonic lethality and chronic arthritis (Gao et al., PNAS USA 112(42), E5699-E5705, 2015).

[0203] Multiple lines of evidence suggest that the same mechanisms involved in the pathogenesis of monogenic diseases contribute to the development of complex autoimmune diseases, such as systemic lupus erythematosus (SLE). Missense Trex1 mutations have been identified in 0.5–2% of SLE patients, and a lupus-like phenotype has been recapitulated in mice carrying the Trex1 D18N mutation, which causes familial lupus pernio (Namjou et al., Genes and Immunity 12(4), pp. 270–279, 2011; Lee-Kirsch et al., Nat Genet 39(9), pp. 1065–1067, 2007; Barizzone et al., Biomed Res Int 2013:471–703, 2013). Similarly, mutations impairing RNase H2 function have been associated with SLE in addition to AGS (Gunther et al., J Clin Invest 125(1), pp. 413–424, 2015). Furthermore, elevated cGAMP levels have been reported in 15% of SLE patients, and cGAMP-positive patients presented with higher SLEDAI scores (An et al., Arthritis Rheumatol 69(4), pp. 800-807, 2017).

[0204] Based on the presence of interferon signatures and overlapping clinical manifestations, diseases including cutaneous lupus erythematosus (CLE), lupus nephritis (LN), and various subtypes of dermatomyositis are predicted to be driven (at least in part) by the same mechanisms involved in the pathogenesis of SLE. UV-induced DNA damage may also activate the cGAS-STING pathway and contribute to disease pathology (Skopelja-Gardner et al., Sci Rep 10(1), 7908, 2020).

[0205] Excessive cGAS-STING activation and cGAS-STING-dependent pathogenesis have been demonstrated in several other autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD). cGAS deficiency rescues the polyarthritis phenotype in DNase II-KO mice and reduces joint swelling in the K / BxN arthritis mouse model (Gao et al., PNAS USA 112(42), E5699-E5705, 2015; Willemsen et al., Cell Rep 37(6), 109977, 2021). Similarly, STING deficiency attenuates IMQ-induced psoriatic symptoms and skin inflammation (Yu et al., J Invest Dermatol 142(3), 898-906, 2022). In IBD, the cGAS-STING pathway plays both protective and detrimental roles. While ablation of cGAS reduces intestinal inflammation and ameliorates colitis associated with IL-10 deficiency, other studies highlight the beneficial role of cGAS and STING in intestinal homeostasis (Ahn et al., Cell Reports 21(13), pp. 3873-3884, 2017; Canesso et al., Mucosal Immunol 11(3), pp. 820-834, 2018; Hu et al., PNAS 118(23), e2105747118, 2021).

[0206] Inflammation is a hallmark of several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Alzheimer's disease. In the case of Parkinson's disease, mutations in the PARKIN and PINK1 genes cause defective mitophagy, mtDNA leakage into the cytosol, and cGAS-STING-dependent cytokine production. Importantly, the motor defects and neuronal loss observed in Parkin mutant mice can be rescued by STING ablation (Slitter et al., Nature 561(7722), pp. 258–262, 2018). Recently, the cGAS-STING pathway has been implicated in neuropathological processes associated with ALS and frontotemporal lobar degeneration. In a preclinical model of ALS driven by overexpression of the human TDP-43(A315T) allele, ablation of STING attenuates neuroinflammation, mitigates rapid disease progression, and protects against premature death (Yu et al., Cell 183(3), pp. 636-649, 2020). Furthermore, administration of cGAS or STING inhibitors ameliorates ongoing inflammation, improves motor function, and increases survival in an SOD1-ALS mouse model (Tan et al., iScience 25:104404, 2022). Finally, ALS patients with C9orf72 repeat expansions display an amplified type I interferon signature, driven at least in part by STING activation (McCauley et al., Nature 585(7823), pp. 96-101, 2020). Increased cGAS activity is also associated with inflammatory responses in HD striatal cells, and microglial activation by tau is linked to the PQBP1-cGAS-STING pathway (Sharma et al., PNAS 117(27), pp. 5989-15999, 2020; Jin et al., Nat Commun 12(1), pp. 6565, 2021).

[0207] Activation of the cGAS-STING pathway at mtDNA has been proposed as a potential mechanism underlying obesity-induced inflammation and metabolic dysfunction. STING deficiency and / or inhibition prevents (at least partially) diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance, and reduces pancreatic B-cell senescence (Mao et al., Arterioscler Thromb Vasc Biol 37(5), pp. 920-929, 2017; Hu et al., FASEB J 36(5), e22266, 2022). Furthermore, excessive cGAS-STING signaling has been implicated in other metabolic diseases, such as NAFLD and NASH. Independent laboratories have demonstrated that STING deficiency reduces the severity of hepatic steatosis, inflammation, and fibrosis in both methionine / choline deficient diet (MCD) and high-fat diet (HFD) mouse models (Luo et al., Gastroenterology 155(6), 1971-1984, 2018; Yu et al., J Clin Invest 129(2), 546-555, 2019; Zhang et al., Front Immunol 13:931-176, 2022).

[0208] Increased cGAS-STING signaling has been demonstrated in acute kidney injury (AKI), chronic kidney disease (CKD), and other indications related to fibrosis. Cisplatin-induced mtDNA leakage induces tubulitis and the progression of acute kidney injury, which can be rescued by STING deficiency or treatment with a STING inhibitor (Maekawa et al., Cell Rep 29(5), pp. 1261–1273, 2019; Gong et al., Am J Physiol Renal Physiol 320(4), F608–F616, 2021). CKD, characterized by kidney injury, inflammation, and tissue fibrosis, is associated with deterioration of mitochondrial integrity and mtDNA release. Furthermore, genetic ablation or pharmacological inhibition of STING ameliorates both TFAM loss- and FA-induced renal inflammation and fibrosis and improves renal function in APOL1 transgenic mice expressing the G2 risk allele (Chung et al., Cell Metab 30(4), pp. 784-799, 2019; Wu et al., J Clin Invest 131(20), e136329, 2021). Recently, Zhang et al. proposed that cGAS-STING-driven fibrosis is driven by a non-canonical cGAS-STING-PERK pathway (Zhang et al., Nat Cell Biol 24(5), pp. 766-782, 2022).

[0209] Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring. Its physiopathology is thought to depend on repeated localized microinjuries that cause DNA damage, cell death, and fibrosis. In the bleomycin-induced mouse model of classical pulmonary fibrosis, the contribution of the cGAS-STING pathway to disease pathology remains controversial. Savigny et al. suggested that STING plays a protective role in the bleomycin model by limiting pulmonary fibrosis, whereas Zhang et al. reported a less severe fibrotic phenotype in STING-deficient mice compared with wild-type mice in response to bleomycin (Savigny et al., Front Immunol 11:588-799, 2021; Zhang et al., Nat Cell Biol 24(5), pp. 766-782, 2022). Administration of STING inhibitors also ameliorates intestinal ischemia-reperfusion-mediated acute lung injury, as demonstrated by reduced lung injury scores and attenuated fibrosis (Yang et al. Eur J Med Res 27(1), 79, 2022). Furthermore, cGAS-STING signaling induces lung inflammation in response to cigarette smoke, a major cause of chronic obstructive pulmonary disease (COPD), and silica particle exposure (Nascimento et al. Sci Rep 9(1), 14848, 2019; Benmerzoug et al. Nat Com 9(1), 5226, 2018).

[0210] Myocardial infarction (MI) causes ischemic cell death in the heart, which results in the release of debris from dying cells. The released cardiomyocyte DNA is phagocytosed by infiltrating macrophages, which triggers cGAS-STING-mediated type I IFN production. Genetic or pharmacological blockade of the cGAS-STING pathway protects against MI-induced adverse ventricular remodeling, improves contractile function, and increases survival after MI (King et al., Nat Med 23(12), pp. 1481-1487, 2017; Cao at al., Circulation 137(24), pp. 2613-2634, 2018; Lai et al., J Am Heart Assoc 10(15), e020754, 2021; Rech et al., Life Sci 291:120-263, 2022). Furthermore, cGAS-STING knockdown blunts pressure overload-induced cardiac hypertrophy and improves cardiac function in a mouse transaortic aortic constriction (TAC) model (Hu et al., Am J Physiol Heart circ Physiol 318(6), H1525-H1537, 2020). Activation of the cGAS-STING pathway has also been implicated in the development of atherosclerosis and ischemic stroke brain injury (Pham et al., Eur Heart J 42(42), pp. 4336-4348, 2021; Li et al., EMBO Mol Med 12(4), e11002, 2020).

[0211] Excessive cGAS-STING signaling contributes to acute and chronic inflammation in multiple tissues, and in addition to the diseases mentioned above, the cGAS-STING pathway has been implicated in the pathogenesis of age-related macular degeneration (AMD) (Kerur et al., Nat Med 24(1), 50-61, 2018), acute pancreatitis (Zhao et al., Gastroenterology 154(6):1822-1835, 2018), acne (Fischer et al., Front Immunol 11:571-334, 2020), and sepsis (Hu et al., BioMedicme 41:497-508, 2019).

[0212] In the last five years, several studies have demonstrated that the release of chromatin fragments into the cytosol can activate the cGAS-STING pathway and induce senescence (Yang et al., PNAS Sci USA 114(23), E4612–E4620, 2017; Gluck et al., Nat Cell Biol 19(9), pp. 1061–1070, 2017). Senescent cells possess a unique secretory phenotype (senescence-associated secretory phenotype) defined by changes in the expression of proinflammatory cytokines, chemokines, extracellular matrix components, and matrix metalloproteinases (MMPs). The senescence-associated secretory phenotype is thought to contribute to many chronic diseases associated with aging, including atherosclerosis and cardiovascular disease, arthritis, type 2 diabetes, neurodegeneration, and other disorders. Inhibition of cGAS can reduce chronic inflammation and benefit many indications associated with the elderly patient population.

[0213] Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19 disease. Interaction between SARS-CoV-2 and host cells has been reported to activate the cGAS-STING pathway via a non-canonical pathway (Neufeldt et al., 2022, Commun Biol 5(1), p. 45, 2022; Di Domizio et al., Nature 603(7899), pp. 145–151, 2022). Fusion of SARS-CoV-2 with host cells results in a cytosolic micronucleus that binds to and activates cGAS, inducing an interferon response (Liu et al., Sci Signal 5(729), eabg8744, 2022). Activation of the cGAS-STING pathway during SARS-CoV-2 infection produces cytokines that can inhibit viral replication, but extensive activation leads to an uncontrolled immune response that contributes to COVID-19 immunopathology (Di Domizio et al., Nature 603(7899), pp. 145-151, 2022). Pharmacological inhibition of the cGAS-STING pathway is expected to modulate immune responses after infection, thereby mitigating the immunopathology associated with disease symptoms. SARS-CoV-2-infected mice administered a STING antagonist 2 days after infection demonstrate reduced pathology and reduced levels of type I IFN and other cytokines in the lungs (Di Domizio et al., Nature 603(7899), pp. 145-151, 2022). Activation of the cGAS-STING pathway has also been associated with a variety of other viral and bacterial pathogens.

[0214] Several laboratories have investigated the role of the cGAS-STING pathway in cancer. Many cancer cells exhibit genomic instability, which leads to micronucleus formation and cGAS activation. Induced cGAS-STING signaling can result in either anti-tumor or pro-tumorigenic processes, depending on the context. Meanwhile, cytokines produced by the activated cGAS-STING pathway, such as type I IFN, boost natural killer (NK) cell responses and prime CD8+ T cells for more potent tumor surveillance (Marcus et al., Immunity 9(4), pp. 754-763, 2018; Woo et al., Immunity 41(5), pp. 830-842, 2014). Meanwhile, activation of the cGAS-STING pathway has been associated with metastasis and immune evasion. Tumor cells with high genomic instability, a hallmark of metastatic tumors, have been proposed to utilize the cGAS-STING pathway to promote cell invasion (Bakhoum et al., Nature 553(7689) 467-472, 2018). Furthermore, cGAS and STING shape the immunosuppressive tumor microenvironment by recruiting regulatory T cells and myeloid suppressor cells and upregulating immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1) (Ding et al., Biochim Biophys Acta 1852(11), 2494-2503, 2015; Liang et al., Nat Commun 8(1), 1736, 2017; Nakamura et al., J Immunother Cancer 9(7), e002852, 2021).

[0215] In embodiments, the present invention relates to compounds, compositions containing same and their use in the treatment of various disorders, in particular autoimmune, autoinflammatory or immune-mediated conditions such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis, scleroderma, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), acute kidney injury, chronic kidney disease, diabetic kidney disease or injury, APOL1 nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, idiopathic pulmonary fibrosis, interstitial lung disease, myocardial infarction, stroke, cardiac hypertrophy / heart failure, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), in particular systemic lupus erythematosus, cutaneous lupus erythematosus and lupus nephritis.

[0216] In embodiments, the present invention relates to compounds, compositions containing same and their use in the treatment of various disorders, particularly autoimmune, autoinflammatory or immune-mediated conditions such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis, scleroderma, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), acute kidney injury, chronic kidney disease, diabetic kidney injury, myocardial infarction, stroke, cardiac hypertrophy / heart failure, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), particularly systemic lupus erythematosus.

[0217] In an aspect of the invention, there is provided a method of treating an autoimmune, autoinflammatory, or immune-mediated condition in a human in need thereof, comprising the step of administering to said human a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0218] In a further aspect, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in therapy.

[0219] In a further aspect, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of an autoimmune, autoinflammatory, or immune-mediated condition.

[0220] In a further aspect, there is provided the use of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, in the manufacture of a medicament for use in the treatment of an autoimmune, autoinflammatory or immune-mediated condition.

[0221] In embodiments, the autoimmune, autoinflammatory or immune-mediated condition is selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis and scleroderma, in particular systemic lupus erythematosus.

[0222] In an embodiment, the autoimmune, autoinflammatory, or immune-mediated condition is systemic lupus erythematosus (SLE). In an embodiment, the systemic lupus erythematosus is characterized as moderate to severe.

[0223] In an embodiment, the autoimmune, autoinflammatory, or immune-mediated condition is lupus nephritis.

[0224] In embodiments, the autoimmune, autoinflammatory or immune-mediated condition is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), acute kidney injury, chronic kidney disease, diabetic kidney injury, myocardial infarction, stroke, cardiac hypertrophy / heart failure, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0225] In embodiments, there is provided a method of treating systemic lupus erythematosus in a human in need thereof, comprising administering to said human a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0226] In an embodiment, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of systemic lupus erythematosus.

[0227] In an embodiment, the systemic lupus erythematosus is characterized as moderate to severe.

[0228] Thus, in an embodiment, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of moderate to severe systemic lupus erythematosus.

[0229] In an embodiment, the systemic lupus erythematosus is characterized as active systemic lupus erythematosus.

[0230] In an embodiment, the systemic lupus erythematosus is moderate to severe active systemic lupus erythematosus.

[0231] In an embodiment, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of lupus nephritis.

[0232] In an embodiment, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of biopsy-identified lupus nephritis.

[0233] In an embodiment, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of cutaneous lupus erythematosus. In an embodiment, the cutaneous lupus erythematosus is subacute or chronic.

[0234] In a further embodiment, there is provided the use of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, in the manufacture of a medicament for use in the treatment of systemic lupus erythematosus.

[0235] In a further embodiment, there is provided the use of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, in the manufacture of a medicament for use in the treatment of lupus nephritis.

[0236] In a further embodiment, there is provided the use of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosus.

[0237] In embodiments, there is provided a compound having the following structure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in treating systemic lupus erythematosus:

[0238] [ka]

[0239] In embodiments, a compound having the following structure is provided for use in treating lupus nephritis:

[0240] [ka]

[0241] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In embodiments, a compound having the following structure for use in treating cutaneous lupus erythematosus:

[0242] [ka]

[0243] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In embodiments, a compound of the following structure for use in treating systemic lupus erythematosus:

[0244] [ka]

[0245] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In embodiments, a compound having the following structure is provided for use in treating lupus nephritis:

[0246] [ka]

[0247] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof. In embodiments, a compound having the following structure for use in treating cutaneous lupus erythematosus:

[0248] [ka]

[0249] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0250] Pharmaceutical Composition / Route of Administration / Dosage While for use in therapy, the compounds of the invention may potentially be administered as the raw chemical, it will usually be presented as the active ingredient as a pharmaceutical composition.

[0251] In a further aspect, the present invention provides a pharmaceutical composition comprising (a) a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, and (b) a pharmaceutically acceptable excipient. The excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0252] Pharmaceutical compositions may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, inhalation, intranasal, topical (including buccal, sublingual or transdermal), ocular (including topical, intraocular, subconjunctival, episcleral, subtenon), parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).

[0253] In one embodiment, pharmaceutical compositions are presented for oral administration, for example, as tablets or capsules.Other compositions suitable for oral administration can be powder or granules;solution or suspension in aqueous or non-aqueous liquid;edible foam or whipped;or oil-in-water liquid emulsion or water-in-oil liquid emulsion.

[0254] The compound of formula (I) or its tautomer, or a pharmaceutically acceptable salt or tautomer of said compound, can be used alone or in combination with other therapeutic agents. Combination therapy according to the present invention therefore comprises the administration of at least one compound of formula (I), or a pharmaceutically acceptable salt or tautomer thereof, and the use of at least one other therapeutically active agent. The compound of formula (I), or a pharmaceutically acceptable salt or tautomer thereof, and the other therapeutically active agent(s) can be formulated and administered together in a single pharmaceutical composition, or can be formulated and administered separately. When formulated and administered separately, administration can occur simultaneously or sequentially in any order.

[0255] The compounds of formula (I) or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers thereof, may be used in combination with one or more other therapeutic agents that may be useful in the treatment of autoimmune, autoinflammatory, or immune-mediated conditions.

[0256] Thus, in a further aspect of the present invention, there is provided a combination of (i) a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, and (ii) an immunomodulatory agent.

[0257] In embodiments, the immunomodulatory agent is belimumab, also known as BENLYSTA.

[0258] In an embodiment, the invention provides a pharmaceutical combination comprising a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, together with an immunomodulatory agent.

[0259] In one embodiment, the invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, together with an immunomodulatory agent for use in combination therapy in the treatment of an autoimmune, autoinflammatory, or immune-mediated condition, particularly systemic lupus erythematosus.

[0260] In one embodiment, the present invention provides a method of treating an autoimmune, autoinflammatory, or immune-mediated condition, comprising administering a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, in combination with an immunomodulatory agent.

[0261] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, may be used in combination with one or more other therapeutic agents useful in the standard of care for treating systemic lupus erythematosus, such as antimalarials, steroids, and immunosuppressants.

[0262] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, may be used to treat SLE patients who have failed standard of care.

[0263] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, may be used to treat patients with SLE who are receiving standard care and who have failed at least one immunosuppressant.

[0264] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, may be used to treat patients with moderate to severe active SLE who are receiving standard of care and who have failed at least one immunosuppressant.

[0265] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, may be used to treat patients with SLE that is not controlled through standard of care treatment alone. [Example]

[0266] General synthesis method The compounds of the present invention can be prepared using the synthetic procedures illustrated in the following reaction schemes and the knowledge of a skilled organic chemist. The syntheses shown in these schemes are applicable to the production of compounds of the present invention having a variety of different substituents, and use appropriate precursors that are suitably protected as necessary to achieve compatibility with the reactions outlined herein. Subsequent deprotection, if necessary, yields compounds of the generally disclosed nature. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art, and examples can be found in "Greene's Protective Groups in Organic Synthesis" (Peter GM Nuts, 5th Edition, J. Wiley and Sons, 2014). Intermediates (compounds used to prepare compounds of the present invention) can also exist as salts.

[0267] General Method 1 (Scheme 1) A suitably protected haloketone triazole compound (A) and pyrimidin-2-amine (B) are combined in a suitable solvent, such as EtOH, and heated to give the resulting imidazopyrimidine (C). Halogenation of the imidazopyrimidine with a suitable reagent, such as N-bromosuccinimide, gives (D), where X is a halogen. Catalyst-mediated coupling of (D) with a suitable reagent, such as a boronate (E), gives a compound protected with a suitable protecting group, where -GZ is R. 3 Removal of the triazole protecting group (Y) and any other potential protecting groups by any suitable method, such as acidic hydrolysis, provides the desired 1H-triazole of formula (I).

[0268] [ka]

[0269] General Method 2 (Scheme 2) General method 1 (R 5The bromoimidazopyrimidine (H) can be prepared via a suitable protecting group, -GZ, where R is Br, by coupling with a suitable partner (i.e., an alkyl halide using photocatalysis) via catalyst-mediated coupling to form a suitable protecting group, -GZ, where R is Br. 3 Removal of the triazole protecting group (Y) and any other potential protecting groups by an appropriate method, such as acidic hydrolysis, provides the desired 1H-triazole of formula (I).

[0270] [ka]

[0271] General Method 3 (Scheme 3) R prepared via Method 1 4 , R 5 or R 6 (As shown, R 5 ), imidazopyrimidines (K) bearing suitably protected functional groups (PG = protecting group) on the aryl group can be selectively deprotected to give L, which can then be further functionalized (e.g., by electrophilic alkylation) to give M. Removal of the remaining protecting groups (Y and Z) gives compounds of formula (I).

[0272] [ka]

[0273] General Method 4 (Scheme 4) R synthesized via Method 1 4 , R 5 or R 6 (As shown, R 5 Imidazopyrimidines (N) bearing a primary alcohol at one (or more) of the positions bearing the protecting groups Y and Z are converted to a leaving group (e.g., mesylate) and substituted with a suitable nucleophile to yield P. Further elaboration is possible to obtain compounds of formula (I) before removing the remaining protecting groups Y and Z.

[0274] [ka]

[0275] General Method 5 (Scheme 5) Method 5 is an extension of Method 1, with an additional functionalization step following imidazopyrimidine formation. 5a If R can be further functionalized (e.g., by introducing new substituents via catalyst-mediated coupling or electrophilic alkylation), the reaction will give a substituted imidazopyrimidine (R). This group can be further functionalized to give a desired R 5 The imidazopyrimidine (S) can be further modified by known methods to obtain the desired group. Subsequent halogenation of the imidazopyrimidine with a suitable reagent, such as N-bromosuccinimide, gives (S). Catalyst-mediated coupling of (S) with a suitable reagent, such as a boronate (E), gives the substituted imidazopyrimidine (T). Removal of the triazole protecting group (Y) and any other potential protecting groups (e.g., Z) by any suitable method, such as acidic hydrolysis, gives the 1H-triazole compound of formula (I). This method can also be applied to molecules in which the groups at the R4 or R6 positions can be modified as above.

[0276] [ka]

[0277] General Method 6 (Scheme 6) General Method 6 employs a synthetic strategy of late-stage triazole formation. The imidazopyrimidine (W) is formed by the reaction of U and V. Amide formation and subsequent halogenation of the imidazopyrimidine with a suitable reagent, such as N-bromosuccinimide, affords X. Catalyst-mediated coupling of X with a suitable reagent, such as boronate E, leads to the substituted imidazopyrimidine Y. The amidine-forming R 1Two-step triazole formation via condensation with a reagent containing (AA) is followed by condensation with hydrazine and cyclization to the triazole (BB). Removal of the protecting group Z can be accomplished either in this step or using a separate deprotection step to provide the 1H-triazole compounds of formula (I).

[0278] [ka]

[0279] General method for preparing prodrugs (Scheme 7) The triazole (I), which can be prepared via one of the general methods described, is reacted with a suitable reagent to give a prodrug of formula (I) (PM = prodrug moiety), which may contain an additional protecting group. If a protecting group is present, removal by a suitable method in step 6 completes the synthesis. The prodrug moiety may also be incorporated at an earlier stage in the synthesis.

[0280] [ka]

[0281] Automated preparative HPLC (MDAP) directly connected to a mass spectrometer Mass-coupled automated preparative HPLC was used to prepare the compounds of the present invention, and the conditions are shown below: UV detection was signal averaged from 210 nm to 350 nm wavelength, and mass spectra were recorded on a mass spectrometer using alternating scan positive and negative mode electrospray ionization.

[0282] MDAP method A Method A was performed at ambient temperature using Xselect CSH C 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of trifluoroacetic acid in water B = 0.1% v / v solution of trifluoroacetic acid in acetonitrile It was.

[0283] The gradient used was:

[0284] [Table 2]

[0285] MDAP method B Method B is performed at ambient temperature using Xselect CSH C 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of formic acid in water B = 0.1% v / v solution of formic acid in acetonitrile It was.

[0286] The gradient used was:

[0287] [Table 3]

[0288] MDAP method C Method C: Xselect CSH C at ambient temperature 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of formic acid in water B = 0.1% v / v solution of formic acid in acetonitrile It was.

[0289] The gradient used was:

[0290] [Table 4]

[0291] MDAP method D Method D was performed using Xselect CSH C at ambient temperature.18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of formic acid in water B = 0.1% v / v solution of formic acid in acetonitrile It was.

[0292] The gradient used was:

[0293] [Table 5]

[0294] MDAP method E Method E was performed using Xselect CSH C at ambient temperature. 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of trifluoroacetic acid in water B = 0.1% v / v solution of trifluoroacetic acid in acetonitrile It was.

[0295] The gradient used was:

[0296] [Table 6]

[0297] MDAP method F Method F: Xselect CSH C at ambient temperature 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of formic acid in water B = 0.1% v / v solution of formic acid in acetonitrile It was.

[0298] The gradient used was:

[0299] [Table 7]

[0300] MDAP method G Method G was performed using Xselect CSH C at ambient temperature. 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of formic acid in water B = 0.1% v / v solution of formic acid in acetonitrile It was.

[0301] The gradient used was:

[0302] [Table 8]

[0303] MDAP method H Method H: Xselect CSH C at ambient temperature 18 The run was carried out on a column (typically 150 mm x 30 mm, id 5 μm packing diameter). The solvents used were: A = 0.1% v / v solution of trifluoroacetic acid in water B = 0.1% v / v solution of trifluoroacetic acid in acetonitrile It was.

[0304] The gradient used was:

[0305] [Table 9]

[0306] Unless otherwise specified, intermediates and starting materials for preparing the examples are commercially available, for example from PharmaTech and Sigma Aldrich.

[0307] Intermediate 1 1-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-2-chloroethanone

[0308] [ka]

[0309] Step 1: 3,5-Dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole To a solution of 3,5-dibromo-1H-1,2,4-triazole (200 g, 882 mmol) in AcCN (300 mL) was added DIEA (308 mL, 176 mmol), 1-(chloromethyl)-4-methoxybenzene (143 mL, 1058 mmol), and KI (14.63 g, 88 mmol) at room temperature. After 16 h, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over NaSO, and concentrated. The residue was dissolved in DCM (250 mL), adsorbed onto silica (100 g), and then purified by column chromatography (100-200 mesh silica gel [1 kg]) eluting with 5-10% EtOAc in hexanes to give the title compound (190 g, 531 mmol, 60% yield) as an off-white solid. LCMS: [M+H] + = 347.92

[0310] [ka]

[0311] Step 2: 1-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-2-chloroethanone To 3,5-dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole (100 g, 280 mmol) in THF (800 mL) was added isopropylmagnesium lithium chloride (1 M in THF) (559 mL, 559 mmol) at −40° C. After 2 h, 2-chloro-N-methoxy-N-methylacetamide (42.3 g, 307 mmol) in THF (200 mL) was added. After 1 h, the reaction was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (2 × 1 L). The combined organic extracts were washed with brine (500 mL), dried over Na2SO4, and concentrated. The residue was adsorbed onto silica (100 g) and purified by column chromatography (100-200 mesh silica gel [400 g]) eluting with 10-20% EtOAc in hexanes to give the title compound (23.45 g, 66.5 mmol, 24% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.33 - 7.41 (m, 2 H), 6.83 - 6.90 (m, 2 H), 5.66 (s, 2 H), 4.87 (s, 2 H), 3.78 (s, 3 H). LCMS: [M+H] + = 345.92

[0312] Intermediate 2 N,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide

[0313] [ka]

[0314] A mixture of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (3.0 g, 4.53 mmol) and bis(pinacolato)diboron (44.0 g, 173 mmol) in THF (150 mL) was stirred at 45° C. for 20 minutes and then treated with a solution of 4,4′-di-tert-butyl-2,2′-dipyridyl (1.50 g, 5.59 mmol) in THF (50 mL). After 20 minutes, a solution of N,N-dimethyl-1H-imidazole-1-sulfonamide (20.0 g, 114 mmol) in THF (80 mL) was added, and the temperature was raised to 65° C. After 2 hours, the reaction was concentrated, and the resulting residue was triturated with pentane to give the title compound (32.2 g, 102 mmol, 89% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J = 1.01 Hz, 1 H), 7.73 (d, J = 1.01 Hz, 1 H), 2.89 (s, 6 H), 1.39 (s, 12 H). LCMS: [M+H] + = 220.1 (boronic acid)

[0315] Intermediate 3 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one

[0316] [ka]

[0317] Step 1: 1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazole To a stirred mixture of (4-methoxybenzyl)hydrazine hydrochloride (50.0 g, 265 mmol) in methanol (500 mL) was added sodium methoxide 25 wt % in methanol (60.0 g, 278 mmol). The white suspension was stirred for 15 min before methyl 2,2,2-trifluoroacetate (36.0 g, 281 mmol) was added dropwise over 30 min. The reaction was stirred for an additional 2 h (LCMS showed tRET A new peak (UV) of 92% was observed at 0.75 min. Weak M+Na + 271.2 is found in acylated PMB hydrazine. PMB hydrazine SM t RET 0.33 min. MS(ES) [M+H] + The reaction was treated with formamidine acetate acetic acid salt (30.0 g, 288 mmol), heated to reflux at 85° C., and stirred for 24 hours (LCMS showed t RET New peak at 0.95 min 47% (UV) and weak MS (ES) [M+H] + The reaction was evaporated to dryness, dissolved in EtOAc, washed with aqueous NaHCO, dried (NaSO), filtered, and evaporated to dryness. Purification was performed by silica gel chromatography (Isco RediSep Rf Gold 330 g, 0%, 4 min to 30%, 2 min, then 70%, 15 min, EtOAc in heptane). Pure fractions were combined and evaporated to dryness to give the product, 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (45.4 g) as a yellow oil, which solidified to a yellow solid under vacuum. This material was used in the next reaction without further purification. The reaction was repeated five more times to give a total of 260.5 g of product. 1 H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.35-7.30 (m, 2H), 6.97 (d, J=8.9 Hz, 2H), 5.36 (s, 2H), 3.87 (s, 3H). LCMS m / z 258.2 [M+H] +

[0318] [ka]

[0319] Step 2 The following reaction was carried out twice at half scale and then combined after purification.

[0320] To a stirred solution of 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (64.0 g, 249 mmol) in tetrahydrofuran (THF) (400 mL) under nitrogen at −10° C. (ice, NaCl) was added dropwise over 30 minutes 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex 1.0 N (400 mL, 400 mmol). The reaction was stirred for 30 minutes and then treated with a solution of 2-chloro-N-methoxy-N-methylacetamide (58.0 g, 422 mmol) in tetrahydrofuran (THF) (140 mL). The reaction was stirred for 1 hour and then carefully quenched with 1 N aqueous HCl (500 mL). The (pH ∼4) reaction was extracted with EtOAc (300 mL), washed with brine, dried (NaSO), filtered, and concentrated in vacuo. Purification was achieved by silica gel chromatography (Isco RediSep Rf Gold 330 g, 25 to 60% CHCl in heptane; the solid was loaded onto 30 g Isolute HM-N). Pure fractions were combined and evaporated to dryness to give the product, 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (53.21 g, 159 mmol, 64.1% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J=8.9 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 5.78 (s, 2H), 4.97 (s, 2H), 3.83 (s, 3H).

[0321] Intermediate 4 2-chloro-1-(3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)ethan-1-one

[0322] [ka]

[0323] Step 1 To a mixture of (4-methoxybenzyl)hydrazine hydrochloride (25 g, 133 mmol) and potassium carbonate (37.5 g, 271 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (250 mL) was added 2,2-difluoroacetic anhydride (25 mL, 201 mmol) dropwise over 30 minutes. The reaction was stirred for 30 minutes and then diluted with EtOAc (300 mL) and water (500 mL). The ethyl acetate phase was removed, washed with brine, dried (NaSO), filtered, and evaporated in vacuo. The residue was dissolved in ethanol (250 mL) and treated with formamidine acetate (20 g, 192 mmol) at 100° C. for 24 hours, after which acetic acid (75 mL, 1310 mmol) was added. The reaction was cooled to room temperature and evaporated in vacuo. The residue was dissolved in EtOAc, washed with aqueous NaHCO, dried (NaSO), filtered, and evaporated in vacuo. Purification by silica gel chromatography (Isco RediSep Rf Gold 220 g, 20 to 80% EtOAc in heptane) afforded 3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (26 g, 75% yield) as a pale yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.28-7.31 (m, 2H), 6.93-6.99 (m, 2H), 6.75 (t, J=53.7 Hz, 1H), 5.33 (s, 2H), 3.86 (s, 3H). LCMS m / z 240.2 [M+H] +

[0324] Step 2 To a stirred solution of 3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (25 g, 105 mmol) in tetrahydrofuran (200 mL) at −10° C. under nitrogen (ice, NaCl), 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex 1.0 N in THF / toluene (180 mL, 180 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred for 30 minutes and then treated with a solution of 2-chloro-N-methoxy-N-methylacetamide (25 g, 182 mmol) in tetrahydrofuran (50 mL). The reaction was stirred for 1 hour and then carefully quenched with 1 N aqueous HCl (450 mL) (pH ∼4). The reaction was extracted with EtOAc (300 mL), washed (brine), dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Isco RediSep Rf Gold 330 g, 10 to 50% EtOAc in heptane). The desired fractions were combined and concentrated in vacuo to give 2-chloro-1-(3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (19.6 g, 59.4% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.42 (d, J=8.87 Hz, 2H), 6.90 (d, J=8.87 Hz, 2H), 6.76 (t, J=53.3 Hz, 1H), 5.76 (s, 2H), 4.98 (s, 2H), 3.83 (s, 3H). LCMS m / z 316.0 [M+H] + (weak).

[0325] Intermediate 5 6-Bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine

[0326] [ka]

[0327] A mixture of 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (4.0 g, 11.99 mmol, Intermediate 3), 5-bromopyrimidin-2-amine (4.2 g, 24.14 mmol) and isopropanol (60 mL) was refluxed for 3 days. The reaction was cooled to room temperature. The resulting suspension was basified with aqueous saturated NaHCO3, filtered, washed with water and dried under vacuum to give the crude product. The crude product was purified by silica gel chromatography (Isco RediSep Rf Gold 120 g, 0 to 20% EtOAc in DCM). The desired fractions were combined and evaporated in vacuo. The residue was triturated with hexane, filtered, and dried under vacuum to give 6-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (1.85 g, 32.3% yield) as a light tan solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=2.45 Hz, 1H), 8.78 (d, J=2.45 Hz, 1H), 8.55 (s, 1H), 7.36 (d, J=8.80 Hz, 2H), 6.86-6.93 (m, 2H), 6.11 (s, 2H), 3.71 (s, 3H). LCMS m / z 453.1, 455.1 [M+H] +

[0328] Intermediate 6 2-(2-aminopyrimidin-4-yl)-2,2-difluoroethan-1-ol

[0329] [ka]

[0330] Step 1 A mixture of 4-iodopyrimidin-2-amine (5.0 g, 22.62 mmol), copper powder (3.8 g, 59.8 mmol), DMSO (10 mL), and ethyl 2-bromo-2,2-difluoroacetate (4.4 mL, 34.3 mmol) was heated to 60 °C for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), neutralized with saturated aqueous NH4Cl (200 mL), and stirred for 15 min. The mixture was filtered to remove insoluble material and rinsed with EtOAc. The clear filtrate was transferred to a separatory funnel, and the aqueous phase was removed. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (Isco RediSep Rf Gold 80 g, 0 to 100% EtOAc in CHCl2). The desired fractions were combined and concentrated in vacuo to give ethyl 2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetate (2.3 g, 44.5% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (d, J=4.89 Hz, 1H), 7.16 (s, 2H), 6.88 (d, J=4.89 Hz, 1H), 4.32 (q, J=6.85 Hz, 2H), 1.18-1.26 (m, 3H).LCMS m / z 218.2 [M+H] +

[0331] Step 2 To a stirred solution of ethyl 2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetate (2.0 g, 9.21 mmol) in ethanol (50 mL) at 0 °C was added sodium borohydride (400 mg, 10.57 mmol) in portions. The reaction was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The reaction was stirred for 1.5 hours and then slowly quenched with 1 N aqueous HCl (25 mL). The reaction was concentrated to near dryness in vacuo, basified with saturated NaHCO3, and filtered to remove insoluble material. The product remained in the aqueous filtrate. The aqueous solution was evaporated to dryness in vacuo. The resulting solid was triturated with 20% MeOH in CHCl3 (100 mL), filtered, and rinsed with 20% MeOH in CHCl3. The filtrate was evaporated to dryness in vacuo to give the crude product as a yellow solid. The crude material was purified by silica gel chromatography (Isco RediSep Rf Gold 80 g, 0 to 20% MeOH in DCM). The desired fractions were combined and evaporated in vacuo to give 2-(2-aminopyrimidin-4-yl)-2,2-difluoroethan-1-ol (1.1 g, 64.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (d, J=4.89 Hz, 1H), 6.98 (s, 2H), 6.78 (d, J=4.89 Hz, 1H), 5.58 (t, J=6.48 Hz, 1H), 3.89 (dt, J=6.48, 14.12 Hz, 2H). LCMS m / z 176.1 [M+H] +

[0332] Intermediate 7 4-(Difluoromethyl)pyrimidin-2-amine

[0333] [ka]

[0334] Step 1 To a stirred solution of ethyl vinyl ether (15.99 mL, 167 mmol) and pyridine (16.4 mL, 203 mmol) in DCM (160 mL) at −70° C. (CO, iPrOH) was added 2,2-difluoroacetic anhydride (25.8 mL, 208 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The organics were separated, dried (NaSO), filtered, and concentrated in vacuo to give (E)-4-ethoxy-1,1-difluorobut-3-en-2-one (25.4 g, 87% yield) as an orange oil. 1 H NMR (400 MHz, chloroform-d) δ 7.84 (d, J=12.23 Hz, 1H), 5.85-5.91 (m, 1H), 5.62 (t, J=54 Hz, 1H), 4.07 (q, J=7.17 Hz, 2H), 1.39 (t, J=7.09 Hz, 3H). LCMS m / z 151.1 [M+H] +

[0335] Step 2 A mixture of guanidine hydrochloride (19.6 g, 205 mmol) and ethanol (80 mL) was stirred for 1 hour, then treated with sodium hydroxide (8.0 g, 200 mmol) and stirred overnight. To this stirred suspension, a solution of the above intermediate, (E)-4-ethoxy-1,1-difluorobut-3-en-2-one (25.4 g, 146 mmol) in DCM (80 mL) was added dropwise over 1 hour. The mixture was stirred for 2 hours and then evaporated in vacuo. The residue was dissolved in water (100 mL) and stirred vigorously. The resulting solid was filtered, washed with water and heptane, and then dried under vacuum to give 4-(difluoromethyl)pyrimidin-2-amine (14.02 g, 55.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=4.89 Hz, 1H), 7.01 (br. s., 2H), 6.76 (d, J=4.89 Hz, 1H), 6.67 (t, J=54.8 Hz, 1H). LCMS m / z 146.0 [M+H] +

[0336] Intermediate 8 tert-Butyl 2-amino-8,8-difluoro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0337] [ka]

[0338] Step 1 tert-Butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (855 mg, 3.63 mmol) was mixed with 1,1-dimethoxy-N,N-dimethylmethanamine (10 mL, 74.7 mmol) and the mixture was heated to 100° C. for 16 h. The reaction was cooled to room temperature and slowly neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (6×) and the combined organics were washed (brine), dried (MgSO), filtered, and concentrated in vacuo to give crude tert-butyl (E)-5-((dimethylamino)methylene)-3,3-difluoro-4-oxopiperidine-1-carboxylate (1055 mg, 100% yield). LCMS m / z 291.2 [M+H] +

[0339] Step 2 tert-Butyl (E)-5-((dimethylamino)methylene)-3,3-difluoro-4-oxopiperidine-1-carboxylate (1050 mg, 3.62 mmol), guanidine hydrochloride (930 mg, 9.74 mmol), and K2CO3 (1353 mg, 9.79 mmol) were suspended in N-methyl-2-pyrrolidone (NMP) (15 mL) and heated to 75°C for 3 h. The solution was cooled to room temperature and then slowly neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (4x), and the combined organics were washed (brine), dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Isco RediSep Rf Gold 80 g, 0-100% EtOAc in heptane). The desired fractions were concentrated in vacuo to give tert-butyl 2-amino-8,8-difluoro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (695 mg, 67.1% yield). LCMS m / z 287.2 [M+H] +

[0340] [Example 1] 5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0341] [ka]

[0342] Step 1 2-Chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (Intermediate 3) (6.20 g, 18.6 mmol) and pyrimidin-2-amine (3.71 g, 39.0 mmol) in EtOH (80 mL) were heated at 90° C. overnight. The reaction was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with EtOH to give 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine hydrochloride (3.85 g, 9.37 mmol, 50% yield) as a white solid. LCMS m / z 375.2 [M+H] +

[0343] Step 2 To 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine hydrochloride (6.07 g, 14.8 mmol) in chloroform (200 mL) was added N-bromosuccinimide (3.68 g, 20.7 mmol) and the mixture was heated to 60 °C for 2 h. The reaction was washed with 1:1 saturated NaSO(aq) / saturated NaHCO(aq) and brine, dried over MgSO, and concentrated. The residue was triturated with 10% DCM in hexanes, and the resulting solid was washed with hexanes to give 3-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (6.22 g, 13.7 mmol, 93% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.76 (dd, J = 4.1, 2.0 Hz, 1H), 8.61 (dd, J = 6.8, 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 7.0, 4.2 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.17 (s, 2H), 3.79 (s, 3H). LCMS m / z 455.3 [M+H] +

[0344] Step 3 A mixture of 3-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (4.51 g, 9.95 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (Intermediate 2) (5.99 g, 19.9 mmol), PdCl(dppf)-CHCl- adduct (1.63 g, 1.99 mmol), and potassium phosphate (3.17 g, 14.9 mmol) in dioxane (20 mL) and water (4 mL) was purged with nitrogen and heated at 100 °C for 10 h. The reaction was concentrated, and the residue was partitioned between saturated aqueous NaHCO and DCM. The organic layer was isolated, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (ISCO 330 g RediSep Rf column, eluting with 20–100% [3:1 EtOAc:EtOH] in hexanes) to give 4-(2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.02 g, 74%). 1 H NMR (400 MHz, CDCl3) δ ppm 9.82 (dd, J = 7.1, 2.0 Hz, 1H), 8.76 (dd, J = 4.1, 2.0 Hz, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.08 (d, J = 1.3 Hz, 1H), 7.49 (d, J = 8.9 Hz, 2H), 7.09 (dd, J = 7.1, 4.1 Hz, 1H), 6.85 (d, J = 8.9 Hz, 2H), 6.23 (s, 2H), 3.79 (s, 3H), 3.01 (s, 6H). LCMS m / z 548.3 [M+H] +

[0345] Step 4 4-(2-(1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.02 g, 7.34 mmol) in TFA (40 mL) was heated to 90° C. for 2 h and concentrated. The residue was dissolved in water (5 mL), and saturated aqueous NaHCO was added to adjust the pH to 7, followed by stirring in a mixture of EtOAc (200 mL) and saturated aqueous NaHCO for 1 h. The resulting precipitate was collected by filtration and suspended in EtOH at 100° C. for 1 h. The solid was collected by filtration, resuspended in EtOH at 100° C. for 1 h, and collected by filtration to give 3-(1H-imidazol-4-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (1.42 g, 4.43 mmol, 60%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.78 (br s, 1H), 9.87 (d, J = 5.6 Hz, 1H), 8.75 (dd, J = 1.9, 3.9 Hz, 1H), 8.49 (s, 1H), 8.33 (br s, 1H), 7.27 (dd, J = 4.1, 6.8 Hz, 1H). LCMS m / z 321.2 [M+H] +

[0346] [Example 2] 5-[6-Fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0347] [ka]

[0348] Step 1 In each of nine separate vessels, a mixture of 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (1.00 g, 3.00 mmol) (Intermediate 3) and 5-fluoropyrimidin-2-amine (508 mg, 4.50 mmol) in MeCN (10 mL) was heated at 170 °C for 4 h in a microwave reactor. The nine reaction mixtures were combined and filtered. The filtrate was evaporated and purified by silica gel chromatography (330 g Isco RediSep Rf Gold column, 10-80% [3:1:0.01 EtOAc / EtOH / EtN] in hexanes). The fractions were combined and concentrated in vacuo to give 6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (7.07 g, 18.0 mmol, 67% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.72 (d, J=2.9 Hz, 1H), 8.55 - 8.43 (m, 1 H), 8.33 (s, 1H), 7.52 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.20 (s, 2H), 3.80 (s, 3H). LCMS m / z 393.1 [M+H] +

[0349] Step 2 To a mixture of 6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (7.07 g, 18.02 mmol) in DCM (400 mL) was added NBS (4.17 g, 23.4 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between 1:1 saturated aqueous NaSO / saturated aqueous NaHCO and DCM. The organic layer was washed with brine, dried over MgSO, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (330 g Isco RediSep Rf Gold column, 10 to 50% [3:1:0.01 EtOAc / EtOH / EtN] in hexanes) to afford 3-bromo-6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (5.76 g, 12.2 mmol, 68% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.74 (d, J=2.7 Hz, 1H), 8.53 (t, J=3.1 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.14 (s, 2H), 3.80 (s, 3H). LCMS m / z 473.0 [M+H] +

[0350] Step 3 A mixture of 3-bromo-6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (5.76 g, 12.2 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (5.52 g, 18.34 mmol) (Intermediate 2), CsF (4.09 g, 26.9 mmol), and PdCl(dppf)-CHCl adduct (0.998 g, 1.222 mmol) in DME (5 ml) was heated under N and stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (220 g Isco RediSep Rf Gold column, 20–80% 3:1 EtOAc:EtOH in hexanes and 2% NHOH) to give 4-(6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.88 g, 8.63 mmol, 70% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 9.95 (dd, J=4.4, 2.9 Hz, 1H), 8.86 - 8.66 (m, 2H), 8.09 (d, J=1.2 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 6.85 (d, LCMS m / z 566.1 [M+H] +

[0351] Step 4 4-(6-Fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (565 mg, 0.999 mmol) in TFA (10 mL) was heated and stirred at 90 ° C. for 4 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (MDAP Method A) to give 5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole as a yellow solid (233 mg, 0.69 mmol, 69%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.75 (br s, 1 H), 12.73 (br s, 1 H), 10.30 (dd, J=5.0, 3.1 Hz, 1 H), 8.93 (d, J=2.9 Hz, 1 H), 8.64 (s, 1 H), 8.06 (d, J=1.2 Hz, 1 H). LCMS:t RET =0.41 min (1-100% gradient from 0.1% v / v TFA in acetonitrile to 0.1% v / v TFA in water over 1.85 min), m / z 339.2 [M+H] +

[0352] [Example 3] 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0353] [ka]

[0354] Step 1 2-Chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (Intermediate 3) (2.46 g, 7.36 mmol), 4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 6.13 mmol) and sodium bicarbonate (0.515 g, 6.13 mmol) in CHCN (20 mL) were heated in a capped vessel at 115° C. overnight. Another 500 mg of 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one was added and heating was continued overnight, followed by the addition of additional 500 mg of 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one. The temperature was raised to 120° C. and the reaction was stirred overnight and cooled. The resulting precipitate was removed by filtration and washed with aqueous citric acid and MeOH. The filtrate was concentrated until only an aqueous solution remained, which was extracted with EtOAc. The organic layer was dried over NaSO, concentrated, and purified by silica gel chromatography (120 g Isco RediSep Rf Gold column, eluting with 0–50% EtOAc in hexanes) to give the crude product. This material was sonicated with MeOH and filtered. The filtrate was treated with water until a solid precipitated, which was collected by filtration and washed with hexanes followed by 10% EtO in hexanes to give 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine (980 mg, 1.88 mmol, 31%) as a tan solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (d, J = 6.8 Hz, 1H), 8.90 (s, 1H), 7.71 (d, J = 6.8 Hz, 1H), 7.36 - 7.40 (m, 2H), 6.90 - 6.94 (m, 2H), 6.15 (s, 2H), 3.72 (s, 3H). LCMS m / z 443.2 [M+H] +

[0355] Step 2 To 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine (500 mg, 1.13 mmol) in chloroform (15 mL) was added N-bromosuccinimide (225 mg, 1.27 mmol), and the mixture was stirred at room temperature for 90 minutes, at 55° C. for 1 hour, and then at 45° C. overnight. The reaction was concentrated, dissolved in DCM, washed with saturated aqueous NaHCO, dried over NaSO, and concentrated. The resulting residue was triturated with 1:4 EtO:hexanes to afford 3-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine (385 mg, 0.687 mmol, 61%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (d, J = 7.1 Hz, 1H), 7.77 (d, J = 7.1 Hz, 1H), 7.35 - 7.40 (m, 2H), 6.90 - 6.95 (m, 2H), 6.05 (s, 2H,) 3.73 (s, 3H). LCMS m / z 523.2 [M+H] +

[0356] Step 3 A mixture of 3-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine (380 mg, 0.729 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (Intermediate 2) (439 mg, 1.46 mmol) in dioxane (8 mL) was stirred for several minutes. Water (400 μL), PdCl(dppf)-CHCl- adduct (107 mg, 0.131 mmol), and potassium phosphate (232 g, 1.09 mmol) were added, and the mixture was purged with nitrogen. The reaction was capped and heated to 100 °C for 3 h and partitioned between EtOAc and water. The organic layer was isolated, concentrated, and purified by silica gel chromatography (120 g Isco RediSep Rf Gold column eluting with 5 to 55% EtOAc in hexanes) to afford 4-(2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (350 mg, 0.512 mmol, 70%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (d, J = 7.3 Hz, 1H), 8.55 (dd, J = 20.0, 1.4 Hz, 2 H), 7.77 (d, J = 7.3 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 2 H), 6.90 - 6.98 (m, 2 H), 5.96 (s, 2 H), 3.73 (s, 3 H), 2.88 (s, 6 H). LCMS m / z 616.3 [M+H] +

[0357] Step 4 4-(2-(1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (350 mg, 0.569 mmol) in TFA (12 mL) was stirred at 68° C. overnight. The reaction was concentrated, azeotroped with MeOH, and purified by preparative HPLC (MDAP Method B). Fractions containing the desired product were treated with sodium citrate buffer and concentrated until only aqueous solution remained. The resulting solid was collected by filtration and washed with water and hexane to give 3-(1H-imidazol-4-yl)-7-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (100 mg, 0.245 mmol, 43%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.88 (br s, 1H), 12.81 (br s, 1H), 10.48 (d, J = 7.4 Hz, 1H), 8.68 (s, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H). LCMS m / z 389.1 [M+H] +

[0358] Examples 4 to 12 were synthesized in the same manner as in Example 2.

[0359] [Table 10-1] [Table 10-2] [Table 10-3]

[0360] The following example was prepared in a similar manner to Example 2, except for the additional steps 3a and 3b that were performed after step 3.

[0361] [Example 13] 1-[3-(1H-imidazol-5-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-7-yl]ethan-1-ol

[0362] [ka]

[0363] Step 3a 4-(7-(1,1-Dimethoxyethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (70.4 mg, 0.11 mmol) was dissolved in THF (4 mL). HCl (2 mL, 8.00 mmol, 4N in dioxane) was added and the reaction was stirred at room temperature for 3 hours. When no reaction was observed so far, 6 drops of 6N aqueous HCl were added and the reaction was stirred at room temperature for 20 hours, then at 60° C. for 4 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was partitioned between saturated aqueous NaHCO and EtOAc. The organic layer was washed with brine, dried (MgSO), filtered, and concentrated to give 1-(3-(1H-imidazol-4-yl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-one (39.8 mg, 0.082 mmol, 74% yield) as a crude yellow residue, which was used in the next step without purification. LCMS m / z 483.2 [M+H] +

[0364] Step 3b 1-(3-(1H-imidazol-4-yl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-one (39.8 mg, 0.08 mmol) was dissolved in THF (4 mL). NaBH (9.36 mg, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding 0.5 mL saturated aqueous NaHCO. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO), filtered, and concentrated in vacuo to give a crude yellow residue of 1-(3-(1H-imidazol-4-yl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-ol (39.2 mg, 0.08 mmol, 98% yield), which was used in the next step without purification. LCMS m / z 485.2 [M+H] +

[0365] Step 4 1-(3-(1H-imidazol-4-yl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-ol (39.2 mg, 0.08 mmol) was dissolved in trifluoroacetic acid (2 mL, 26.0 mmol). The mixture was stirred at 60° C. for 6 hours. The reaction mixture was cooled and concentrated to a yellow residue. The residue was dissolved in 2 mL THF and 6 drops of 16N aqueous NaOH were added. The mixture was stirred for 1 hour and then concentrated to a yellow residue. This residue was purified by preparative HPLC (Xselect CSH C 18Purification was performed on a column (150 mm x 30 mm, id 5 μm packing diameter), 30–85% 10 mM ammonium bicarbonate in water and acetonitrile. The desired fractions were concentrated to give 1-(3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-ol (3.5 mg, 0.009 mmol, 12% yield) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ ppm 9.44 (d, J=7.1 Hz, 1H), 7.89 (d, J=0.98 Hz, 1H), 7.61 (s, 1H), 7.34 (d, J=7.1 Hz, 1H), 5.08-4.85 (m, 1H), 1.57 (d, J=6.8 Hz, 3H). LCMS m / z 365.1 [M+H] +

[0366] The following example was prepared in a similar manner to Example 2, except that step 4a was performed after step 3.

[0367] [Example 14] 1-[3-(1H-imidazol-5-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-7-yl]ethan-1-one

[0368] [ka]

[0369] Step 4a 4-(7-(1,1-dimethoxyethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (58.1 mg, 0.091 mmol) was dissolved in trifluoroacetic acid (2 mL, 26.0 mmol). The reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was cooled and the mixture was concentrated to a brown residue. This residue was purified by reverse-phase HPLC (Xselect CSH C). 18 Purification was performed on a column (150 mm x 30 mm, id 5 μm packing diameter), 15–50% acetonitrile / water, each with 0.1% formic acid. The desired fractions were concentrated to give 1-(3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-one (15 mg, 0.041 mmol, 45% yield) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ ppm 9.82 (d, J=7.3 Hz, 1 H), 8.39 (s, 1 H), 8.00 (d, J=0.98 Hz, 1 H), 7.72 (d, J=7.1 Hz, 1 H), 2.79 (s, 3 H). LCMS m / z 363.1 [M+H] +

[0370] Examples 15-17 were synthesized in a similar manner to Example 2, except that an additional step 3c was performed after step 3.

[0371] [Example 15] 5-[6-(cyclohexylmethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole, trifluoroacetate

[0372] [ka]

[0373] Step 2 To a solution of 6-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (1 g, 2.21 mmol) (Intermediate 5) in acetonitrile (50 mL) was added NIS (0.596 g, 2.65 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography (220 g column, 2:1, PE:EtOAc) to afford 6-bromo-3-iodo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (1.1 g, 1.823 mmol, 83% yield) as a yellow solid. LCMS m / z 578.9 [M+H] +

[0374] Step 3c 4-(6-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (100 mg, 0.16 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8.96 mg, 7.98 μL) in DME (10 ml). To a solution of (MeSi)2SiH (0.05 mL, 0.16 mmol) and (bromomethyl)cyclohexane (42.4 mg, 0.24 mmol) was added (MeSi)3SiH (0.05 mL, 0.16 mmol) and (bromomethyl)cyclohexane (42.4 mg, 0.24 mmol) with stirring under N2. The reaction was stirred at room temperature for 3 h using a 37 W blue LED. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography (100 g column, 1:1, PE:EtOAc) to give 4-(6-(cyclohexylmethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (80 mg, 0.123 mmol, 77% yield) as a yellow solid. LCMS m / z 644.2 [M+H] +

[0375] Step 4 A solution of 4-(6-(cyclohexylmethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (80 mg, 0.124 mmol) in TFA (4 mL) was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and concentrated to remove TFA. The residue was dissolved in DMF (2.0 mL), filtered, and purified by preparative HPLC (SunFire C18 OBD Prep column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water [0.05% TFA], mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 28% B to 45% B over 7 min). The product was collected, concentrated, and lyophilized to give 6-(cyclohexylmethyl)-3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine, trifluoroacetate salt (9.4 mg, 0.018 mmol, 14% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 2.52 (d, J = 6.8 Hz, 2H), 1.61-1.58 (m, 6H), 1.09-1.07 (m, 3H), 1.02-0.83 (m, 2H). LCMS m / z 417.1 [M+H] +

[0376] [Example 16] 5-[6-Cyclopentyl-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole, trifluoroacetate

[0377] [ka]

[0378] Step 3c 4-(6-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (100 mg, 0.16 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8.96 mg, 7.98 mmol) in DME (8 ml) To a solution of (MeSi)2SiH (0.05 mL, 0.160 mmol) and LiOH (7.65 mg, 0.32 mmol), (MeSi)3SiH (0.05 mL, 0.160 mmol) and bromocyclopentane (0.03 mL, 0.24 mmol) were added with stirring under N2. The reaction was stirred at room temperature for 3 h using a 37 W blue LED. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography (100 g column, 1:1, PE:EtOAc) to give 4-(6-cyclopentyl-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (40 mg, 0.062 mmol, 39% yield) as a yellow solid. LCMS m / z 616.15 [M+H] +

[0379] Step 4 A solution of 4-(6-cyclopentyl-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (40 mg, 0.065 mmol) in (TFA) (4 mL) was stirred at 80° C. for 3 h. The mixture was cooled and concentrated to remove TFA. The residue was dissolved in DMF (2.0 mL), filtered, and purified by preparative HPLC (SunFire C18 OBD Prep column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water [0.05% TFA], mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 20% B to 33% B over 10 min). The product was collected, concentrated, and lyophilized to give 6-cyclopentyl-3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine, trifluoroacetate salt (10.4 mg, 0.020 mmol, 31% yield) as a white solid. 1 H NMR (400 MHz,DMSO-d6) δ 9.20 (s, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 3.16-3.11 (m, 1H), 2.12-2.10 (m, 2H), 1.82-1.81 (m, 2H), 1.72-1.64 (m, 4H). LCMS m / z 389.05 [M+H] +

[0380] [Example 17] 5-[6-(cyclopentylmethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole, trifluoroacetate

[0381] [ka]

[0382] Step 3c 4-(6-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (150 mg, 0.239 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (13.43 mg, 0.012 mmol) in DME (14 ml) To a solution of (2,4-di-tert-butyl-2,2-bipyridine) (6.43 mg, 0.024 mmol), NiCl glyme (5.26 mg, 0.024 mmol), LiOH (11.47 mg, 0.479 mmol), and 4,4-di-tert-butyl-2,2-bipyridine (6.43 mg, 0.024 mmol), (bromomethyl)cyclopentane (0.044 mL, 0.359 mmol) and (MeSi)SiH (0.074 mL, 0.239 mmol) were added at room temperature under N. The reaction was stirred at room temperature for 3 h using a 34 W blue LED. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography (100 g column, 1:1, PE:EtOAc) to give 4-(6-(cyclopentylmethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (80 mg, 0.119 mmol, 49.9% yield) as a yellow solid. LCMS m / z 630.3 [M+H] +

[0383] Step 4 A solution of 4-(6-(cyclopentylmethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (80 mg, 0.127 mmol) in TFA (4 mL) was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and concentrated to remove TFA. The residue was dissolved in DMF (2.0 mL), filtered, and purified by preparative HPLC (SunFire C18 OBD Prep column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water [0.05% TFA], mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 30% B to 35% B over 7 min). The product was collected, concentrated, and lyophilized to give 6-(cyclopentylmethyl)-3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine, trifluoroacetate salt (8.9 mg, 0.017 mmol, 14% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 2.64 (d, J = 7.6 Hz, 2H), 2.13-2.05 (m, 1H), 1.65-1.52 (m, 4H), 1.48-1.43 (m, 2H), 1.20-1.11 (m, 2H). LCMS m / z 403.1 [M+H] +

[0384] The following example was synthesized in a similar manner to Example 2, except that additional steps 3d and 3e were performed after step 3.

[0385] [Example 18] 13,13-Difluoro-6-(1H-imidazol-5-yl)-11-methyl-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]-2,4,7,11-tetraazatricyclo[7.4.0.0 3 , 7]Trideca-1,3,5,8-tetraene, trifluoroacetate

[0386] [ka]

[0387] Step 3d tert-Butyl 3-(1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)-9,9-difluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-8,9-dihydroimidazo[1,2-a]pyrido[4,3-d]pyrimidine-7(6H)-carboxylate (90 mg, 0.122 mmol) was dissolved in DCM (15 mL), followed by the addition of TFA (2 mL, 26.0 mmol). The solution was stirred at room temperature for 5 hours. The solution was concentrated in vacuo. The resultant was dissolved (MeOH, 5 mL), neutralized with aqueous NHOH (5 drops), and concentrated in vacuo to give 4-(9,9-difluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (88 mg, 0.138 mmol), which was used in the next step without purification. LCMS m / z 639.3 [M+H] +

[0388] Step 3e 4-(9,9-Difluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (53 mg, 0.083 mmol) was dissolved in THF (3 mL). Acetic acid (0.095 mL, 1.660 mmol) and formaldehyde (0.025 mL, 0.332 mmol) were added, and the mixture was stirred for 20 minutes. Sodium triacetoxyborohydride (48 mg, 0.226 mmol) was added. The reaction mixture was stirred for several minutes, then additional formaldehyde (0.1 mL) and NaBH(OAc)3 (10 mg) were added in multiple batches until LCMS indicated complete conversion to the product. Finally, MeOH (1 mL) was added, and the mixture was stirred for 20 minutes. The reaction was diluted with EtOAc. Saturated aqueous NaHCO3 was added, and the combined mixture was extracted with EtOAc (3x). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (Isco RediSep Rf Gold 24 g column, 25-100% EtOAc in heptane). The product fractions were concentrated to give 4-(9,9-difluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-methyl-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (27 mg, 0.041 mmol, 50% yield). LCMS m / z 653.2 [M+H] +

[0389] Step 4 4-(9,9-Difluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-methyl-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (27 mg, 0.041 mmol) was dissolved in TFA (5 mL, 64.9 mmol). The reaction was heated at 60° C. overnight. The reaction was cooled to room temperature, concentrated in vacuo, and then evaporated from DCM / EtOAc / MeOH (3×). The residue was suspended in IPA (5 mL), neutralized with aqueous NH4OH, and then concentrated. The resulting solid was purified by ISCO reverse-phase prep HPLC (30–100% MeCN in water, +0.1% TFA in each solvent, Gemini Prep C18 5 μM, 50 × 30 mm, AXIA packed column). The product fractions were concentrated in vacuo and then lyophilized to afford 9,9-difluoro-3-(1H-imidazol-5-yl)-7-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidine, trifluoroacetate salt (3.4 mg, 6.30 μmol, 15% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.23 - 9.22 (m, 1 H), 9.21 - 9.20 (m, 1 H), 8.22 - 8.20 (m, 1 H), 4.28 (s, 2 H), 2.84 (s, 3 H), 2H Unclear in solvent. LCMS m / z 426.2 [M+H] +

[0390] The following example was synthesized in a similar manner to Example 2, except that an additional step 1a was performed after step 1.

[0391] [Example 19] 5-[7-(1,1-difluoro-2-methoxyethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0392] [ka]

[0393] Step 1a A stirred solution of 2,2-difluoro-2-(2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-7-yl)ethan-1-ol (1.0 g, 2.201 mmol) in N,N-dimethylformamide (15 mL) was treated portionwise with 60% dispersion of sodium hydride (100 mg, 2.50 mmol) at 0° C. for 15 minutes. Iodomethane (170 μL, 2.72 mmol) was added and the reaction was stirred at 0° C. for 15 minutes, then allowed to warm to room temperature before quenching with water. The reaction was extracted with EtOAc and the organic layer was washed with aqueous NaSO, dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (80 g Isco RediSep Rf Gold column, 0–60% EtOAc in CHCl). The desired fractions were combined and concentrated in vacuo to give 7-(1,1-difluoro-2-methoxyethyl)-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (0.67 g, 1.359 mmol, 62% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=6.9 Hz, 1H), 8.81 (s, 1H), 7.53 (d, J=6.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.94-6.88 (m, 2H), 6.14 (s, 2H), 4.15 (t, J=13.9 Hz, 2H), 3.71 (s, 3H), 3.38 (s, 3H). LCMS m / z 468.8 [M+H] +

[0394] Final product 7-(1,1-difluoro-2-methoxyethyl)-3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine: 1 H NMR (400 MHz, DMSO-d6) δ 15.77 (br s, 1H), 12.73 (br s, 1H), 10.34 (d, J=7.3 Hz, 1H), 8.63 (br s, 1H), 8.05 (s, 1H), 7.53 (d, J=7.3 Hz, 1H), 4.16 (t, J=13.7 Hz, 2H), 3.39 (s, 3H). LCMS m / z 415.1 [M+H] + The following example was synthesized in a similar manner to Example 2, except that step 1b was performed instead of step 2.

[0395] [Example 20] 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl methanesulfonate

[0396] [ka]

[0397] Step 1b To a solution of 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-6-ol (0.120 g, 0.307 mmol) and triethylamine (0.043 mL, 0.307 mmol) in DCM (2 mL) was added methanesulfonyl chloride (0.024 mL, 0.307 mmol) dropwise. The reaction was stirred at room temperature for 30 minutes. NBS (0.082 g, 0.461 mmol) was added and the reaction was stirred for 1 hour. The reaction was partitioned between DCM and saturated aqueous sodium carbonate. The organic layer was concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel chromatography (Combiflash, 0-30% [3:1 EtOAc:EtOH] in DCM). The product fractions were concentrated to give 3-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl methanesulfonate (0.137 g, 0.250 mmol, 81% yield) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.66 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 7.44 - 7.38 (m, 2H), 6.84 - 6.78 (m, 2H), 6.10 (s, 2H), 3.75 (s, 3H), 3.39 (s, 3H). LCMS m / z 547.0, 548.9 [M+H] +

[0398] Final product 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl methanesulfonate: 1H NMR (400MHz, DMSO-d6) δ = 15.77 (br s, 1H), 12.73 (br s, 1H), 10.39 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.9 Hz, 1H), 8.66 (s, 1H), 8.06 (d, J = 1.0 Hz, 1H), 3.60 (s, 3H). LMCS m / z 415.0 [M+H] + The following example was synthesized in a similar manner to Example 2, except that step 5 was performed instead of step 1.

[0399] [Example 21] 5-[3-(1H-imidazol-5-yl)-7-(methylsulfanyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0400] [ka]

[0401] Step 5 To a stirred solution of 4-chloropyrimidin-2-amine (1.0 g, 7.72 mmol) in DMF (20 mL) was added sodium thiomethoxide (0.55 g, 7.85 mmol) in portions over 10 minutes. The reaction was stirred at room temperature for 1 hour. The reaction was treated with 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (1.5 g, 4.50 mmol) and stirred at 100° C. for 18 hours. The mixture was triturated with saturated aqueous NaHCO, filtered, washed with water, and dried under vacuum to give 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(methylthio)imidazo[1,2-a]pyrimidine (1.6 g, 3.58 mmol, 80% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 1H), 8.49 (s, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.17-7.13 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 6.13 (s, 2H), 3.71 (s, 3H), 2.62 (s, 3H). LCMS m / z 421.2 [M+H] +

[0402] Step 4 4-(2-(1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-7-(methylthio)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (500 mg, 0.842 mmol) in TFA (15 mL) was heated at 70° C. for 12 h. The reaction was concentrated in vacuo. The crude material was suspended in water (5 mL) and adjusted to approximately pH 7 with saturated NaHCO. The mixture was treated with ammonium citrate buffer (0.2 M), then triturated and filtered. The resulting filtered solid was washed with water, followed by a small volume of EtOH, and dried. The solid was then washed with DCM and dried under vacuum to give 3-(1H-imidazol-5-yl)-7-(methylthio)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (273 mg, 0.711 mmol, 84%) as a pale orange solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.60 (br s, 1 H), 12.72 (br s, 1 H), 9.84 (d, J = 7.3 Hz, 1 H), 8.57 (s, 1 H), 8.03 (s, 1 H), 7.14 (d, J = 7.3 Hz, 1 H), 2.62 (s, 3 H). LCMS m / z 367.1 [M+H] +

[0403] The following example was synthesized in a similar manner to Example 2, except that step 1c was performed after step 1 and step 3f was performed after step 3.

[0404] [Example 22] 5-[3-(1H-imidazol-5-yl)-6-methanesulfonylimidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0405] [ka]

[0406] Step 1c Sodium thiomethoxide (310 mg, 4.42 mmol) was added to a mixture of 6-bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (1.8 g, 3.97 mmol) and dimethyl sulfoxide (DMSO) (20 mL) under nitrogen. The reaction was sealed and stirred at 100 °C for 4 h. The reaction was cooled to room temperature and diluted with EtOAc. The organic phase was washed with water and brine, then dried (Na SO ), filtered, and evaporated in vacuo. The crude material was purified by silica gel chromatography (Isco RediSep Rf Gold 120 g column, 30-100% EtOAc in heptane). The fractions were combined and concentrated in vacuo to give 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6-(methylthio)imidazo[1,2-a]pyrimidine (0.70 g, 1.582 mmol, 40% yield) as a light tan solid. 1H NMR (400 MHz, DMSO- d6) δ 8.92 (d, J=2.93 Hz, 1H), 8.64 (d, J=2.45 Hz, 1H), 8.44 (s, 1H), 7.27 (d, J=8.80 Hz, 2H), 6.79-6.84 (m, 2H), 6.03 (s, 2H), 3.62 (s, 3H), 2.50 (s, 3H). LCMS m / z 421.2 [M+H] + .

[0407] Step 3f To a stirred solution of 4-(2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6-(methylthio)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (350 mg, 0.590 mmol) in chloroform (20 mL) was added mCPBA 77 wt% (470 mg, 2.72 mmol) in an ice bath at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was washed with aqueous NaCO, dried (NaSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Isco RediSep Rf Gold 40 g, 0 to 60% EtOAc in CHCl). Pure fractions were combined and evaporated to dryness to give the product 4-(2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6-(methylsulfonyl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (249 mg, 0.382 mmol, 64.8% yield) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) δ 10.29 (s, 1H), 9.19-9.15 (m, 1H), 8.64 (d, J=1.5 Hz, 1H), 8.61-8.60 (m, 1H), 7.41 (d, J=8.8 Hz, 2H), 6.94-6.87 (m, 2H), 5.98 (s, 2H), 3.72 (s, 3H), 3.47 (s, 3H), 2.88 (s, 6H). LCMS m / z 626.1 [M+H] + .

[0408] Step 4 4-(2-(1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-6-(methylsulfonyl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (240 mg, 0.384 mmol) in TFA (10 mL) was stirred at 70° C. for 12 h. The reaction was concentrated in vacuo and suspended in water (5 mL). The mixture was brought to pH 7 by the addition of saturated aqueous NaHCO3 and then treated with ammonium citrate (0.2 M) buffer (50 mL). The resulting solid was filtered, washed with water, EtOH, DCM and dried to give 3-(1H-imidazol-5-yl)-6-(methylsulfonyl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (128 mg, 0.302 mmol, 79%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br s, 1 H), 10.45 (d, J = 2.5 Hz, 1 H), 9.13 (d, J = 2.5 Hz, 1 H), 8.38 (s, 1 H), 8.19 (s, 1 H), 3.48 (s, 3 H), 1H not observed. LCMS m / z 399.0 [M+H] +

[0409] [Example 23] 4-oxo-4-[(4-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methoxy]butanoic acid

[0410] [ka]

[0411] Step 1 To a solution of 4-(tert-butoxy)-4-oxobutanoic acid (3 g, 17.22 mmol) in a solvent mixture of ethanol (75 mL) and water (11 mL) was added cesium carbonate (2.81 g, 8.61 mmol). The mixture was briefly sonicated and then stirred for 15 minutes. The solvent was evaporated, and the residue was dried under high vacuum overnight.

[0412] The dried Cs-salt was dissolved in DMF (55.00 mL), bromochloromethane (72.8 mL, 1119 mmol) was added, and the solution was stirred at room temperature overnight. The resulting precipitate was filtered off, and the solution was concentrated to give a residue. The residue was partitioned between water and EtOAc. The organic phase was washed with water (1×) and brine (2×), dried over sodium sulfate, and evaporated to give tert-butyl(chloromethyl)succinate (3.484 g, 15.65 mmol, 91% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 5.86 (s, 2H), 2.58-2.66 (m, 2H), 2.48-2.53 (m, 2H), 1.39 (s, 9H).

[0413] Step 2 A solution of 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (100 mg, 0.312 mmol, Example 1), tert-butyl(chloromethyl)succinate (87 mg, 0.390 mmol), tetrabutylammonium iodide (144 mg, 0.390 mmol) and DBU (0.059 mL, 0.390 mmol) in DMF (2 mL) was stirred at room temperature overnight. The major product was isolated by MDAP preparative HPLC (MDAP method F) to give tert-butyl ((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl)succinate (49 mg, 0.097 mmol, 31.0% yield) as a yellow lyophilizate. LCMS m / z 507.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 15.66 (br s, 1H), 10.00 (dd, J=2.01, 7.03 Hz, 1H), 8.74 (dd, J=2.01, 4.02 Hz, 1H), 8.67 (d, J=1.26 Hz, 1H), 8.18 (d, J=1.25 Hz, 1H), 7.26 (dd, J=4.02, 7.03 Hz, 1H), 6.13 (s, 2H), 2.54-2.61 (m, 2H), 2.44-2.49 (m, 2H), 1.29 (s, 9H).

[0414] Step 3 To a solution of tert-butyl ((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl)succinate (46 mg, 0.091 mmol) in DCM (4 mL) was added TFA (4 mL, 51.9 mmol), and the mixture was stirred at room temperature for 2 h and then evaporated to dryness. The oily residue was triturated with ether to give 4-oxo-4-((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methoxy)butanoic acid (41 mg, 0.091 mmol, 100% yield) as a pale yellow solid. LCMS m / z 451.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.71 (br s, 1H), 12.26 (br s, 1H), 9.98 (dd, J=2.03, 7.10 Hz, 1H), 8.74 (dd, J=2.03, 4.06 Hz, 1H), 8.65 (d, J=1.27 Hz, 1H), 8.19 (d, J=1.27 Hz, 1H), 7.26 (dd, J=4.06, 7.10 Hz, 1H), 6.13 (s, 2H), 2.55-2.65 (m, 2H), 2.45-2.50 (m, 2H).

[0415] [Example 24] (4-{2-[1-({[(2S)-2-amino-3-methylbutanoyl]oxy}methyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methyl (2S)-2-amino-3-methylbutanoate, 2-trifluoroacetate

[0416] [ka]

[0417] Step 1 To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (3 g, 13.81 mmol) in a solvent mixture of ethanol (75 mL) and water (11 mL), cesium carbonate (2.249 g, 6.90 mmol) was added and stirred until the carbonate dissolved and gas evolution ceased (approximately 15 min). The solvent was evaporated and the residue was dried under high vacuum overnight.

[0418] The dried Cs-salt was dissolved in DMF (55.00 mL), bromochloromethane (58.4 mL, 898 mmol) was added, and the solution was stirred at room temperature overnight. The CsBr precipitate was filtered off, and the solution was evaporated. The residue was partitioned between water and EtOAc, and the organic phase was washed with water (1×), brine (1×), dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (80 g Isco RediSep Rf Gold column eluting with 0–20% EtOAc in hexanes) to give (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (2.817 g, 10.60 mmol, 77% yield) as a clear oil. LCMS m / z 288 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J=7.86 Hz, 1H), 5.96 (d, J=6.08 Hz, 1H), 5.85 (d, J=6.34 Hz, 1H), 3.90 (dd, J=6.59, 7.60 Hz, 1H), 1.94-2.12 (m, 1H), 1.39 (s, 9H), 0.86-0.96 (m, 6H).

[0419] Step 2 A solution of 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (27.7 mg, 0.086 mmol, Example 1), chloromethyl(tert-butoxycarbonyl)-L-valinate (28.7 mg, 0.108 mmol), tetrabutylammonium iodide (39.9 mg, 0.108 mmol) and DBU (0.016 mL, 0.108 mmol) in DMF (0.5 mL) was stirred at room temperature for 4 hours. Additional chloromethyl(tert-butoxycarbonyl)-L-valinate (5.74 mg, 0.022 mmol) and DBU (0.003 mL, 0.22 mmol) were added, and the mixture was stirred for 28 hours. Additional chloromethyl(tert-butoxycarbonyl)-L-valinate (22.96 mg, 0.086 mmol) and DBU (0.013 mL, 0.086 mmol) were added, and the mixture was stirred over the weekend (approximately 2.5 days). The product was isolated by preparative HPLC (MDAP Method G) to give (5-(3-(1-((((tert-butoxycarbonyl)-L-valyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl(tert-butoxycarbonyl)-L-valinate (32 mg, 0.041 mmol, 47.5% yield) as an off-white lyophilizate. LCMS m / z 779.3 [M+H] + .

[0420] Step 3 To a solution of (5-(3-(1-((((tert-butoxycarbonyl)-L-valyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl(tert-butoxycarbonyl)-L-valinate (30 mg, 0.039 mmol) in DCM (4 mL) was added TFA (4 mL, 51.9 mmol) and the mixture was stirred at room temperature for 1 h and then evaporated to dryness. The residue was dissolved in 5 mL of water and lyophilized to give (5-(3-(1-(((L-valyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl L-valinate, 2-trifluoroacetate salt (30 mg, 0.037 mmol, 97% yield) as a pale yellow lyophilate. LCMS m / z 579.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (dd, J=1.88, 7.15 Hz, 1H), 8.79 (dd, J=2.01, 4.02 Hz, 1H), 8.34-8.45 (m, 7H), 8.24 (d, J=1.00 Hz, 1H), 7.32 (dd, J=4.02, 7.03 Hz, 1H), 7.06 (d, J=10.54 Hz, 1H), 6.83 (d, J=10.54 Hz, 1H), 6.34 (d, J=10 Hz, 1H), 6.26 (d, J=10 Hz, 1H), 4.03 (dd, J=4.52, 9.03 Hz, 2H), 2.02-2.24 (m, 2H), 0.80-0.91 (m, 12H).

[0421] [Example 25] {2-[methyl({[1-(5-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)ethoxy]carbonyl})amino]pyridin-3-yl}methyl 2-(methylamino)acetate, hydrochloride

[0422] [ka]

[0423] Step 1 A mixture of 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (75 mg, 0.234 mmol, Example 1), (2-(((1-chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate (107 mg, 0.258 mmol), tetrabutylammonium iodide (95 mg, 0.258 mmol) and DBU (0.044 mL, 0.293 mmol) in DMF (2 mL) was heated at 60° C. overnight. The major product was isolated by preparative HPLC (MDAP Method E) to give (2-(methyl((1-(5-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)ethoxy)carbonyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate (64 mg, 0.091 mmol, 39.1% yield). LCMS m / z 700.5 [M+H] + .

[0424] Step 2 To a solution of (2-(methyl((1-(5-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)ethoxy)carbonyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate (64 mg, 0.091 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol) and the mixture was stirred for 15 min. The solvent was evaporated and the product was isolated by preparative HPLC (MDAP method A) to give 24 mg of an off-white lyophilisate. The lyophilisate was dissolved in a minimum volume of ACN, 4 M HCl in dioxane (0.114 mL, 0.457 mmol) was added and the solvent was evaporated. The HCl treatment was repeated once more, and then the residue was dissolved in 3 mL water and lyophilized to give (2-(methyl((1-(5-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)ethoxy)carbonyl)amino)pyridin-3-yl)methyl methylglycinate, hydrochloride (20 mg, 0.031 mmol, 34.4% yield) as an off-white lyophilate. LCMS m / z 600.2 [M+H] + . The structure was confirmed by 2D NMR (HMBC).

[0425] [Examples 26, 27, and 28] 2-(Methylamino)ethyl (4-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methyl carbonate, 2-trifluoroacetate [4-(2-{1-[({[2-(methylamino)ethoxy]carbonyl}oxy)methyl]-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl}imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl]methyl 2-(methylamino)ethyl carbonate, 2-trifluoroacetate {5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl}methyl 2-(methylamino)ethyl carbonate, 2-trifluoroacetate

[0426] [ka]

[0427] Step 1 To an ice-cooled solution of tert-butyl (2-hydroxyethyl) (methyl)carbamate (0.986 g, 5.63 mmol), TEA (0.863 mL, 6.19 mmol), and pyridine (0.501 mL, 6.19 mmol) in DCM (40 mL) was added chloromethyl carbonochloridate (0.500 mL, 5.63 mmol) dropwise over 1 minute. The mixture was stirred at room temperature overnight. 1N HCl (20 mL, 20.00 mmol) was added, stirred vigorously for 2 minutes, and then the layers were separated. The aqueous layer was further extracted with DCM (2 x 5 mL) and the combined organic layers were washed with saturated aqueous sodium bicarbonate (1 x), brine (1 x), dried over sodium sulfate and evaporated to give tert-butyl (2-(((chloromethoxy)carbonyl)oxy)ethyl)(methyl)carbamate (1.098 g, 2.71 mmol, 48.1% yield) as a colorless oil. The product was 33% contaminated with starting material ( 1 H-NMR) was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 5.75 (s, 2H), 4.29-4.43 (m, 2H), 3.50-3.61 (m, 2H), 2.94 (s, 3H), 1.48 (s, 9H)

[0428] Step 2 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (100 mg, 0.312 mmol, Example 1), tert-butyl (2-(((chloromethoxy)carbonyl)oxy)ethyl)(methyl)carbamate (158 mg, 0.390 mmol), potassium carbonate (64.7 mg, 0.468 mmol) and potassium iodide (51.8 mg, 0.312 mmol) in DMF (2 mL) was stirred at room temperature overnight. The mixture was filtered and the product isolated by preparative HPLC (MDAP Method H) to give tert-butyl (2-((((5-(3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)ethyl)(methyl)carbamate (22 mg, 12.8% yield). LCMS m / z 552.1 [M+H] + The structure was confirmed after deprotection in step 5.

[0429] tert-Butyl methyl (2-((((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methoxy)carbonyl)oxy)ethyl)carbamate (24 mg, 13.9% yield). LCMS m / z 552.09 [M+H] + . The structure was confirmed after deprotection in step 3

[0430] tert-Butyl methyl (2-((((3-(trifluoromethyl)-5-(3-(1-(7,10,10-trimethyl-3,8-dioxo-2,4,9-trioxa-7-azaundecyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)ethyl)carbamate (35 mg, 14.3% yield). LCMS m / z 783.28 [M+H] + . The structure was confirmed after deprotection in step 4.

[0431] Step 3 A solution of tert-butyl methyl (2-((((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methoxy)carbonyl)oxy)ethyl)carbamate (24 mg, 0.044 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 10 minutes. The mixture was evaporated to dryness, and the residue was dissolved in water and lyophilized to give 2-(methylamino)ethyl ((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl)carbonate, 2-trifluoroacetate salt (Example 26) (26 mg, 0.038 mmol, 88% yield). LCMS m / z 452.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (dd, J=2.01, 7.03 Hz, 1H), 8.72-8.79 (m, 2H), 8.51-8.66 (m, 2H), 8.24 (d, J=1.25 Hz, 1H), 7.28 (dd, J=4.02, 7.03 Hz, 1H), 6.21 (s, 2H), 4.35-4.43 (m, 3H), 3.21-3.32 (m, 2H), 2.58 (t, J=5.27 Hz, 2H). The structure was confirmed by 2D NMR (HMBC).

[0432] Step 4 A solution of tert-butyl methyl (2-((((3-(trifluoromethyl)-5-(3-(1-(7,10,10-trimethyl-3,8-dioxo-2,4,9-trioxa-7-azaundecyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)ethyl)carbamate (35 mg, 0.045 mmol) and TFA (2 mL, 26.0 mmol) in DCM (2 mL) was stirred at room temperature for 10 minutes. The mixture was evaporated to dryness, and the residue was dissolved in water and lyophilized to give (5-(3-(1-((((2-(methylamino)ethoxy)carbonyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl(2-(methylamino)ethyl)carbonate, 2-trifluoroacetate salt (Example 27) (37 mg, 0.046 mmol, 102% yield). LCMS m / z 583.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (dd, J=2.01, 7.28 Hz, 1H), 8.79 (dd, J=2.01, 4.02 Hz, 1H), 8.54-8.71 (m, 4H), 8.40 (d, J=1.25 Hz, 1H), 8.24 (d, J=1.25 Hz, 1H), 7.31 (dd, J=4.02, 7.03 Hz, 1H), 6.79 (s, 2H), 6.18 (s, 2H), 4.34-4.43 (m, 4H), 3.22-3.31 (m, J=1.00 Hz, 4H), 2.54-2.64 (m, 6H). The structure was confirmed by 2D NMR (HMBC).

[0433] Step 5 A solution of tert-butyl (2-((((5-(3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)ethyl)(methyl)carbamate (22 mg, 0.040 mmol) and TFA (2 mL, 26.0 mmol) in DCM (2 mL) was stirred at room temperature for 10 min. The mixture was evaporated to dryness and the residue was dissolved in water (some ACN was required) and lyophilized to give (5-(3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl(2-(methylamino)ethyl)carbonate, 2-trifluoroacetate salt (Example 28) (21 mg, 0.031 mmol, 77% yield), LCMS m / z 452.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.74-9.85 (m, 1H), 8.78 (dd, J=2.01, 4.02 Hz, 1H), 8.45-8.58 (m, 2H), 8.20 (s, 2H), 7.30 (dd, J=4.02, 7.03 The structure was confirmed by 2D NMR (HMBC, 15N HMBC).

[0434] [Examples 29 and 30] {4-oxo-4-[(4-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methoxy]butoxy}phosphonic acid, trifluoroacetate {4-oxo-4-[(5-{3-[1-({[4-(phosphonooxy)butanoyl]oxy}methyl)-1H-imidazol-4-yl]imidazo[1,2-a]pyrimidin-2-yl}-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy]butoxy}phosphonic acid, trifluoroacetate

[0435] [ka]

[0436] Step 1 A solution of methyl 4-hydroxybutanoate (1.170 g, 9.90 mmol) and di-tert-butyl diisopropyl phosphoramidite (4.69 mL, 14.86 mmol) in DCM (20 mL) was evaporated to dryness and dried under high vacuum for 30 min. The mixture was azeotroped with acetonitrile (20 mL), then dissolved in acetonitrile (60.00 mL) and evaporated to approximately half its volume. A solution of 0.45 M 1H-tetrazole in acetonitrile (44.0 mL, 19.81 mmol) was added. A white precipitate immediately began to form. The mixture was stirred at room temperature for 1.5 h, then cooled to 0 °C, and mCPBA (5.55 g, 24.76 mmol) (77% purity) was introduced. The mixture was stirred at 0 °C for 10 min, then at room temperature for 1 h. Sodium sulfite (3.12 g, 24.76 mmol) dissolved in 40 mL of water was added to quench excess mCPBA, and acetonitrile was evaporated. The residue was partitioned between water (30 mL) and EtOAc (50 mL). The organic phase was washed with water (1×), saturated aqueous sodium bicarbonate (2×), water (1×), and brine (1×), dried over sodium sulfate, and evaporated to give the crude product as an oil (3.4 g). The crude product was purified in two batches (0.5 g / 2.9 g) by silica gel chromatography (24 g / 120 g Isco RediSep Rf Gold column eluting with 0–20% EtOAC / EtOH in hexanes (3 / 1)) to give methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (1.043 g, 33.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.88 (q, J=6.36 Hz, 2H), 3.60 (s, 3H), 2.40 (t, J=7.28 Hz, 2H), 1.80-1.89 (m, 2H), 1.41 (s, 18H).

[0437] Step 2 To a stirred, cold solution of methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (1.043 g, 3.36 mmol) in methanol (15 mL) and water (3 mL) was added 5 M aqueous NaOH (2.017 mL, 10.08 mmol) and stirring was continued at 0 °C for 5 h. A solution of 6 M aqueous HCl (1.680 mL, 10.08 mmol) was added and then MeOH was evaporated. The residue was extracted with EtOAc (2 ×), and the organic phase was washed with brine (1 ×), dried over sodium sulfate, and evaporated to give 4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (876 mg, 2.96 mmol, 88% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (br s, 1H), 3.88 (q, J=6.53 Hz, 2H), 2.31 (t, J=7.28 Hz, 2H), 1.81 (quintet, J=6.84 Hz, 2H), 1.41 (s, 18H). 31 P NMR (162 MHz, DMSO-d6) δ -9.89 (br t, J=5.87 Hz, 1P).

[0438] Step 3 To a solution of 4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (680 mg, 2.295 mmol) in ethanol (12 mL) was added cesium carbonate (374 mg, 1.147 mmol) dissolved in water (2 mL), and the mixture was stirred until gas evolution ceased (approximately 15 min). The solvent was evaporated, and the residue was dried under high vacuum overnight to give cesium 4-((di-tert-butoxyphosphoryl)oxy)butanoate (976 mg, 2.279 mmol, 99% yield) as a colorless oil.

[0439] The dried Cs-salt was dissolved in DMF (9 mL), bromochloromethane (9.70 mL, 149 mmol) was added, and the solution was stirred at room temperature overnight. The CsBr precipitate was filtered off, and the solution was evaporated. The residue was partitioned between water and EtOAc, and the organic phase was washed with water (1×), brine (1×), dried over sodium sulfate, and evaporated to give chloromethyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (723 mg, 2.097 mmol, 91% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 5.86 (s, 2H), 3.89 (q, J=6.36 Hz, 2H), 1.80-1.93 (m, 2H), 1.41 (m, 20H).

[0440] Step 4 A suspension of 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (100 mg, 0.312 mmol, Example 1), chloromethyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (118 mg, 0.343 mmol), potassium iodide (51.8 mg, 0.312 mmol) and potassium carbonate (86 mg, 0.625 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was filtered and separated by preparative HPLC (MDAP Method H) to give (4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (78 mg, 0.124 mmol, 39.7% yield) as a pale yellow oil; LCMS m / z 629.3 [M+H] +, and (5-(3-(1-(((4-((di-tert-butoxyphosphoryl)oxy)butanoyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (53 mg, 0.057 mmol, 18.12% yield) was obtained as a pale yellow oil. LCMS m / z 937.4 [M+H] + .

[0441] Step 5 (4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (78 mg, 0.124 mmol) was dissolved in TFA (2 mL, 26.0 mmol), allowed to stand for 10 min, then evaporated and eluted with 3 mL of TFA. Coevaporated with ACN (2x) and dried. The residue was dissolved in water and lyophilized to give (4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl 4-(phosphonooxy)butanoate, trifluoroacetate (Example 29) (66 mg, 0.105 mmol, 33.5% yield) as a beige lyophilizate. LCMS m / z 517.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 15.70 (br s, 1H), 9.95 (dd, J=1.96, 7.09 Hz, 1H), 8.75 (dd, J=2.08, 4.03 Hz, 1H), 8.64 (d, J=1.22 Hz, 1H), 8.25 (d, J=1.22 Hz, 1H), 7.26 (dd, J=4.16, 7.09 Hz, 1H), 6.13 (s, 2H), 3.78-3.89 (m, 2H), 2.43-2.49 (m, J=7.50, 7.50 Hz, 2H), 1.84 (quintet, J=6.91 Hz, 2H). Two phosphate H's were not observed. The structure was confirmed by 2D NMR (ROESY).

[0442] Step 6 (5-(3-(1-(((4-((di-tert-butoxyphosphoryl)oxy)butanoyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (53 mg, 0.057 mmol) was dissolved in TFA (2 mL, 26.0 mmol), allowed to stand for 10 min, then evaporated and co-evaporated with 3 mL ACN (2×) to dryness. The residue was dissolved in water and lyophilized to give (5-(3-(1-(((4-(phosphonooxy)butanoyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl 4-(phosphonooxy)butanoate, trifluoroacetate (Example 30) (39 mg, 0.047 mmol, 15.11% yield) as a beige lyophilate. LCMS m / z 713.05 [M+H] + . 1H NMR (400 MHz, DMSO-d₆) δ 9.76 (dd, J = 2.20, 7.09 Hz, 1H), 8.77 (dd, J = 1.96, 4.16 Hz, 1H), 8.26 (d, J = 1.47 Hz, 1H), 8.21 (d, J = 1.22 Hz, 1H), 7.28 (dd, J = 4.03, 6.97 Hz, 1H), 6.69 (s, 2H), 6.09 (s, 2H), 3.75-3.89 (m, 4H), 2.39-2.48 (m, 4H), 1.73-1.90 (m, 4H). No four phosphate groups were observed. The structure was confirmed by 2D NMR (ROESY, HMBC, 15N HMBC).

[0443] [Examples 31, 32, and 33] 3-({[(4-{2-[1-({[(2-carboxyethoxy)carbonyl]oxy}methyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methoxy]carbonyl}oxy)propanoic acid, trifluoroacetate 3-({[(4-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methoxy]carbonyl}oxy)propanoic acid, 0.5 trifluoroacetate 3-{[({5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl}methoxy)carbonyl]oxy}propanoic acid, 2-trifluoroacetate

[0444] [ka]

[0445] Step 1 To an ice-cooled solution of tert-butyl 3-hydroxypropanoate (1 g, 6.84 mmol) and pyridine (0.609 mL, 7.52 mmol) in DCM (25 mL) was added chloromethyl carbonochloridate (0.608 mL, 6.84 mmol) dropwise over approximately 1 minute. The mixture was stirred at room temperature overnight. A solution of 1 N aqueous HCl (20 mL, 658 mmol) was added, the mixture was stirred vigorously for 2 minutes, and then the layers were separated. The aqueous layer was further extracted with DCM (2 × 5 mL), and the combined organic layers were washed with saturated aqueous sodium bicarbonate (1 ×), brine (1 ×), dried over sodium sulfate, and evaporated to give tert-butyl 3-(((chloromethoxy)carbonyl)oxy)propanoate (1.468 g, 6.15 mmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 5.77 (s, 2H), 4.50 (t, J=6.46 Hz, 2H), 2.68 (t, J=6.34 Hz, 2H), 1.50 (s, 9H).

[0446] Step 2 A suspension of 3-(1H-imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (100 mg, 0.312 mmol, Example 1), tert-butyl 3-(((chloromethoxy)carbonyl)oxy)propanoate (93 mg, 0.390 mmol), potassium carbonate (64.7 mg, 0.468 mmol) in DMF (2 mL) was stirred overnight. The mixture was filtered and the product isolated by preparative HPLC (MDAP Method H) to give tert-butyl 3-((((5-(3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)propanoate (14 mg, 8.6% yield). MS ES+ m / z 523.1 [M+H] + The structure was confirmed after deprotection in step 5.

[0447] tert-Butyl 3-((((5-(3-(1-((((3-(tert-butoxy)-3-oxopropoxy)carbonyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)propanoate (73 mg, 32.3% yield). MS ES+ m / z 725.2 [M+H] + The structure was confirmed after deprotection in step 3.

[0448] tert-Butyl 3-((((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methoxy)carbonyl)oxy)propanoate (25 mg, 15.3% yield). MS ES+ m / z 523.1 [M+H] + . The structure was confirmed after deprotection in step 4.

[0449] Step 3 A solution of tert-butyl 3-((((5-(3-(1-((((3-(tert-butoxy)-3-oxopropoxy)carbonyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)propanoate (73 mg, 0.101 mmol) and TFA (2 mL, 26.0 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness and the residue was dissolved in water (some ACN was required) and lyophilized to give 3-((((5-(3-(1-((((2-carboxyethoxy)carbonyl)oxy)methyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)propanoic acid, trifluoroacetate salt (Example 31) (75 mg, 0.103 mmol, 100% yield). LCMS m / z 613.1; 1H NMR (400 MHz, DMSO-d6) δ 9.77 (dd, J = 2.01, 7.03 Hz, 1H), 8.77 (dd, J = 2.01, 4.02 Hz, 1H), 8.32 (d, J = 1.25 Hz, 1H), 8.24 (d, J = 1.25 Hz, 1H), 7.29 (dd, J = 4.14, 7.15 Hz, 1H), 6.73 (s, 2H), 6.12 (s, 2H), 4.25-4.35 (m, 4H), 2.56-2.67 (m, 4H). Two carboxyl protons were not observed.

[0450] Step 4 A solution of tert-butyl 3-((((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methoxy)carbonyl)oxy)propanoate (25 mg, 0.048 mmol) and TFA (2 mL, 26.0 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness and the residue was dissolved in water (some ACN was required) and lyophilized to give 3-((((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methoxy)carbonyl)oxy)propanoic acid, 0.5 trifluoroacetate salt (Example 32) (25 mg, 0.047 mmol, 97% LCMS m / z 467.2 [M+H] + . 1H NMR (400 MHz, DMSO-d₆) δ 15.71 (br s, 1H), 9.99 (dd, J = 2.01, 7.03 Hz, 1H), 8.75 (dd, J = 2.01, 4.02 Hz, 1H), 8.69 (d, J = 1.26 Hz, 1H), 8.24 (d, J = 1.25 Hz, 1H), 7.26 (dd, J = 4.02, 7.03 Hz, 1H), 6.16 (s, 2H), 4.32 (t, J = 6.15 Hz, 2H), 2.63 (t, J = 6.15 Hz, 2H). No triazole NH was observed.

[0451] Step 5 A solution of tert-butyl 3-((((5-(3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)propanoate (14 mg, 0.027 mmol) and TFA (2 mL, 26.0 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness and the residue was dissolved in water (some ACN was required) and lyophilized to give 3-((((5-(3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy)carbonyl)oxy)propanoic acid, 2-trifluoroacetate salt (Example 33) (14 mg, 0.020 mmol, 75% yield). LCMS m / z 467.16 [M+H] + ; 1 H NMR (400 MHz, DMSO-d₆) δ 9.39-9.51 (m, 1H), 8.82 (dd, J=2.03, 4.06 Hz, 1H), 8.63-8.77 (m, 1H), 8.20 (d, J=1.27 Hz, 1H), 7.29-7.37 (m, 1H), 6.81 (s, 2H), 4.30 (t, J=6.21 Hz, 2H), 2.60 (t, J=6.08 Hz, 2H). No carboxyl or imidazole H groups were observed.

[0452] [Example 34] ({5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl}methoxy)phosphonic acid

[0453] [ka]

[0454] Step 1 A mixture of 6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (24 g, 61.2 mmol, prepared, for example, according to Step 1 of Example 2) and TFA (90 ml, 1168 mmol) was heated at 70° C. for 10 hours. The mixture was cooled, poured onto ice, and then carefully neutralized to pH 7 with potassium carbonate.

[0455] The aqueous layer was extracted with ethyl acetate (3 x 200 mL) and the combined extracts were washed with water and brine, then dried (anhydrous NaSO), evaporated onto ISOLUTE HM-N sorbent and purified by flash chromatography (330 g Redisep RF Gold silica gel column, CombiFlash RF using 0-10% ethyl acetate in dichloromethane) to give the crude product.

[0456] Trituration with TBME (200 mL) gave a tan solid which was collected and washed with TBME and hexanes to give 6-fluoro-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (13.2 g, 48.5 mmol, 79% yield). LCMS electrospray, me / z 273.1 (M+H + ); 1H NMR (400 MHz, DMSO-d6) δ ppm 15.76 (br s, 1 H) 9.32 (dd, J=4.40, 2.93 Hz, 1 H) 8.90 (d, J=2.93 Hz, 1 H) 8.55 (s, 1 H).

[0457] Step 2 A suspension of 6-fluoro-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (11.5 g, 42.3 mmol) and NBS (8.27 g, 46.5 mmol) in chloroform (200 mL) was stirred at ambient temperature for 2 hours. The mixture was filtered through a terracotta filter and a paper filter using vacuum filtration, and the cake was washed with dichloromethane and hexane to give 3-bromo-6-fluoro-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (12.0 g, 34.2 mmol, 81% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 15.87 (s, 1 H) 9.32 (dd, J=3.91, 2.93 Hz, 1 H) 8.96 (d, J=2.45 Hz, 1 H); LCMS m / e 351.0.

[0458] Step 3 A suspension of 3-bromo-6-fluoro-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (11.6 g, 33.0 mmol) and potassium carbonate (13.70 g, 99 mmol) in N,N-dimethylformamide (120 mL) was vigorously stirred at 55° C., di-tert-butyl(chloromethyl)phosphate (15.54 mL, 66.1 mmol) was added, and the mixture was stirred overnight.

[0459] The mixture was poured into water (1 L) and extracted with ethyl acetate (x3). The combined organic extracts were washed with water (x2) and brine, dried over anhydrous Na2SO4 and evaporated.

[0460] The product was adsorbed onto Isolute® HM-N sorbent and purified by flash chromatography (330 g Redisep RF Gold® silica gel column, CombiFlash® RF using 0-30% ethyl acetate in dichloromethane) to give (5-(3-bromo-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl di-tert-butyl phosphate (8.6 g, 15.00 mmol, 45% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.71 (d, J=2.93 Hz, 1 H) 8.51 (t, J=2.93 Hz, 1 H) 6.69 - 6.75 (m, 2 H) 1.45 (s, 18 H); LCMS: [M+H] + 573.0, 575.0 Br pattern.

[0461] Step 4 A mixture of (5-(3-bromo-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl di-tert-butyl phosphate (1.0 g, 1.75 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (788 mg, 2.62 mmol, Intermediate 2), cesium fluoride (530 mg, 3.5 mmol), and PdCl(dppf) (192 mg, 0.26 mmol) in 1,2-dimethoxyethane (DME) (15 mL) was sealed in a 45 mL microwave vial, stirred, and thermally heated at 130 °C for 90 min.

[0462] This reaction was carried out seven other times, and the reaction mixtures were then combined and purified as shown below.

[0463] The reaction mixture was filtered through a pad of Celite®, washed with ethyl acetate, and evaporated in vacuo. The residue was dissolved in dichloromethane (50 mL) and adsorbed onto a silica gel (35 g) precolumn. Flash chromatography (40 g Redisep RF Gold® silica gel column, CombiFlash® RF using 0 to 40% ethyl acetate in dichloromethane) afforded di-tert-butyl ((5-(3-(1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl)phosphate (5.6 g, 8.39 mmol, 60% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 9.94 (dd, J=4.40, 2.93 Hz, 1 H), 8.77 (d, J=1.47 Hz, 1 H), 8.72 (d, J=2.94 Hz, 1 H), 8.09 (d, J=1.47 Hz, 1 H), 6.78 (s, 1 H), 6.76 (s, 1 H), 3.00 (s, 6 H), 1.42 (s, 18 H); LCMS: m / e 668.2 (M+H + ).

[0464] Step 5 A solution of di-tert-butyl ((5-(3-(1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl)phosphate (6.0 g, 8.99 mmol) in dichloromethane (5 mL) in a 250 mL round-bottom flask was treated with 4 M HCl in dioxane (25 mL, 100 mmol). The flask was stoppered and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was neutralized to approximately pH 7 with 20% aqueous potassium carbonate, and the mixture was evaporated in vacuo and azeotroped with ethanol to give a crude solid.

[0465] The solid was desalted by preparative HPLC as shown below.

[0466] [Table 11]

[0467] The product was freeze-dried to give ({5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl}methoxy)phosphonic acid (2.02 g, 4.37 mmol, 49% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (dd, J=4.89, 2.93 Hz, 1 H), 8.96 (d, J=2.93 Hz, 1 H), 8.16 (d, J=0.98 Hz, 1 H), 8.11 (s, 1 H), 6.44 (d, J=10.76 Hz, 2 H) (2OH and 1NH not observed); LCMS: t RET = 0.41 min (1-100% gradient from 0.1% v / v solution of formic acid in acetonitrile to 0.1% v / v solution of formic acid in water over 1.85 min), m / e 449.1 (M+H + ).

[0468] [Examples 35 and 36] Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate

[0469] [ka]

[0470] Step 1: Methyl 2-aminopyrimidine-4-carboxylate A mixture of 2-aminopyrimidine-4-carboxylic acid (5.3 g, 38.1 mmol), 4 M HCl in dioxane (20.0 mL, 80 mmol), and methanol (80.0 mL) was heated to 64° C. for 4 hours. The reaction mixture was cooled to room temperature, and then excess diethyl ether was added to the reaction mixture. The resulting precipitate was collected by filtration and then dried in a vacuum oven to give the desired product as the HCl salt. This material was stirred and sonicated in 160 mL of saturated aqueous NaHCO for 20 minutes. Gas evolution was observed. The suspended solid was collected by filtration and washed with deionized water. The solid was dried in a vacuum oven at 50° C. overnight to give the title compound (4.97 g, 32.5 mmol, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.48 (d, J = 4.8 Hz, 1H), 7.05 - 7.10 (br s, 2H), 7.06 (d, J = 5.1 Hz, 1H), 3.85 (s, 3H). LCMS: [M+H] + = 154.0

[0471] Step 2: Methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine-7-carboxylate A mixture of 1-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-2-chloroethan-1-one (520.0 mg, 1.509 mmol, Intermediate 1) and methyl 2-aminopyrimidine-4-carboxylate (462 mg, 3.02 mmol) in acetonitrile (20 mL) was heated to 115° C. overnight in a sealed reaction tube. The reaction showed only slight conversion to the desired product. Another batch of methyl 2-aminopyrimidine-4-carboxylate (462 mg, 3.02 mmol) was added to the reaction mixture. The mixture was heated to 115° C. overnight in a sealed reaction tube. The reaction mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with acetonitrile. The solid was vigorously stirred in a 1:1 mixture of EtOAc / 1N aqueous HCl for 20 minutes to remove residual methyl 2-aminopyrimidine-4-carboxylate. The suspended solid was collected by filtration to give the title compound (423 mg, 0.96 mmol, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ = 9.21 (d, J = 7.1 Hz, 1H), 8.78 (s, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.05 (s, 2H), 3.97 (s, 3H), 3.72 (s, 3H). LCMS: [M+H] + = 443.2, 445.2 (Br isotope peaks).

[0472] Step 3: Methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine-7-carboxylate A mixture of methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine-7-carboxylate (379.0 mg, 0.855 mmol), a catalytic amount of TFA (0.066 μL, 0.855 μmol), and NIS (289 mg, 1.283 mmol) in acetonitrile (20.0 mL) was heated to 60 °C for 1 h. The reaction mixture was cooled to room temperature, and the resulting precipitate was collected by filtration to give the title compound (320 mg, 0.56 mmol, 66% yield). The filtrate was concentrated, and then DCM (40 mL) was added. The organic solution was washed with saturated aqueous NaHCO and brine. The organic layer was dried over NaSO, filtered, and concentrated to a residue. The residue was purified on silica eluting with 0-50% EtOAc in DCM to give another batch of the title compound (129 mg, 0.23 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ = 9.10 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.35 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 5.92 (s, 2H), 3.98 (s, 3H), 3.72 (s, 3H). LCMS: [M+H] + = 569.0, 571.0 (Br isotope peaks).

[0473] Step 4: Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate A mixture of methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine-7-carboxylate (121 mg, 0.213 mmol), PdCl(dppf)-CHCl adduct (27.8 mg, 0.034 mmol), KPO (61.3 mg, 0.289 mmol), and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (95 mg, 0.34 mmol) in DMF (9 mL) and water (3 mL) was sonicated in a microwave vial for 3 min and heated at 75 °C for 8 min in a Biotage microwave unit. To the reaction mixture was added EtOAc (10 mL), and the mixture was washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on silica (12 g column) eluting with 10–50% EtOAc in hexanes to give the protected intermediate methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate (48 mg). This material was suspended in TFA (4 mL), and the reaction mixture was heated to 60 °C for >2 h until the protecting group was removed, as monitored by LCMS. The reaction was cooled to room temperature and concentrated to a residue. The residue was stirred in hot MeOH and collected by filtration to give the title compound (Example 35) (37 mg, 0.095 mmol, 45%) as a yellow solid. 1 H NMR (600 MHz, DMSO-d6) δ ppm 15.23 (br. s., 1 H), 13.42 (br. s., 1 H), 8.98 - 9.07 (m, 1 H), 8.25 (br. s., 2 H), 7.57 - 7.66 (m, 1 H), 3.96 (s, 3H). LCMS: [M+H] + = 389.0, 391.0 (Br isotope peak)

[0474] Step 4: Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate A mixture of methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine-7-carboxylate (122 mg, 0.214 mmol), PdCl(dppf)-CHCl adduct (18 mg, 0.021 mmol), CsF (81 mg, 0.54 mmol), and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (103 mg, 0.343 mmol, Intermediate 2) in DME (10 ml) was sonicated in a microwave vial for 5 min and heated at 130 °C for 40 min in a Biotage microwave unit. The reaction mixture was cooled to room temperature, diluted with EtOAc, and then washed with water. The organic layer was dried over NaSO and concentrated, and the residue was purified on silica (24 g column) eluting with 35–40% EtOAc in hexanes. The fractions containing the protected intermediate methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-(1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate were concentrated, and the residue was recrystallized from EtOAc to give the protected intermediate methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-(1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate (43 mg). This material was suspended in TFA (4 mL), and the reaction mixture was heated to 61° C. for 16 hours. The reaction mixture was concentrated to a residue. The residue was suspended in DCM, and the partially pure product was collected by filtration. The collected solid was stirred under reflux in EtOH for 5 minutes and collected by filtration to give the title compound (Example 36) (14 mg, 0.036 mmol, 17%) as a yellowish solid.1H NMR (700 MHz, DMSO-d6) δ 15.61 - 15.25 (br s, 1H), 13.66 - 12.19 (br s, 1H), 10.21 - 9.93 (m, 1H), 8.53 (br s, 1H), 8.39 - 8.19 (m, 1H), 7.75 (d, J = 7.3 Hz, 1H), 3.97 (s, 3H) LCMS: [M+H]. + = 389.1, 391.1 (Br isotope peak)

[0475] [Example 37] 3-Bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole, trifluoroacetate

[0476] [ka]

[0477] Step 2: 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine A mixture of 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (274.0 mg, 0.711 mmol), a catalytic amount of TFA (0.055 μL, 0.711 μmol), and NIS (208 mg, 0.925 mmol) in acetonitrile (10.0 mL) was heated to 60° C. for 15 min. The reaction mixture was cooled to room temperature, and the resulting precipitate was collected by filtration to give the title compound (307.0 mg, 0.60 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.94 (dd, J = 1.9, 7.0 Hz, 1H), 8.71 (dd, J = 1.9, 4.2 Hz, 1H), 7.39 - 7.21 (m, 3H), 6.90 (d, J = 8.9 Hz, 2H), 5.91 (s, 2H), 3.72 (s, 3H). LCMS: M+H] += 510.8, 512.8 (Br isotope peak)

[0478] Step 3: 4-(2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide A mixture of 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine (212.0 mg, 0.415 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (200 mg, 0.664 mmol, Intermediate 2), CsF (158 mg, 1.037 mmol), and PdCl(dppf)-CHCl adduct (33.9 mg, 0.041 mmol) in DME (9 ml) was thoroughly sonicated for 5 min and then heated at 130 °C for 20 min using an Anton-Parr microwave unit. The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration. The collected solid was diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified on silica eluting with 15% to 70% 3:1 EtOAc-EtOH in DCM to give the title compound (110 mg, 0.20 mmol, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (dd, J = 2.0, 7.1 Hz, 1H), 8.79 (dd, J = 2.0, 4.1 Hz, 1H), 8.52 (d, J = 1.3 Hz, 1H), 8.43 (d, J = 1.3 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.31 (dd, J = 4.1, 7.1 Hz, 1H), 6.95 - 6.85 (m, 2H), 5.87 (s, 2H), 3.72 (s, 3H), 2.91 (s, 6H). LCMS: [M+H] + = 558.2, 560.1 (Br isotope peaks).

[0479] Step 4: 3-Bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole, trifluoroacetate A suspension of 4-(2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (107 mg, 0.192 mmol) in TFA (5 mL) was heated at 60° C. until complete by LCMS. The reaction mixture was concentrated and the residue was suspended in hot DCM with sonication. The resulting solid was collected by filtration and still showed traces of the protected intermediate. The material was treated with TFA and heated to 64° C. for 4 hours to complete the deprotection. The reaction mixture was concentrated and the residue was suspended in DCM with sonication. The solid was collected by filtration to give the title compound (50.0 mg, 0.112 mmol, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.42 (br d, J = 2.3 Hz, 1H), 8.87 - 8.72 (m, 2H), 8.35 (d, J = 1.0 Hz, 1H), 7.28 (dd, J = 4.1, 6.8 Hz, 1H). No 2NH proton observed. LCMS: [M+H] + = 331.0, 333.0 (Br isotope peak)

[0480] [Example 38] 5-[6-Fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0481] [ka]

[0482] Step 3: 6-Fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine To a mixture of 3-bromo-6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine (150 mg, 0.318 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (133 mg, 0.477 mmol), potassium phosphate (203 mg, 0.955 mmol) in dioxane (2 mL) was added PdCl(dppf)-CHCl adduct (26.0 mg, 0.032 mmol). The reaction mixture was heated in a microwave vial at 120° C. for 10 minutes in an Anton-Parr microwave unit. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to a brown residue. This residue was purified by Isco Combiflash (20% to 100% (3:1 EtOAc / EtOH) / Hexanes; 40 g RediSep column). The collected fractions containing the product were combined and concentrated to give the title compound as a yellow solid (147 mg, 0.27 mmol, 85% yield). LCMS: [M+H] + = 543.3.

[0483] Step 4: 5-[6-Fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole A suspension of 6-fluoro-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine (147 mg, 0.271 mmol) in TFA (5 mL) was heated to 80 °C for 8 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (Xselect CSH C) eluting with 15-55% CH3CN in water (each with 0.1% formic acid). 18 Purification by column (150 mm x 30 mm id 5 μm packing diameter) gave the title compound (35.5 mg, 0.105 mmol, 39%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.62 (br s, 1 H), 13.38 (br s, 1 H), 9.10 (dd, J = 4.4, 2.9 Hz, 1 H), 8.90 (d, J = 2.9 Hz, 1 H), 8.44 (s, 1 H), 8.11 (s, 1 H). LCMS: [M+H] + = 339.1.

[0484] Examples 39-165 were prepared using methods similar to those described herein and known in the art. The following table shows the general synthetic methods by which these compounds were prepared, as well as their theoretical and observed molecular weights.

[0485] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4]

[0486] Solubility Data The solubility of certain compounds in FASSIF (fasted state simulated intestinal fluid) was measured and is listed in Table 2 below.

[0487] The solubility of solid compounds in FaSSIF at pH 6.5 was determined after 4 hours of equilibration at room temperature. 1 mL of FaSSIF buffer (3 mM sodium taurocholate, 0.75 mM lecithin in sodium phosphate buffer at pH 6.5) was added to a manually weighed 1 mg of solid compound in a 4 mL vial. The resulting suspension was shaken at 900 rpm for 4 hours at room temperature and then transferred to a Multiscreen HTS, 96-well solubility filter plate. Residual solids were removed by filtration. The supernatant solution was quantified by HPLC-UV using a single-point calibration of known concentrations of compound in DMSO. The dynamic range of the assay was 1 to 1000 μg / mL.

[0488] [Table 13]

[0489] Biological data Generation of recombinant human cGAS. Human cGAS(157-522) was purified by Ni-IDA affinity chromatography in lysis buffer (20 mM HEPES, pH 7.5, 400 mM NaCl, 10% glycerol, 30 mM imidazole, 1 mM PMSF, 1 mM TCEP, 100 mM arginine, 100 mM glutamate, and protease inhibitors (Roche complete EDTA-free)) into E. coli (BL21(DE3)) expressing an amino-terminal His-MBP-tev tag. * ) and stepwise eluted using 50 and 500 mM imidazole in wash buffer (20 mM HEPES, pH 7.5, 400 mM NaCl, 10% glycerol, 1 mM TCEP). The eluted protein was further purified by size-exclusion chromatography using a Superdex 75 column equilibrated in 20 mM HEPES, pH 7.5, 400 mM NaCl, 1 mM TCEP, 1 mM PMSF.

[0490] RapidFire 300 mass spectrometry (RF-MS300) assay. Compounds were resuspended to 10 mM stock concentrations using DMSO and tested to determine their IC50 values ​​against human CGAS(157-522) using a RapidFire mass spectrometry assay. Compounds were serially diluted 2-, 3-, or 4-fold in neat DMSO to generate 11-point dose-response curves, and then 250 nL compound or DMSO solution was transferred to a Greiner 384-well V-bottom assay plate (catalog #781280) using an Echo acoustic dispenser (Labcyte). A solution of 150 μM ATP, 150 μM GTP, 20 μM pppGpA (GTP-2'5'-AMP, custom synthesized from ChemGenes) and 10 μg / mL sheared salmon sperm DNA (Sigma, catalog #D1626) in assay buffer (20 mM Trizma, pH 7.5, 10 mM magnesium chloride, 0.3 mM CHAPS, and 0.01% (w / v) bovine serum albumin) was added at 12.5 μL / well to columns 1-17 and 19-24 of the plate using a Combi liquid handler (ThermoFisher). A 12.5 μL / well low control solution containing 150 μM ATP, 150 μM GTP, 20 μM pppGpA in assay buffer was added to column 18 using a Combi. Using a Combi-centrifuge, 12.5 μL / well of a 10–100 nM solution of human CGAS(157-522) in assay buffer was then added to all wells of the plate. The plate was centrifuged to mix the solution and then incubated at room temperature for 1–2 hours. The reaction was quenched by adding 50 μL / well of 0.5% (v / v) trifluoroacetic acid (TFA) in mass spectrometry-grade deionized water containing 5 μM cyclic-di-UMP (ci-di-UMP; Invivogen catalog #tlrl-cdu) as an internal standard (IS). The plate was centrifuged for 1 minute, and the quenched reaction was then analyzed using an RF-MS 300 system operating in multiple reaction monitoring (MRM) detection mode.

[0491] Samples (10 μL injection volume) were passed through a silica C18 / Type C solid-phase extraction (SPE) cartridge for adsorption of the analyte (2'3'-cyclic guanosine monophosphate adenosine monophosphate (2'3'-cGAMP), the product of the biochemical reaction) / pppGpA / c-di-UMP IS. The adsorbed sample was desalted for 3000 ms using eluent A / desalting solution of 100% water. The desalted sample was then eluted using eluent B / elution solution of 20% / 80% acetonitrile / 0.5% TFA in water directly into either a Sciex 4000, 5000, or 5500 triple quadrupole mass spectrometer (QQQ-MS) for MRM analyte / IS detection. The QQQ-MS detection conditions were as follows: scan type: MRM; curtain (CUR) gas: 30 psi; nebulizer (GS1) gas: 50 psi; drying (GS2) gas: 60 psi; collision-activated dissociation (CAD) gas: relative setting of 12; precursor ion (Q1) mass: 2'3'-cGAMP: m / z 675.1 Da / pppGpA: m / z 853.0 Da / c-di-UMP: m / z 613.1 Da; fragment ion (Q3) mass: 2'3'-cGAMP: m / z 524.1 Da / pppGpA: m / z 702.0 Da / c-di-UMP: 307.1 Da; Declustering Potential (DP): 2'3'-cGAMP: +81 V / pppGpA: +85 V / c-di-UMP: +85 V; Entrance Potential: +10 V (all analytes); Collision Energy (CE): 2'3'-cGAMP: +33 V / pppGpA: +36 V / c-di-UMP: +35 V; Collision Cell Exit Potential (CXP): +10 V (all analytes); Interface Heater (Sciex 4000 / 5000 only): On; Q1 Resolution: Units (all analytes); Q3 Resolution: Units (all analytes). The area under the curve (AUC) for all analytes was obtained using the RapidFire Integrator software application, and the AUC-2'3'-cGAMP / AUC-c-di-UMP intensity ratio was calculated. The percent of product formation was calculated by comparison with the response in column 6 (high control) / column 18 (low control). The % of product inhibition was calculated as follows: % Inhibition = 100 x [(sample - mean of low control) / (mean of high control - mean of low control)] Curve fitting is done by the equation

[0492]

number

[0493] where A is the minimum response, B is the maximum response, and C is log 10 * where XC50, D is the slope coefficient, and x is log 10 The assay was performed using ABASE XE using the compound concentration [M].

[0494] cGAS whole blood cytokine release assay Blood collection: Blood was collected into tubes containing 10% sodium heparin (5 ml / 45 ml blood final).

[0495] Protocol for cGAS whole blood cytokine release assay: 150 nL of compound per well, serially diluted 1:3, was prepared in a 384-well polypropylene microplate (cat. 781280; Greiner Bio-One, Frickenhausen, Germany). 5 μL of PBS / 20% Null BacMam was dispensed into all wells except column 18 using a Multidrop Combi (Thermo Scientific, Waltham, MA). 5 μL of PBS was dispensed into column 18. 45 μL of donor blood was transferred into the compound plate using a Bravo (Agilent, Santa Clara, CA). The Bravo protocol mixed blood and compound / PBS five times. The plate was incubated for 6 hours at 37°C and 5% CO2. At the 6-hour time point, the plate was removed and centrifuged at 3000 RPM for 10 minutes. Three microliters of supernatant was transferred from the plate to a 384-well NBS microplate (cat. 4513; Corning Life Sciences, Corning, NY). The plates were sealed with adhesive foil and stored in a −80°C freezer until ready for analysis.

[0496] For cytokine detection, human IP-10 BD cytometric bead array (CBA) beads (BD Biosciences, Franklin Lakes, NJ) were used. Capture bead solution was prepared by making a 1:50 dilution of IP-10 capture bead stock solution in BD diluent for serum / plasma (cat. 51-9003991 BD Biosciences, Franklin Lakes, NJ). 2 μL of this solution was added per well to the assay microplate, which was then sealed with adhesive foil and incubated for 2 hours at room temperature in the dark. Detection reagent was further prepared by making a 1:50 dilution of the detection reagent stock solution. 2 μL of detection reagent was added per well, and the microplate was sealed with adhesive foil and incubated for 1 hour at room temperature in the dark. After 1 hour of incubation, 3 μL of BD CBA wash buffer was added per well of the microplate. Data were acquired on an iQue Screener flow cytometer. The iQue used fluorescence detection to quantify the inhibition of IP-10 present in the sample wells. A 1 second sip time was used per sample. The blue laser with 488 nm excitation and emission filter 585 / 40 nm was used to capture mean and median IP-10 values ​​with the detector in logarithmic mode (FL2-H).

[0497] All data analysis was performed in IDBS ActivityBase XE. Percent inhibition is determined using the formula 100-(100(U-C2) / (C1-C2)), where U is the unknown, C1 is the high control mean response of the mixture in DMSO only, and C2 is the mean of the minimum response in column 18 of the no BacMam stimulation control.

[0498] Curve fitting is done by the equation

[0499]

number

[0500] where A is the minimum response, B is the maximum response, and C is log 10 * where XC50, D is the slope coefficient, and x is log 10 The assay was performed using ABASE XE using the compound concentration [M].

[0501] Biological data for the compounds from the RF-MS 300 assay and the whole blood (hWB) cytokine release assay are shown in Table 3 below.

[0502] [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4]

[0503] For prodrug compounds, activity in the RF-MS assay is believed to be due to the unchanged form from impurities in the sample. In the hWB assay, some prodrugs are unstable under the assay conditions, so the activity of the prodrug may be due to the unchanged form from impurities or removal of the prodrug moiety.

[0504] Additional data Certain compounds disclosed in WO2022 / 137082 and WO2022 / 137085 were tested and biological data for the compounds from RF-MS300 assays and whole blood (hWB) cytokine release assays is shown below in Table 4. Exemplary compounds of the present invention are shown to have an improved profile relative to certain compounds disclosed in WO2022 / 137082 and WO2022 / 137085.

[0505] Whole blood (hWB) cytokine release assays were performed as follows.

[0506] Human whole blood was collected from individual healthy donors into 60 ml syringes containing sodium heparin (5 ml sodium heparin per syringe; Cat# 309653, Becton-Dickinson, NJ, US). In a biosafety cabinet, 140 μl of collected blood was transferred to each well of a 96-well flat-bottom plate (Cat# 167008, VWR, PA, US). DMSO stock solutions of small molecule cGAS inhibitors (10 mM stock solutions) were diluted in PBS to prepare 10x solutions (3-fold dilutions), and 20 μl of the prepared 10x solutions were added to the appropriate wells. The plate was shaken for 5 minutes at room temperature and then incubated at 37°C for 30 minutes. A purified Bacmam stock solution was diluted with PBS + 0.1% BSA to prepare a 4% (v / v) solution (10x). To activate the cGAS pathway, 20 μL of Bacmam was added to the blood and the plate was shaken for 10 minutes at room temperature. PBS was added to achieve a final volume of 200 μL. The plate was then incubated at 37°C for 6 hours.

[0507] The plate was removed from the incubator, and 100 μL / well of PBS was added. The plate was gently shaken at room temperature for 10 minutes and centrifuged (3000 rpm, 10 minutes) at room temperature. The plasma layer was removed and transferred to another 96-well plate and kept at -80°C.

[0508] Plasma samples were measured for IP-10 levels using IP-10 detection (U-plex or V-plex) plates (Cat#K151-UFK-4; Cat#K151-NVD-4; Meso-Scale Discovery, Inc.).

[0509] [Table 15]

Claims

1. Formula (I) 【Chemical 1】 (In the formula, R １ is hydrogen or a prodrug moiety, R ２ is hydrogen, halo, cyano, nitro, C １～３ Alkyl, halo (C １～３ ) alkyl, halo (C １～３ ) alkoxy, —S(O)R ７ , -SO ２ R ７ , —C(O)NR ７ R ８ , -NR ７ C(O)R ８ , -CO ２ R ７ and C １～３ Alkyl, halo (C １～３ ) alkyl and halo(C １～３ ) the alkoxy is hydroxyl or —NR ７ R ８ and optionally substituted by R ３ is C １～３ Alkyl, —C(O)R ８ or a 5- or 6-membered heteroaryl optionally substituted with a prodrug moiety; Each R ４ , R ５ and R ６ are independently -LY; Each L is independently a bond, -(CR ａ R ｂ ) ｎ -, -O-, (CR ａ R ｂ ) ｎ O-, -O(R ａ R ｂ ) ｎ -or- (CR ａ R ｂ ) ｎ O (CR ａ R ｂ ) ｍ - is selected from, each n or m is independently 1, 2, or 3; Each R ａ and R ｂ is independently selected from hydrogen, halo, and methyl; Each Y is independently hydrogen, halo, hydroxyl, cyano, C １～４ Alkyl, C １～４ Alkoxy, C ３～７ Cycloalkyl, C ２～４ Alkenyl, C １～４ Thioalkyl, C １～６ Hydroxyalkyl, C １～４ Cyanoalkyl, halo(C １～４ ) alkyl, halo (C ２～４ ) alkenyl, —NR ９ R １０ , —C(O)NR ９ R １０ , -CO ２ R １０ , -C(O)R １０ , -SO ２ R １０ , -OSO ２ R １０ , -S(O)R １０ , -SO ２ NR ９ R １０ , -N(R １０ ) SO ２ R １０ , -CF ２ CH ２ OR １０ phenyl, 5- or 6-membered heteroaryl and 4- to 10-membered heterocycloalkyl rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; ３～７ The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are independently halo, hydroxyl, —C(O)R １０ , oxo, C １～４ Alkyl, halo (C １～４ ) alkyl and C １～４ hydroxyalkyl; or R ４ and R ５ together with the carbon atoms to which they are attached form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C １～４ Alkyl, oxo, —C(O)R １０ and -SO ２ R １０ and optionally substituted with 1, 2 or 3 substituents selected from R ７ and R ８ is hydrogen and C １～４ independently selected from alkyl, R ９ are independently hydrogen, C １～４ Alkyl, —C(O)C １～４ Alkyl and halo (C １～４ ) alkyl; R １０ are independently hydrogen and C １～６ alkyl, or R ９ and R １０ together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

2. R ３ 2. The compound of claim 1, wherein: is a 5-membered heteroaryl; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

3. R ３ 2. The compound of claim 1, wherein: is a five-membered nitrogen-containing heteroaryl; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

4. Formula (I) 【Chemistry 2】 (In the formula, R １ is hydrogen or a prodrug moiety, R ２ is hydrogen, halo, cyano, nitro, C １～３ Alkyl, halo (C １～３ ) alkyl, halo (C １～３ ) alkoxy, —S(O)R ７ , -SO ２ R ７ , —C(O)NR ７ R ８ , -NR ７ C(O)R ８ , -CO ２ R ７ and C １～３ Alkyl, halo (C １～３ ) alkyl and halo(C １～３ ) the alkoxy is hydroxyl or —NR ７ R ８ and optionally substituted by R ３ is imidazolyl or pyrazolyl, R ３ But C １～３ Alkyl, —C(O)R ８ or may be substituted with a prodrug moiety. Each R ４ , R ５ and R ６ are independently -LY; Each L is independently a bond, -(CR ａ R ｂ ) ｎ -, -O-, (CR ａ R ｂ ) ｎ O-, -O(R ａ R ｂ ) ｎ -or- (CR ａ R ｂ ) ｎ O (CR ａ R ｂ ) ｍ - is selected from, each n or m is independently 1, 2, or 3; Each R ａ and R ｂ are independently selected from hydrogen or methyl; Each Y is independently hydrogen, halo, hydroxyl, cyano, C １～４ Alkyl, C １～４ Alkoxy, C ３～７ Cycloalkyl, C ２～４ Alkenyl, C １～４ Thioalkyl, C １～６ Hydroxyalkyl, C １～４ Cyanoalkyl, halo(C １～４ ) alkyl, halo (C ２～４ ) alkenyl, —NR ９ R １０ , —C(O)NR ９ R １０ , -CO ２ R １０ , -C(O)R １０ , -SO ２ R １０ , -OSO ２ R １０ , -S(O)R １０ , -SO ２ NR ９ R １０ , -N(R １０ ) SO ２ R １０ , -CF ２ CH ２ OR １０ phenyl, 5- or 6-membered heteroaryl and 4- to 10-membered heterocycloalkyl rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; ３～７ The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are independently halo, hydroxyl, —C(O)R １０ , oxo, C １～４ Alkyl, halo (C １～４ ) alkyl and C １～４ hydroxyalkyl; or R ４ and R ５ together with the carbon atoms to which they are attached form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C １～４ Alkyl, oxo, —C(O)R １０ and -SO ２ R １０ and optionally substituted with 1, 2 or 3 substituents selected from R ７ and R ８ is hydrogen and C １～３ independently selected from alkyl, R ９ are independently hydrogen, C １～４ Alkyl, —C(O)C １～４ Alkyl and halo (C １～４ ) alkyl; R １０ are independently hydrogen and C １～６ alkyl, or R ９ and R １０ together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

5. R ａ and R ｂ 5. The compound according to any one of claims 1 to 4, wherein is hydrogen, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

6. Each prodrug moiety is independently —CH ２ O-P(O)(OR ｄ ) (OR ｅ ), -CH ２ O-C(O)-C １～６ Alkylene-O-P(O)(OR ｄ ) (OR ｅ ), -CH ２ O-C(O)-C １～６ Alkylene-P(O)(OR ｄ ) (OR ｅ ), -CH ２ O-C(O)-C １～６ Alkylene-CO ２ H, —CH ２ O-C(O)R ｄ , -CH ２ O-C(O)O-C １～６ Alkylene-CO ２ H, —CH ２ O-C(O)-C １～６ Alkylene -NR ｄ R ｅ , -CH ２ O-C(O)O-C １～６ Alkylene -NR ｄ R ｅ , -C(O)R ｄ , -CH ２ O-C(O)-C １～６ Alkylene-heterocycloalkyl, —CH ２ O-C(O)-C １～６ Alkylene-heterocycloalkyl and -CR ｄ R ｅ -O-(C(O)-NR) ｄ -heteroarylene-CH ２ O—C(O)—CH ２ -NR ｄ R ｅ is selected from the group consisting of R ｄ and R ｅ are each independently hydrogen or C １～６ is alkyl, each heterocycloalkyl is 4-6 membered and contains 1 or 2 heteroatoms independently selected from N, O, and S; 6. The compound according to any one of claims 1 to 5, wherein each heteroarylene is a 5- or 6-membered ring and contains 1 or 2 heteroatoms independently selected from N, O and S, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

7. Each prodrug moiety is independently —CH ２ O-P(O)(OR ｄ ) (OR ｅ ), -CH ２ O-C(O)-C １～６ Alkylene-O-P(O)(OR ｄ ) (OR ｅ ), -CH ２ O-C(O)-C １～６ Alkylene-P(O)(OR ｄ ) (OR ｅ ), -CH ２ O-C(O)-C １～６ Alkylene-CO ２ H, —CH ２ O-C(O)R ｄ , -CH ２ O-C(O)O-C １～６ Alkylene-CO ２ H, —CH ２ O-C(O)-C １～６ Alkylene -NR ｄ R ｅ , -CH ２ O-C(O)O-C １～６ Alkylene -NR ｄ R ｅ and -C(O)R ｄ 7. The compound of claim 6, wherein:

8. Each prodrug moiety is independently 【Chemistry 3】 7. The compound of claim 6, wherein:

9. Each prodrug moiety is independently 【Chemistry 4】 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, of claim 8 selected from:

10. Each prodrug moiety is —CH ２ O-P(O)(OR ｄ ) (OR ｅ 8. The compound according to any one of claims 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein

11. Each prodrug moiety is 【Chemistry 5】 11. The compound of claim 10, wherein: or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

12. R ３ is imidazolyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

13. R １ is the prodrug moiety and R ３ 13. The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein is imidazolyl.

14. R １ but, 【Chemistry 6】 14. The compound of claim 13, wherein: or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

15. R １ is hydrogen, and R ３ The compound according to any one of claims 1 to 4, wherein is imidazolyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

16. R ２ Br, cyano, -C(O)NH ２ , -CF ２ CH ２ NH ２ , -CF ２ CH ２ OH, -CH ２ F, -CHF ２ , -CF ３ , -CF ２ CF ３ , -CF ２ CH ３ , -CF ２ CHF ２ , -OCHF ２ and -S(O)CH ３ or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, according to any one of claims 1 to 15, selected from the group consisting of:

17. R ２ Ga-CF ３ 17. The compound of claim 16, wherein: or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

18. 18. The compound of any one of claims 1 to 17, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein each L is a bond.

19. Each Y is independently hydrogen, halo, cyano, C １～４ Alkyl, C １～４ Alkoxy, C ３～７ Cycloalkyl, C １～４ Thioalkyl, C １～６ Hydroxyalkyl, C １～４ Cyanoalkyl, halo(C １～４ ) alkyl, —NR ９ R １０ , -CO ２ R １０ , -C(O)R １０ , -CF ２ CH ２ OR １０ and a 4- to 10-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O and S; Heterocycloalkyl and C ３～７ Cycloalkyl is independently halo, hydroxyl, —C(O)R １０ , oxo, C １～４ Alkyl, halo (C １～４ ) alkyl and C １～４ hydroxyalkyl; or R ４ and R ５ together with the carbon atoms to which they are attached form a 5-8 membered monocyclic or bicyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, O and S, and the rings are independently selected from halo, C １～４ Alkyl, oxo, —C(O)R １０ and -SO ２ R １０ 19. The compound of claim 18, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, optionally substituted with up to three substituents selected from:

20. Each Y is independently hydrogen, halogen, CO ２ R １０ and halo (C １～４ 20. The compound of any one of claims 1 to 19, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein:

21. R ６ 21. The compound of any one of claims 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein is hydrogen.

22. R ４ and R ６ is hydrogen, and R ５ 22. The compound of any one of claims 1 to 21, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein is fluoro.

23. 5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyramidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-chloro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(difluoromethyl)-1H-1,2,4-triazole; 3-(difluoromethyl)-5-[6-fluoro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[7-chloro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 3-(difluoromethyl)-5-[7-(difluoromethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; {4-oxo-4-[(4-{2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidin-3-yl}-1H-imidazol-1-yl)methoxy]butoxy}phosphonic acid, {4-oxo-4-[(5-{3-[1-({[4-(phosphonooxy)butanoyl]oxy}methyl)-1H-imidazol-4-yl]imidazo[1,2-a]pyrimidin-2-yl}-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methoxy]butoxy}phosphonic acid; ({5-[6-fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl}methoxy)phosphonic acid; Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate; Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate; 3-bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[6-fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-chloro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 3-(difluoromethyl)-5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-bromo-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 3-(difluoromethyl)-5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 3-bromo-5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-pyrazol-4-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[7-(difluoromethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-methyl-1H-1,2,4-triazole; Methyl 3-(1H-imidazol-4-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidine-7-carboxylate; 3-(1H-imidazol-4-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidine-7-carboxylic acid; 3-(difluoromethoxy)-5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole; 5-[6-(difluoromethyl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-fluoro-3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[6-chloro-3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(2-methyl-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; 5-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; and 3-Bromo-5-[6-fluoro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, selected from the group consisting of:

24. 【Chemical 7】 5. The compound of claim 1 or 4, wherein:

25. [Chemical 8] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, of claim 1 or 4, which is a prodrug of

26. 【Chemical 9】 and R １ 26. The compound of claim 25, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein:

27. ​​[Catalog 10] 27. The compound of claim 26, wherein: or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

28. A compound according to any one of claims 1 to 27.

29. 29. A pharmaceutical composition comprising: (a) a compound according to any one of claims 1 to 28 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof; and (b) a pharmaceutically acceptable excipient.

30. 30. A method of treating an autoimmune, autoinflammatory, or immune-mediated condition in a human in need thereof, comprising administering to said human a therapeutically effective amount of a compound of any one of claims 1 to 28 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

31. 29. A compound according to any one of claims 1 to 28, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in therapy.

32. 30. A compound according to any one of claims 1 to 28, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, for use in the treatment of an autoimmune, autoinflammatory or immune-mediated condition.

33. 30. Use of a compound according to any one of claims 1 to 28 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, in the manufacture of a medicament for use in the treatment of an autoimmune, autoinflammatory or immune-mediated condition.

34. 32. The method of treatment, compound for use, or use of any one of claims 30, 30, or 31, wherein the condition is selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis, scleroderma, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), acute kidney injury, chronic kidney disease, diabetic kidney injury, myocardial infarction, stroke, cardiac hypertrophy / heart failure, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).

35. 35. The method, compound for use, or use of claim 34, wherein the condition is systemic lupus erythematosus or lupus nephritis.

36. 29. A combination of (i) a compound according to any one of claims 1 to 28 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, and (ii) an immunomodulatory agent.

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