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

Abstract

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

Description

Technical Field

[0001] The present invention relates to compounds, compositions containing them, 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), particularly systemic lupus erythematosus, cutaneous lupus erythematosus, and lupus nephritis. Background Art

[0002] Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that mediates the production of type I interferons and inflammatory cytokines in response to dsDNA (Sun et al., Science, 33(6121)786 - 791, 2013; Cai et al., Mol Cell, 54(2)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)421 - 430, 2014; Gao et al., Cell, 153(5)1094 - 1107, 2013; Civril et al., Nature, 498(7454)332 - 337, 2013). The resulting cGAMP acts as a second messenger that binds to and activates the stimulator of interferon genes (STING). Activated STING recruits TANK-binding kinase 1 (TBK1), which phosphorylates STING and subsequently phosphorylates the transcription factor IFN regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates to the nucleus, where it acts together with nuclear factor kB (NF-kB), a transcription factor also activated by STING, to initiate the expression of type I IFN and inflammatory cytokines (Ablasser and Chen, Science, 363(6431)eaat8657, 2019).

[0003] Although the cGAS-STING pathway has evolved to be a major defense mechanism for detecting microbial infections, activation of cGAS by self-DNA has been associated with a variety of monogenic diseases (AGS, FCL, RVCL) as well as multi-factorial autoimmune / inflammatory diseases.

[0004] Therapeutic targeting of the cGAS-STING pathway with small molecule cGAS inhibitors can be beneficial in a wide range of autoinflammatory, autoimmune, and immune-mediated diseases. Accordingly, there is a need for novel chemical compounds capable of inhibiting the cGAS pathway. SUMMARY OF THE INVENTION

[0005] In a first aspect, the present invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof,

[0006]

[0007] wherein

[0008] R 1 is hydrogen or a prodrug moiety;

[0009] R 2 is selected from hydrogen, halogen, 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 , wherein C 1-3 alkyl, halo(C 1-3 )alkyl and halo(C 1-3 )alkoxy are optionally substituted with hydroxy or -NR 7 R 8 ;

[0010] R 3 is a 5- or 6-membered heteroaryl, which is optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety;

[0011] Each R 4 , R 5 and R 6 is independently -L-Y;

[0012] Each L is independently selected from 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 -;

[0013] where each n or m is independently 1, 2, or 3;

[0014] Each R a and R b are independently selected from hydrogen, halogen, and methyl;

[0015] Each Y is independently selected from hydrogen, halogen, hydroxy, 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, a 5- or 6-membered heteroaryl, and a 4- to 10-membered heterocycloalkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, where the C 3-7The cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl groups are optionally substituted by one, two, or three substituents independently selected from halogen, hydroxy, -C(O)R 10 , oxo, C 1-4 alkyl, halo(C 1-4 )alkyl, and C 1-4 hydroxyalkyl; or

[0016] R 4 and R 5 , together with the carbon atom to which they are attached, form a 5- to 8-membered monocyclic or bicyclic ring which optionally contains one or two heteroatoms independently selected from N, O, and S, wherein the ring is optionally substituted by one, two, or three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 ;

[0017] R 7 and R 8 are independently selected from hydrogen and C 1-4 alkyl;

[0018] R 9 is independently selected from hydrogen, C 1-4 alkyl, -C(O)C 1-4 alkyl, and halo(C 1-4 )alkyl; and

[0019] R 10 is independently selected from hydrogen and C 1-6 alkyl; or

[0020] wherein R 9 and R 10 , together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted by oxo.

[0021] In a second aspect, the present invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof,

[0022]

[0023] wherein

[0024] R 1 is hydrogen or a prodrug moiety;

[0025] R 2 is selected from hydrogen, halogen, cyano, nitro, C 1-3 alkyl, halo(C 1-3 )alkyl, halo(C1-3 ) 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 , wherein C 1-3 alkyl, halo(C 1-3 ) alkyl and halo(C 1-3 ) alkoxy are optionally substituted with hydroxy or -NR 7 R 8 ;

[0026] R 3 is imidazolyl or pyrazolyl, wherein R 3 is optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety;

[0027] Each R 4 , R 5 and R 6 is independently -L-Y;

[0028] Each L is independently selected from 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 -;

[0029] wherein each n or m is independently 1, 2 or 3;

[0030] Each R a and R b are independently selected from hydrogen or methyl;

[0031] Each Y is independently selected from hydrogen, halogen, hydroxy, 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, C1-4 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 one, two or three heteroatoms independently selected from N, O and S, wherein said C 3-7 cycloalkyl, phenyl, heteroaryl and heterocycloalkyl groups are optionally substituted by one, two or three substituents independently selected from halogen, hydroxy, -C(O)R 10 , oxo, C 1-4 alkyl, halo(C 1-4 )alkyl and C 1-4 hydroxyalkyl; or

[0032] R 4 and R 5 together with the carbon atom to which they are attached form a 5- to 8-membered monocyclic or bicyclic ring which optionally contains one or two heteroatoms independently selected from N, O and S, wherein said ring is optionally substituted by one, two or three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 ;

[0033] R 7 and R 8 are independently selected from hydrogen and C 1-3 alkyl;

[0034] R 9 is independently selected from hydrogen, C 1-4 alkyl, -C(O)C 1-4 alkyl and halo(C 1-4 )alkyl; and

[0035] R 10 independently selected from hydrogen and C 1-6 alkyl; or

[0036] wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo.

[0037] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0038] In a fourth aspect, the present invention provides a method of treating an autoimmune, autoinflammatory or immune-mediated disorder in a person in need thereof, which comprises administering to the person a therapeutically effective amount of a compound of the present invention as disclosed herein.

[0039] In a fifth aspect, the present invention provides a compound of the present invention as disclosed herein for use in therapy.

[0040] In a sixth aspect, the present invention provides the use of a compound of the present invention as disclosed herein in the preparation of a medicament for treating an autoimmune, autoinflammatory or immune-mediated disorder. DETAILED DESCRIPTION OF THE INVENTION

[0042] Definitions

[0043] As used herein, the term halogen refers to a chloro, fluoro, bromo or iodo substituent.

[0044] As used herein, the term cyano refers to the group -CN.

[0045] As used herein, the term nitro refers to the group -NO 2 .

[0046] As used herein, the term hydroxy refers to the group -OH.

[0047] As used herein, the term "prodrug" refers to a compound that readily undergoes a chemical change under physiological conditions to provide the parent compound having pharmacological activity. The term "prodrug moiety" refers to the chemical moiety of the prodrug that is released under physiological conditions to form the active parent compound.

[0048] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon group having the specified number of carbon atoms. For example, the term "C 1-6"Alkyl" refers to an alkyl group having 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. The term "C 1-4 alkyl" refers to an alkyl group having 1 to 4 carbon atoms.

[0049] As used herein, the term "cycloalkyl" refers to a non-aromatic saturated monocyclic hydrocarbon ring containing a specified number of carbon atoms. For example, "C 3-7 cycloalkyl" refers to a cycloalkyl group containing 3 to 7 carbon atoms. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0050] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched-chain saturated hydrocarbon group having, for example, 1 to 6 carbon atoms (C 1-6 alkylene). Exemplary groups include, but are not limited to, -CH 2 -(methylene), -CH 2 CH 2 -(ethylene), -CH 2 CH 2 CH 2 -(propylene), and -CH 2 CH(CH 3 ) 2 -(isobutylene).

[0051] As used herein, the term "C 2-4 alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing a specified number of carbon atoms and at least 1 double bond. For example, "C 2-4 alkenyl" has 2 to 4 carbon atoms. Exemplary groups include, but are not limited to, vinyl and propenyl.

[0052] As used herein, the term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group linked through an oxygen linking atom, where "alkyl" is defined as above. For example, the term "C 1-4 alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0053] As used herein, the term "halo(C 1-4 )alkyl" is intended to mean a group having one or more halogen atoms (which may be the same or different) at one or more carbon atoms of an alkyl moiety containing 1 to 4 carbon atoms, said alkyl moiety being a straight-chain or branched-chain carbon group. Exemplary groups include, but are not limited to, -CF 3 (trifluoromethyl), -CCl 3(Trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Thus, the term halo(C 1-2 )alkyl refers to a group having one or more halogen atoms (which may be the same or different) at one or more carbon atoms of an alkyl moiety having 1 to 2 carbon atoms.

[0054] As used herein, the term "halo(C 1-4 )alkoxy" refers to a straight-chain or branched-chain hydrocarbon group having at least 1 and at most 4 carbon atoms, and one or more halogen atoms (which may be the same or different) attached to one or more carbon atoms, and the hydrocarbon group is attached through an oxygen linking atom. Exemplary groups include, but are not limited to, -OCHF 2 (difluoromethoxy), -OCF 3 (trifluoromethoxy), and -OCH(CF 3 ) 2 (hexafluoroisopropoxy).

[0055] As used herein, the term "C 1-4 thioalkyl" refers to an -S-alkyl group, i.e., an alkyl group attached through a sulfur linking atom, where "alkyl" is defined as above. For example, the term "C 1-4 thioalkyl" refers to a thioalkyl group having 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thioisopropyl, etc.

[0056] As used herein, the term "C 1-6 hydroxyalkyl" is intended to mean a group having one or more hydroxy groups at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, and the alkyl moiety is a straight-chain or branched-chain carbon group. Exemplary groups include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl (-CH 2 CH 2 OH), and hydroxyisopropyl.

[0057] As used herein, the term "C 1-4 cyanoalkyl" is intended to mean a group having one or more cyano groups at one or more carbon atoms of an alkyl moiety having 1 to 4 carbon atoms, and the alkyl is a straight-chain or branched-chain carbon group.

[0058] As used herein, the term "halo(C 2-4 )alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having at least 2 and at most 4 carbon atoms and at least one double bond, and one or more halogen atoms (which may be the same or different) are attached to one or more carbon atoms. Exemplary groups include, but are not limited to, -CH=CHF, -CH=CF 2 , and -CF=CF 2 .

[0059] As used herein, the term "5- or 6-membered heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic group having 5 or 6 ring atoms, including at least one carbon atom and at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom and optionally contain 1, 2, or 3 additional nitrogen ring atoms. The selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Exemplary groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0060] As used herein, the term "5-membered nitrogen-containing heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic group having 5 ring atoms, containing at least one carbon atom, at least one nitrogen atom, and optionally at least one additional 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.

[0061] As used herein, the term "heteroarylene" refers to a group or moiety comprising an aromatic divalent monocyclic or bicyclic group having 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. For example, the term "heteroarylene" refers to a group or moiety comprising an aromatic divalent monocyclic or bicyclic group having 5 to 10 ring atoms, including one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] As used herein, the term "heterocycloalkyl" refers to a non-aromatic saturated monocyclic or bicyclic group having a 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 4 to 10 atoms.

[0063] As used herein, the term "5- to 8-membered monocyclic or bicyclic" refers to a ring having 5 to 8 ring atoms and may be saturated or unsaturated.

[0064] As used herein, the term "bicyclic" may refer to a bridged, fused, or spiro bicyclic group.

[0065] As used herein, the term "optionally substituted" means that a group may be unsubstituted or substituted with one or more substituents as defined herein. The term "substituted" with respect to a group means that a hydrogen atom attached to a member atom within the group is replaced by one of the defined substituents. Where a group may be selected from multiple alternative groups, the selected groups may be the same or different.

[0066] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits 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.

[0067] The term "treatment" refers to ameliorating or stabilizing a designated disorder, reducing or eliminating the symptoms of the disorder, slowing or eliminating the progression of the disorder, and preventing or delaying the recurrence of the disorder in a previously affected patient or subject.

[0068] The term "prevention" refers to avoiding the disease in a subject who does not have the disease.

[0069] The term "compound of the invention" refers to a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof.

[0070] The term "therapeutically effective amount" refers to the amount of the compound of the invention that will elicit a desired biological response in a human. It can vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

[0071] Reference to a compound of formula (I) includes reference to any one of formulae (IA), (IAA), (IB), (IBB), (IC) and (ICC).

[0072] Statement of the Invention

[0073] In a first aspect, the invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof,

[0074]

[0075] wherein

[0076] R 1 is hydrogen or a prodrug moiety;

[0077] R 2 is selected from hydrogen, halogen, 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 、-CO2 R 7 , wherein C 1-3 alkyl, halo(C 1-3 )alkyl, and halo(C 1-3 )alkoxy are optionally substituted by hydroxy or -NR 7 R 8 ;

[0078] R 3 is a 5- or 6-membered heteroaryl, which is optionally substituted by C 1-3 alkyl, -C(O)R 8 or a prodrug moiety;

[0079] Each R 4 , R 5 and R 6 is independently -L-Y;

[0080] Each L is independently selected from 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 -;

[0081] wherein each n or m is independently 1, 2, or 3;

[0082] Each R a and R b is independently selected from hydrogen, halogen, and methyl;

[0083] Each Y is independently selected from hydrogen, halogen, hydroxy, 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 ring containing one, two or three heteroatoms independently selected from N, O and S, wherein said C 3-7 cycloalkyl, phenyl, heteroaryl and heterocycloalkyl groups are optionally substituted by one, two or three substituents independently selected from halogen, hydroxy, -C(O)R 10 , oxo, C 1-4 alkyl, halo(C 1-4 )alkyl and C 1-4 hydroxyalkyl; or

[0084] R 4 and R 5 together with the carbon atom to which they are attached form a 5 - to 8 - membered monocyclic or bicyclic ring which optionally contains one or two heteroatoms independently selected from N, O and S, wherein said ring is optionally substituted by one, two or three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 ;

[0085] R 7 and R 8 are independently selected from hydrogen and C 1-4 alkyl;

[0086] R 9 is independently selected from hydrogen, C 1-4 alkyl, -C(O)C 1-4 alkyl and halo(C 1-4 )alkyl; and

[0087] R 10 is independently selected from hydrogen and C 1-6 alkyl; or

[0088] wherein R 9 and R 10Together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with oxo.

[0089] In an embodiment, R 3 is a 5-membered heteroaryl optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety.

[0090] In an embodiment, R 3 is a 5-membered nitrogen-containing heteroaryl optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety.

[0091] In an embodiment, R 3 is a 5-membered nitrogen-containing heteroaryl optionally containing one, two, or three additional heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety.

[0092] In an embodiment, R 3 is imidazolyl or pyrazolyl, wherein R 3 is optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety.

[0093] In a second aspect, the present invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof,

[0094]

[0095] wherein

[0096] R 1 is hydrogen or a prodrug moiety;

[0097] R 2 is selected from hydrogen, halogen, 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 , wherein C 1-3An alkyl, halo(C 1-3 )alkyl, or halo(C 1-3 )alkoxy is optionally substituted with a hydroxyl group or -NR 7 R 8 ;

[0098] R 3 is an imidazolyl or pyrazolyl group, wherein R 3 is optionally substituted with a C 1-3 alkyl, -C(O)R 8 or a prodrug moiety;

[0099] Each R 4 , R 5 and R 6 is independently -L-Y;

[0100] Each L is independently selected from 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 -;

[0101] wherein each n or m is independently 1, 2, or 3;

[0102] Each R a and R b is independently selected from hydrogen or methyl;

[0103] Each Y is independently selected from hydrogen, halogen, 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 , -SO2 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 a 4 - to 10 - membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O and S, wherein said C 3-7 cycloalkyl, phenyl, heteroaryl and heterocycloalkyl groups are optionally substituted by one, two or three substituents independently selected from halogen, hydroxy, -C(O)R 10 、 oxo, C 1-4 alkyl, halo(C 1-4 )alkyl and C 1-4 hydroxyalkyl; or

[0104] R 4 and R 5 together with the carbon atom to which they are attached form a 5 - to 8 - membered monocyclic or bicyclic ring which optionally contains one or two heteroatoms independently selected from N, O and S, wherein said ring is optionally substituted by one, two or three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 ;

[0105] R 7 and R 8 are independently selected from hydrogen and C 1-3 alkyl;

[0106] R 9 is independently selected from hydrogen, C 1-4 alkyl, -C(O)C 1-4 alkyl and halo(C 1-4 )alkyl; and

[0107] R 10 is independently selected from hydrogen and C 1-6 alkyl; or

[0108] wherein R 9 and R 10Together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with oxo.

[0109] In an embodiment, only one of R 1 and R 3 contains a prodrug moiety. In an embodiment, the prodrug moiety is located at R 1 and not at R 3 . In another embodiment, the prodrug moiety is located at R 3 and not at R 1 . In an embodiment, R 1 is a prodrug moiety, and R 3 is a 5-membered heteroaryl optionally substituted with C 1-3 alkyl or -C(O)R 8 . In an embodiment, R 1 is a prodrug moiety, and R 3 is a 5-membered nitrogen-containing heteroaryl optionally substituted with 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, wherein R 3 is optionally substituted with C 1-3 alkyl or -C(O)R 8 .

[0110] In an embodiment, each R a and R b is independently selected from hydrogen, fluorine, and methyl.

[0111] In an embodiment, each R a and R b is independently selected from hydrogen and methyl.

[0112] In an embodiment, R 1 is a prodrug moiety.

[0113] In an embodiment, the prodrug moiety is a prodrug of the phosphate ester, ester, or amino acid type.

[0114] In an embodiment, the prodrug moiety is a phosphate ester.

[0115] In an embodiment, R 1 is a phosphate ester prodrug.

[0116] In an embodiment, each prodrug moiety is independently selected from: -CH(R c )O-P(O)(OR d )(OR e ), -CH(Rc )O-C(O)-C 1-6 Alkylene-O-P(O)(OR d )(OR e )、-CH(R c )O-C(O)-C 1-6 Alkylene-P(O)(OR d )(OR e )、-CH(R c )O-C(O)-C 1-6 Alkylene-CO 2 H、-CH(R c )O-C(O)R d 、-CH(R c )O-C(O)O-C 1-6 Alkylene-CO 2 H、-CH(R c )O-C(O)-C 1-6 Alkylene-NR d R e 、-CH(R c )O-C(O)O-C 1-6 Alkylene-NR d R e 、-C(O)R d 、-CH(R c )O-C(O)-C 1-6 Alkylene-heterocycloalkyl、-CH(R c )O-C(O)-C 1-6 Alkylene-heterocycloalkyl and -CR d R e -O-(C(O)-NR d -heteroaryl-CH 2 O-C(O)-CH 2 -NR d R e ; wherein R c is independently selected from hydrogen and methyl; R d and R e are each independently hydrogen or C 1-6 alkyl; each heterocycloalkyl is 4- to 6-membered and contains one or two heteroatoms independently selected from N, O, and S; and each heteroaryl is 5- or 6-membered and contains one or two heteroatoms independently selected from N, O, and S.

[0117] In an embodiment, R c is independently selected from hydrogen, halogen, and C 1-3 alkyl.

[0118] In an embodiment, R cIndependently selected from hydrogen, fluorine, and methyl.

[0119] In an embodiment, R c is independently selected from hydrogen and methyl.

[0120] In an embodiment, R c is hydrogen.

[0121] In an embodiment, each prodrug moiety is independently selected from: -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 -heteroaryl-CH 2 O-C(O)-CH 2 -NR d R e ; wherein R d and R e are each independently hydrogen or C 1-6alkyl; each heteroalkyl is 4- to 6-membered and contains one or two heteroatoms independently selected from N, O, and S; and each heteroarylene is 5- or 6-membered and contains one or two heteroatoms independently selected from N, O, and S.

[0122] In embodiments, each prodrug moiety is independently selected from: -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 。

[0123] In embodiments, each prodrug moiety is independently selected from: -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 2O-C(O)O-C 1-6 alkylene-CO 2 H, -CH 2 O-C(O)-C 1-6 alkylene-NR d R e and -CH 2 O-C(O)O-C 1-6 alkylene-NR d R e 。

[0124] In an embodiment, each prodrug moiety is independently selected from: -CH 2 O-P(O)(OR d )(OR e )、-CH 2 O-C(O)-C 1-3 alkylene-O-P(O)(OR d )(OR e )、-CH 2 O-C(O)-C 1-3 alkylene-P(O)(OR d )(OR e )、-CH 2 O-C(O)-C 1-3 alkylene-CO 2 H, -CH 2 O-C(O)R d 、-CH 2 O-C(O)O-C 1-3 alkylene-CO 2 H, -CH 2 O-C(O)-C 1-3 alkylene-NR d R e 、-CH 2 O-C(O)O-C 1-3 alkylene-NR d R e 、-C(O)R d 、-CH 2 O-C(O)-C 1-3 alkylene-heterocycloalkyl、-CH 2 O-C(O)-C 1-3 alkylene-heterocycloalkyl and -CR d R e -O-(C(O)-NR d -heteroarylalkylene-CH 2 O-C(O)-CH 2 -NR d R e ; wherein R dand R e each independently is hydrogen or C 1-6 alkyl; each heterocycloalkyl is 4 - to 6 - membered and contains one or two heteroatoms independently selected from N, O, and S; and each heteroarylene is 5 - or 6 - membered and contains one or two heteroatoms independently selected from N, O, and S.

[0125] In an embodiment, each prodrug moiety is independently selected from: -CH 2 O - P(O)(OR d )(OR e )、-CH 2 O - C(O)-C 1-3 alkylene - O - P(O)(OR d )(OR e )、-CH 2 O - C(O)-C 1-3 alkylene - P(O)(OR d )(OR e )、-CH 2 O - C(O)-C 1-3 alkylene - CO 2 H、-CH 2 O - C(O)R d 、-CH 2 O - C(O)O - C 1-3 alkylene - CO 2 H、-CH 2 O - C(O)-C 1-3 alkylene - NR d R e 、-CH 2 O - C(O)O - C 1-3 alkylene - NR d R e and -C(O)R d .

[0126] In an embodiment, each prodrug moiety is independently selected from: -CH 2 O - P(O)(OR d )(OR e )、-CH 2 O - C(O)-C 1-3 alkylene - O - P(O)(OR d )(OR e )、-CH 2 O - C(O)-C 1-3 alkylene - P(O)(OR d )(OR e )、-CH 2 O - C(O)-C 1-3Alkylene-CO 2 H, -CH 2 O-C(O)O-C 1-3 Alkylene-CO 2 H, -CH 2 O-C(O)-C 1-3 Alkylene-NR d R e and -CH 2 O-C(O)O-C 1-3 Alkylene-NR d R e 。

[0127] In an embodiment, each prodrug moiety is independently selected from

[0128]

[0129] In an embodiment, each prodrug moiety is independently selected from

[0130]

[0131] In an embodiment, each prodrug moiety is -CH 2 O-P(O)(OR d )(OR e ), where R d and R e are as defined above.

[0132] In an embodiment, each prodrug moiety is

[0133]

[0134] In an embodiment, R 1 is a prodrug moiety as defined according to any of the above embodiments. In an embodiment, R 1 is independently selected from: -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)Rd 、 -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 ; wherein R d and R e are each independently hydrogen or C 1-6 alkyl; each heterocycloalkyl is 4 - to 6 - membered and contains one or two heteroatoms independently selected from N, O, and S; and each heteroarylene is 5 - or 6 - membered and contains one or two heteroatoms independently selected from N, O, and S.

[0135] In an embodiment, R 1 is independently selected from

[0136]

[0137] In an embodiment, R 1 is -CH 2 O-P(O)(OR d )(OR e )), wherein R d and R e are as defined above.

[0138] In an embodiment, R 1 is

[0139]

[0140] In an embodiment, the compound of formula (I) is a compound of formula (IA) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof:

[0141]

[0142] wherein R 2 、R 3 、R 4 、R 5 and R 6 are as defined herein with respect to formula (I).

[0143] In an embodiment, R 1 is hydrogen.

[0144] In an embodiment, the compound of formula (I) is a compound of formula (IAA) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof:

[0145]

[0146]

[0147] wherein R 2 、R 3 、R 4 、R 5 and R 6 are as defined herein with respect to formula (I).

[0148] In an embodiment, R 2 is selected from halogen, cyano, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, -S(O)R 7 , -C(O)NR 7 R 8 and CO 2 R 7 , wherein halo(C 1-3 )alkyl and halo(C 1-3 )alkoxy are optionally substituted with hydroxy or -NR 7 R 8 ;

[0149] In an embodiment, R 2 is selected from halogen, cyano, -C(O)NH 2 , halo(C 1-4- )alkoxy, halo(C 1-2 )alkyl, -CF 2 CH 2 NH 2 , -CF 2 CH 2 OH and -S(O)CH 3 .

[0150] In an embodiment, R 2Selected from Br, cyano, -C(O)NH 2 , -CF 2 CH 2 NH 2 , -CF 2 CH 2 , -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 .

[0151] In an embodiment, R 2 is selected from hydrogen, halogen, C 1-3 alkyl, halo(C 1-3 )alkyl and halo(C 1-3 )alkoxy.

[0152] In an embodiment, R 2 is selected from hydrogen, Br, -CF 3 , -CHF 2 , -CH 3 and -OCHF 2 .

[0153] In an embodiment, R 2 is CF 3 .

[0154] In an embodiment, the compound of formula (I) is a compound of formula (IB) or formula (IBB) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof:

[0155]

[0156] wherein R 3 , R 4 , R 5 and R 6 are as defined herein for formula (I).

[0157] In an embodiment, R 3 is imidazolyl or pyrazolyl. In an embodiment, R 3 is imidazolyl. For the avoidance of doubt, in an embodiment, R 3 is unsubstituted imidazolyl.

[0158] In an embodiment, R 3is an imidazolyl or pyrazolyl group linked through carbon, i.e., a C-linked imidazolyl or C-linked pyrazolyl group. In an embodiment, R 3 is a C-linked imidazolyl group. In an embodiment, R 3 is imidazol-4-yl or imidazol-5-yl. In an embodiment, R 3 is imidazol-5-yl.

[0159] In an embodiment, R 1 is a prodrug moiety and R 3 is an imidazolyl group, particularly a C-linked imidazolyl group.

[0160] In an embodiment, R 1 is H and R 3 is substituted with a prodrug moiety.

[0161] In an embodiment, R 1 is and R 3 is an imidazolyl group, particularly a C-linked imidazolyl group.

[0162] In an alternative embodiment, R 1 is hydrogen and R 3 is an imidazolyl group, particularly a C-linked imidazolyl group.

[0163] In an embodiment, the compound of formula (I) is a compound of formula (IC) or formula (ICC) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof:

[0164]

[0165] wherein R 4 , R 5 and R 6 are as defined above for formula (I).

[0166] In an embodiment, each R 4 , R 5 and R 6 is independently -L-Y and each L is a bond.

[0167] In an embodiment, each L is a bond; and each Y is independently selected from hydrogen, halogen, hydroxy, 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)NR9 R 10 、 -CO 2 R 10 、 -C(O)R 10 、 -SO 2 R 10 、 -OSO 2 R 10 、 -CF 2 CH 2 OR 10 、 phenyl, 5 - or 6 - membered heteroaryl, and 5 - or 6 - membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein said heterocycloalkyl is optionally substituted by one, two, or three substituents independently selected from halogen, hydroxy, -C(O)R 10 and C 1-4 alkyl; or R 4 and R 5 together with the carbon atom to which they are attached form a 5 - to 8 - membered monocyclic heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein said ring is optionally substituted by up to three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 of the substituents.

[0168] In embodiments, each L is independently selected from a bond, -(CR a R b ) n -, -O-, -(CR a R b ) n O-, -O(CH 2 ) n - or -(CR a R b ) n O(CR a R b ) m -; and each Y is independently selected from hydrogen, halogen, hydroxy, 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 、 -CO 2 R 10, -C(O)R 10 , -SO 2 R 10 , -OSO 2 R 10 , -CF 2 CH 2 OR 10 , phenyl, 5 - or 6 - membered heteroaryl, and 5 - or 6 - membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein said C 3-7 cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted by one, two, or three substituents independently selected from halogen, hydroxy, -C(O)R 10 and C 1-4 alkyl.

[0169] In an embodiment, each L is independently selected from a bond, -(CH 2 ) n -, -O-, -(CH 2 ) n O-, -O(CH 2 ) n -, and -(CH 2 ) n O(CH 2 ) m -; and each Y is independently selected from hydrogen, halogen, 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 4 - to 10 - membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein said heterocycloalkyl and C 3-7 cycloalkyl are optionally substituted by one, two, or three substituents independently selected from halogen, hydroxy, -C(O)R 10 , oxo, C 1-4 alkyl, halo(C 14- )alkyl, and C 1-4 hydroxyalkyl.

[0170] In an embodiment, each L is a bond; and each Y is independently selected from hydrogen, halogen, hydroxy, 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 , -CO 2 R 10 , -C(O)R 10 , -SO 2 R 10 , -OSO 2 R 10 , -CF 2 CH 2 OR 10 , phenyl, a 5- or 6-membered heteroaryl, and a 5- or 6-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein the C 3-7 cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted by one, two, or three substituents independently selected from halogen, hydroxy, -C(O)R 10 and C 1-4 alkyl. In an embodiment, R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, CO 2 R 10 and halo(C 1-4 )alkyl.

[0171] In an embodiment, R 6 is hydrogen.

[0172] In an embodiment, R 4 and R 5 are independently selected from hydrogen, halogen, CO 2 R 10 and halo(C 1-4 )alkyl and R 6 is hydrogen.

[0173] In an embodiment, R 4 and R 6 are hydrogen.

[0174] In an embodiment, R 4 , R 5 and R 6 are hydrogen.

[0175] In an embodiment, R 4 and R 6 are hydrogen and R 5 is a halogen.

[0176] In an embodiment, R 4 and R 6 are hydrogen and R 5 is fluorine.

[0177] In an embodiment, R a and R b are hydrogen.

[0178] In an embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a 5- to 8-membered monocyclic or bicyclic ring, which optionally contains one or two heteroatoms independently selected from N, O, and S, wherein the ring is optionally substituted with up to three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 8 and -SO 2 R 8 .

[0179] In an embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a 5-membered monocyclic ring. In an embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a 5-membered monocyclic ring containing one heteroatom selected from N and O. In an embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a 6-membered monocyclic ring. In an embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a 6-membered monocyclic ring containing one heteroatom selected from N and O.

[0180] In an embodiment, each L is independently selected from a bond, -(CH 2 ) n - and -(CH 2 ) n O-.

[0181] In an embodiment, each Y is independently selected from hydrogen, halogen, CO 2 R 10 and halo(C 1-4 )alkyl.

[0182] In an embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or its tautomer,

[0183]

[0184] wherein

[0185] R 1 is hydrogen or a prodrug moiety;

[0186] R 2 is selected from hydrogen, halogen, C 1-3 alkyl, and halo(C 1-3 )alkyl;

[0187] R 3 is imidazolyl or pyrazolyl, wherein R 3 is optionally substituted with a prodrug moiety;

[0188] Each R 4 , R 5 and R 6 is independently -L-Y;

[0189] Each L is independently selected from a bond, -(CR a R b ) n- or -O-;

[0190] wherein each n is independently 1, 2, or 3;

[0191] Each R a and R b is independently selected from hydrogen or methyl; and

[0192] Each Y is independently selected from hydrogen, halogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 thioalkyl, C 1-6 hydroxyalkyl, halo(C 1-4 )alkyl, -CO 2 R 10 , -COR 10 , -SO 2 R 10 , -OSO 2 R 10 , -CF 2 CH 2 OR 10 ; or

[0193] R 4 and R 5 together with the carbon atom to which they are attached form a 5- to 8-membered monocyclic or bicyclic ring, which optionally contains one or two heteroatoms independently selected from N, O, and S, wherein the ring is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-4 alkyl, -C(O)R 10and -SO 2 R 10 is substituted with a substituent of;

[0194] R 10 is independently selected from hydrogen and C 1-6 alkyl. In an embodiment, the compound of formula (I) is selected from:

[0195] 5-[3-(1H-Imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0196] 5-[6-Fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0197] 5-[3-(1H-Imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0198] 5-[6-Chloro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(difluoromethyl)-1H-1,2,4-triazole;

[0199] 3-(Difluoromethyl)-5-[6-fluoro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0200] 5-[7-Chloro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0201] 3-(Difluoromethyl)-5-[7-(difluoromethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0202] 5-[3-(1H-Pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0203] {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;

[0204] {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;

[0205] ({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;

[0206] Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate;

[0207] Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate;

[0208] 3-Bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0209] 5-[6-Fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0210] 5-[6-Chloro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0211] 3-(Difluoromethyl)-5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0212] 5-[3-(1H-imidazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0213] 5-[6-Bromo-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0214] 3-(Difluoromethyl)-5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0215] 3-Bromo-5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0216] 5-[3-(1H-pyrazol-4-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0217] 5-[7-(difluoromethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0218] 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0219] 5-[3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-methyl-1H-1,2,4-triazole;

[0220] Methyl 3-(1H-imidazol-4-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidine-7-carboxylate;

[0221] 3-(1H-imidazol-4-yl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-a]pyrimidine-7-carboxylic acid;

[0222] 3-(difluoromethoxy)-5-[3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole;

[0223] 5-[6-(difluoromethyl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0224] 5-[6-fluoro-3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0225] 5-[6-chloro-3-(1H-imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0226] 5-[3-(2-Methyl-1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole;

[0227] 5-[3-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole; and

[0228] 3-Bromo-5-[6-fluoro-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole,

[0229] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0230] In an embodiment, the compound of formula (I) is

[0231]

[0232] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0233] In an embodiment, the compound of formula (I) is depicted by one of the following structures, which depict the available tautomers when R 3 is imidazolyl, R 2 is CF 3 :

[0234]

[0235] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0236] In an embodiment, the compound of formula (I) is depicted by one of the following structures, which depict the available tautomers when R 3 is imidazolyl, R 2 is CF 3 :

[0237]

[0238] or a pharmaceutically acceptable salt thereof.

[0239] In an embodiment, the compound of formula (I) is a prodrug of the following:

[0240]

[0241] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof.

[0242] In an embodiment, the compound of formula (I) is

[0243]

[0244] wherein R 1 is a prodrug moiety, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof.

[0245] In an embodiment, the compound of formula (I) is

[0246]

[0247] or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof.

[0248] In an embodiment, the compound of formula (I) is depicted by one of the following structures, which depict the available tautomers when R 3 is imidazolyl:

[0249]

[0250] or a pharmaceutically acceptable salt thereof.

[0251] In an embodiment, the compound of formula (I) is in the form of a free base. In an embodiment, the compound of formula (I) in the form of the free base is any one of the compounds of Examples 1 to 165.

[0252] In an embodiment, the compound of formula (I) is in the form of a pharmaceutically acceptable salt. In an embodiment, the compound of formula (I) in the form of the pharmaceutically acceptable salt is any one of the compounds of Examples 1 to 165.

[0253] The compound of formula (I) or a tautomer thereof may contain acidic or basic functional groups, and thus those skilled in the art will understand that pharmaceutically acceptable salts of the compound of formula (I) can be prepared.

[0254] Pharmaceutically acceptable salts include in particular those described in Berge, J. Pharm. Sci., 1977, 66, 1-19 or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0255] Suitable pharmaceutically acceptable salts can include acid addition salts or base addition salts.

[0256] Such base addition salts can be formed by reacting a compound of formula (I) which, for example, contains a carboxylic acid or other acidic functional group with a suitable base, optionally in a suitable solvent (such as an organic solvent), to obtain the salt.

[0257] Such acid addition salts can be formed by reacting a compound of formula (I) which, for example, contains a basic amine or other basic functional group with a suitable acid, optionally in a suitable solvent (such as an organic solvent), to obtain the salt.

[0258] The salts can be prepared in situ during the final isolation and purification of the compound of formula (I). If the 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 treating the salt with an inorganic or organic base. Similarly, if the 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 treating the salt with an inorganic or organic acid.

[0259] It should be understood that if the compound of formula (I) contains two or more basic moieties, the stoichiometry of salt formation can include 1, 2 or more equivalents of acid. Such salts will contain 1, 2 or more acid counterions, such as dihydrochloride salts.

[0260] The stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compound of formula (I) are included within the scope of the present invention, including sub-stoichiometric salts.

[0261] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (d-camphorsulfonate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclohexanesulfamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (lauryl sulfate propionate), edetate (ethylenediaminetetraacetate), lauryl sulfate propionate (lauryl sulfate), ethane-1,2-disulfonate (ethanedisulfonate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucates), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-bis(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (naphthalenesulfonate), 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-chlorotheophylline), thiocyanate, triethyl iodide, undecanoate, undecylenate, and valerate.

[0262] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, phenylethylbenzylamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, climidazole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethylenetriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, and zinc.

[0263] The compounds of the present invention may exist in tautomeric forms. It is understood that any reference to a named compound or a structurally described compound is intended to cover all tautomers of such compounds.

[0264] For example, when R 1 is hydrogen, the following tautomers exist:

[0265]

[0266] For example, when R 1 is a prodrug moiety and R 3 is an imidazolyl group (bonded through carbon), the following tautomers exist:

[0267]

[0268] In an embodiment, when R 1 is hydrogen and R 3 is an imidazolyl group (bonded through C), the following tautomers exist:

[0269]

[0270] The present invention also includes all suitable isotopic variants of the compounds of the present invention. Isotopic variants of the compounds of the present invention are defined as variants 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 commonly found in nature.

[0271] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 18F, and 36Cl, respectively. Certain isotope variants of the compounds of formula (I) or their salts or solvates, such as those in which a radioactive isotope (e.g., 3H or 14C) is incorporated, can be used for drug and / or substrate tissue distribution studies. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with an isotope such as deuterium (i.e., 2H) can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain cases. 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. Isotope variants of the compounds of the present invention can generally be prepared by conventional procedures (e.g., by the illustrative methods or by the preparations described in the examples below using appropriate isotope variants of suitable reagents).

[0272] In an embodiment, the present invention includes

[0273]

[0274] in which one or more hydrogen atoms attached to a carbon atom are replaced by deuterium.

[0275] Representative compounds of formula (I) are listed in Table 1 below:

[0276] Table 1

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] Statement of use

[0307] Therapeutic targeting of the cGAS-STING pathway with small molecule cGAS inhibitors can be beneficial in a wide range of autoinflammatory, autoimmune, and immune-mediated diseases.

[0308] In an embodiment, "treatment" means ameliorating or stabilizing a designated condition, reducing or eliminating the symptoms of the condition, and slowing or eliminating the progression of the condition.

[0309] The compounds of the invention are useful for preventing disorders in which cGAS or downstream elements of its pathway may play a known or anticipated role, such as immune disorders, inflammatory disorders, autoimmune disorders, autoinflammatory disorders, Type I interferonopathies, allergies, infectious disorders, organ damage, tissue damage, and other cGAS-dependent or related disorders.

[0310] The compounds of the invention are useful for treating conditions in which cGAS or downstream elements of its pathway may play a known or anticipated role. Thus, the compounds of the invention are useful for treating a variety of immune conditions, inflammatory conditions, autoimmune conditions, autoinflammatory conditions, type I interferon diseases, allergies, infectious conditions, organ damage, tissue damage, and other cGAS-dependent or related conditions.

[0311] The compounds of the present invention are useful for treating cGAS-related diseases or disorders.

[0312] The compounds of the present invention are useful for preventing cGAS-related diseases or disorders.

[0313] The compounds of the present invention can be used to treat autoimmune diseases selected from, but not limited to, STING-associated vasculitis beginning in infancy (SAVI), Aicardi Goutieres syndrome (AGS), familial pernio lupus, ataxia-telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with cerebral leukodystrophy (RVCL), systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis (LN), psoriasis, diabetes mellitus (including insulin-dependent diabetes mellitus (IDDM)), dermatomyositis, human immunodeficiency virus (HIV), AIDS, polymyositis, systemic sclerosis (scleroderma) and Sjögren's syndrome (SS), rheumatoid arthritis (RA), 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 disease), spondylitis, giant cell arteritis, polymyalgia rheumatica, Raynaud's phenomenon, primary biliary cirrhosis, primary vasculitis of the central nervous system, microscopic polyangiitis, neuromyelitis optica, and mixed connective tissue disease.

[0314] The compounds of the present invention can be used to treat acute or chronic inflammation in any tissue or organ of the human body, including but not limited to musculoskeletal inflammation, vascular inflammation, cardiovascular inflammation, neuroinflammation, digestive system inflammation, respiratory system inflammation, renal system inflammation, reproductive system inflammation, ocular inflammation, periodontal inflammation, and other inflammations (as exemplified below), as well as subsequent tissue and organ damage.

[0315] The compounds of the present invention can be used to treat musculoskeletal inflammation (i.e., any inflammatory disorder of the musculoskeletal system), including but not limited to disorders affecting the skeletal joints (including the joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knee, ankle, and foot), and disorders affecting the tissues (such as tendons) connecting muscles and bones. Examples of musculoskeletal inflammation treatable 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), tendinitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, pubic osteitis, and osteitis fibrosa cystica).

[0316] The compounds of the present invention can be used to treat inflammation of the vascular or lymphatic system, including but not limited to atherosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[0317] The compounds of the present invention can be used to treat cardiovascular disorders and cardiomyopathies, including but not limited to heart failure, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, endomyocardial fibrosis, aortic aneurysm, and aortic dissection (AAD).

[0318] The compounds of the present invention can be used to treat inflammation of the nervous system, including but not limited to encephalitis, sepsis-associated encephalopathy (SAE), ischemic stroke, traumatic brain injury (TBI), ataxia-telangiectasia, Guillain-Barré syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, CNS vasculitis, and schizophrenia.

[0319] The compounds of the present invention can be used to treat inflammatory disorders of the digestive system, including but not limited to cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), ileitis, proctitis, and colorectal cancer.

[0320] The compounds of the present invention can be used to treat inflammatory conditions of the respiratory system, 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 can be used to improve pulmonary inflammation, endothelial and vascular damage, and skin lesions caused by COVID-19 infection.

[0321] The compounds of the present invention can be used to treat inflammatory disorders and diseases of the liver and kidneys, 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.

[0322] The compounds of the present invention can be used to treat metabolic disorders, including but not limited to diabetes, obesity, insulin resistance, and glucose intolerance.

[0323] The compounds of the present invention can be used to treat 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.

[0324] The compounds of the present invention can be used to treat ocular inflammation, including but not limited to inflammation of any structure of the eye (including the eyelids). Examples of ocular inflammation that can be treated with the compounds of the present invention include blepharitis, blepharochalasis, conjunctivitis, dacryadenitis, keratitis, fungal keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis. In addition, other eye-related disorders, including age-related macular degeneration (AMD), can be treated.

[0325] The compounds of the present invention can be used to treat inflammatory periodontal diseases (also known as gum diseases), including but not limited to gingivitis, odontoblast inflammation, chronic periodontitis, aggressive periodontitis, necrotizing ulcerative gingivitis / periodontitis, and periodontal-endodontic lesions.

[0326] The compounds of the present invention can be used for treating autoimmune diseases having an inflammatory component, including but not limited to acute disseminated alopecia universalis, Behcet's disease, Chagas disease, STING-associated vasculopathy onset in infancy (SAVI), Aicardi Goutieres syndrome (AGS), lupus erythematosus pernio, ataxia telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with leukoencephalopathy of the brain (RCVL), ANCA)-associated vasculitis, chronic fatigue syndrome, familial dysautonomia, 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, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia rheumatica, 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.

[0327] The compounds of the present invention can be used for treating T cell-mediated hypersensitivity diseases having an inflammatory component, including but not limited to contact hypersensitivity, contact dermatitis (including contact dermatitis caused by poison ivy), urticaria, skin allergy, respiratory allergy (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0328] The compounds of the present invention can be used for treating other inflammatory conditions, including but not limited to appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, pneumonia, 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 allograft, skin homograft, and heart valve xenograft, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory syndrome, Sezary syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, cancer-related hypercalcemia, pemphigus, dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis, and iridocyclitis, choroidoretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated tuberculosis chemotherapy, adult idiopathic thrombocytopenic purpura, adult secondary thrombocytopenia, acquired (autoimmune) hemolytic anemia, adult leukemia and lymphoma, acute leukemia in children, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis.

[0329] The compounds of the present invention can be used for treating one or more diseases afflicting humans, which are characterized by cell proliferation in the area of disorders associated with neovascularization and / or vascular permeability, including angiogenic disorders (including arthritis (rheumatoid arthritis) and restenosis); fibrotic disorders, including cirrhosis and atherosclerosis; mesangial cell proliferative disorders, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, proliferative retinopathy, organ transplant rejection, and glomerulopathy; and other disorders, including psoriasis, diabetes, and chronic wound healing.

[0330] The compounds of the present invention can be used for treating 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).

[0331] The compounds of the present invention can be used to treat inflammatory conditions resulting from infectious diseases, which are any diseases triggered by or occurring concomitantly with pathogen infections. Pathogens can be broadly defined as any species or organism that is foreign to the human tissue environment. Common pathogenic pathogens include bacteria (many such as TB), viruses (many such as HBV, HIV, influenza), and parasitic protozoa (such as Plasmodium falciparum that causes malaria). The compounds of the present invention can be used to treat infectious diseases originating from bacteria, such as TB infection {Mycobacterium tuberculosis}, chlamydia, tularemia infection {Francisella tularensis}, malaria parasite infection, or infections from DNA or RNA viruses. The compounds of the present invention can be used to treat infectious diseases originating from the DNA virus family: Herpesviridae (herpes simplex virus-1, Kaposi's sarcoma-associated virus, and Epstein-Barr virus), Papillomaviridae (human papillomavirus), Adenoviridae, and Hepadnaviridae (hepatitis B virus). Examples of the RNA virus family include Retroviridae (human immunodeficiency virus), Flaviviridae (dengue virus, Zika virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronavirus, MERS, SARS, and SARS-CoV2 coronavirus).

[0332] The compounds of the present invention can be used to improve organ damage or impairment caused by cGAS-mediated diseases or disorders, such as acute kidney injury, liver injury, lung injury, heart injury, etc.

[0333] The compounds of the present invention can be particularly used to treat systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjogren's syndrome, dermatomyositis, and scleroderma, especially systemic lupus erythematosus and lupus nephritis.

[0334] The compounds of the present invention can be particularly used to treat 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).

[0335] Aicardi-Goutières syndrome (AGS) is an early-onset disease that exhibits features of autoinflammatory and autoimmune diseases, presenting with progressive encephalopathy and chilblain skin lesions, and is biochemically characterized by increased type I interferon (Stetson et al. Cell 134(4)587-598, 2008; Crow et al. Nat Rev Immunol 15(7)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 carry mutations in Trex1 or RnaseH2, leading to the accumulation of cytoplasmic DNA due to insufficient DNA clearance (Trex1) or micronucleus formation driven by DNA damage (RnaseH2). Importantly, knockout of these nucleases and / or knock-in of inactivating AGS mutations leads to a fatal autoimmune disease in mice, which can be rescued by cGAS or STING deficiency (Gray et al. 2015 J Immunol 195(5)1939-1943, 2015; Gao et al. PNAS USA 112(42)E5699-E5705, 2015; Pokatayevet et al. JExp Med 213(3)329-336, 2016; Mackenzie et al. EMBO J 35(8)831-844, 2016). In addition to AGS, Trex1 mutations are also associated with familial chilblain lupus (FCL) (a cutaneous form of systemic lupus erythematosus) and retinal vasculopathy with cerebral leukodystrophy (RVCL) (Rice et al. J Clin Immunol 35(3)235-243, 2015). Recently, biallelic mutations in the LSM11 and RNU7-1 genes, which encode components of the histone pre-mRNA processing complex, have been identified in genetically uncharacterized AGS patients and are associated with excessive cGAS signaling (Uggenti et al. Nat Genet 52(12)1364–1372, 2020).

[0336] Direct evidence that STING activation causes inflammatory diseases comes from the identification of gain-of-function mutations in the TMEM173 gene encoding STING in patients presenting with early-onset vascular lesions and pulmonary inflammation (Liu et al. N Engl J Med 371(6)507-518, 2014). Diseases caused by such mutations (now classified as SAVI (STING-associated vasculopathy with onset in infancy)) are characterized by recurrent fevers, ulcerative skin lesions, vasculitis, and interstitial lung disease. It is thought that SAVI-associated STING mutations lead to spontaneous dimerization and activation of STING in the absence of cGAMP (Ergun et al. Cell, 178(2)290-301, 2019).

[0337] COPA syndrome (named for defects in the COPA protein involved in Golgi-to-ER transport) is also associated with abnormal cGAS-STING signaling. It is thought that due to COPA mutations, STING spends a proportionally longer time in the activated state in the Golgi, leading to constitutive signaling (Lepelley et al. J Exp Med 217(11)e20200600, 2020; Mukai et al. Nat Commun 12(1)61, 2021). While all COPA patients present with lung disease, a subset of patients develop arthritis and kidney disease.

[0338] DNAseII deficiency was first described in humans in 2017. Affected patients present with severe neonatal anemia, membranoproliferative glomerulonephritis, arthropathy, and elevated levels of anti-dsDNA antibodies (Rodero et al. Nature Communications 8(1)2176, 2017). Although DNAseII is an endosomal nuclease, it is hypothesized that the accumulation of dsDNA in endolysosomes ultimately leads to their rupture, exposing DNA to cGAS. DnaseII-deficient mice die during embryonic development due to severe anemia and develop chronic polyarthritis if crossed with IFNAR-deficient 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 DnaseII-deficient mice from embryonic lethality and chronic arthritis (Gao et al. PNAS USA 112(42)E5699–E5705, 2015).

[0339] 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 SLE. Missense Trex1 mutations have been identified in 0.5-2% of SLE patients, and the lupus-like phenotype was recapitulated in mice carrying the Trex1D18N mutation that causes familial pernio lupus (Namjou et al. Genes and Immunity 12(4)270-279, 2011; Lee-Kirsch et al. Nat Genet 39(9)1065-1067, 2007; Barizzone et al. Biomed Res Int 2013:471703, 2013). Similarly, in addition to AGS, mutations that impair RnaseH2 function are also associated with SLE (Günther et al. J Clin Invest 125(1)413–424, 2015). In addition, elevated cGAMP levels were reported in 15% of SLE patients, and cGAMP-positive patients showed higher SLEDAI scores (An et al. Arthritis Rheumatol 69(4)800–807, 2017).

[0340] Based on the presence of an interferon signature and overlapping clinical presentations, diseases including various subtypes of cutaneous lupus erythematosus (CLE), lupus nephritis (LN), and dermatomyositis are expected to be driven (at least in part) by the same mechanisms implicated 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).

[0341] Overactivation of cGAS-STING and cGAS-STING-dependent pathogenesis have been implicated in several other autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD). Deletion of cGAS rescued the polyarthritis phenotype in DnaseII-KO mice and reduced 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, deletion of STING attenuated IMQ-induced psoriasis 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 harmful roles. Although elimination of cGAS reduced intestinal inflammation and improved colitis associated with IL-10 deficiency, other studies have highlighted the beneficial roles of cGAS and STING in intestinal homeostasis (Ahn et al. Cell Reports 21(13)3873-3884, 2017; Canesso et al. Mucosal Immunol 11(3)820-834, 2018; Hu et al. PNAS 118(23)e2105747118, 2021).

[0342] Inflammation is a prominent hallmark of multiple 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 result in defects in mitophagy, leakage of mtDNA into the cytosol, and cGAS-STING-dependent cytokine production. Importantly, the motor deficits and neuronal cell loss observed in Parkin mutant mice can be rescued by STING ablation (Slitter et al. Nature 561(7722)258-262, 2018). Recently, the cGAS-STING pathway has been implicated in the neuropathological processes associated with ALS and frontotemporal degeneration. In a preclinical model of ALS driven by overexpression of the human TDP-43 (A315T) allele, STING ablation inhibits neuroinflammation, slows the rapid progression of the disease, and prevents early death (Yu et al. Cell 183(3)636–649, 2020). Additionally, in the SOD1-ALS mouse model, administration of a cGAS or STING inhibitor improved ongoing inflammation, improved motor function, and increased survival (Tan et al. iScience 25:104404, 2022). Finally, ALS patients with C9orf72 repeat expansions exhibit an enhanced type I interferon signature, which is at least partially driven by STING activation (McCauley et al. Nature585(7823)96-101, 2020). Increased cGAS activity has also been associated with inflammatory responses in HD striatal cells, and microglial activation by Tau is associated with the PQBP1-cGAS-STING pathway (Sharma et al. PNAS117(27)5989–15999, 2020; Jin et al. Nat Commun 12(1)6565, 2021).

[0343] Activation of the cGAS-STING pathway by mtDNA has been proposed as a potential mechanism underlying obesity-induced inflammation and metabolic dysfunction. Deletion and / or inhibition of STING (at least in part) prevents diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance, and reduces senescence of pancreatic β cells (Mao et al. Arterioscler Thromb Vasc Biol 37(5)920-929, 2017; Hu et al. FASEB J 36(5)e22266, 2022). In addition, excessive cGAS-STING signaling has been associated with other metabolic diseases such as NAFLD and NASH. Independent laboratories have demonstrated that STING deletion reduces the severity of hepatic steatosis, inflammation, and fibrosis in 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 13:931176, 2022).

[0344] Enhanced cGAS-STING signaling has been demonstrated in acute kidney injury (AKI), chronic kidney disease (CKD), and other fibrosis-related indications. Cisplatin-induced mtDNA leakage triggers tubular inflammation and the progression of acute kidney injury, which can be rescued by STING deletion or treatment with STING inhibitors (Maekawa et al. Cell Rep 29(5)1261-1273, 2019; Gong et al., Am J Physiol Renal Physiol 320(4)F608-F616, 2021). Chronic kidney disease (CKD), which is characterized by kidney injury, inflammation, and tissue fibrosis, is associated with impaired mitochondrial integrity and mtDNA release. In addition, genetic ablation or pharmacological inhibition of STING improves TFAM loss-induced and FA-induced kidney inflammation and fibrosis, and improves renal function in APOL1 transgenic mice expressing the G2 risk allele (Chung et al. Cell Metab 30(4)784-799, 2019; Wu et al. J Clin Invest 131(20)e136329, 2021). Recently, Zhang et al. proposed that cGAS-STING-driven fibrosis is promoted by the non-canonical cGAS–STING–PERK pathway (Zhang et al. Nat Cell Biol 24(5)766-782, 2022).

[0345] Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring. It is believed that this pathophysiology depends on repetitive local microinjuries that lead to DNA damage, cell death, and fibrosis. In the classical bleomycin-induced mouse model of pulmonary fibrosis, the contribution of the cGAS-STING pathway to disease pathology is controversial. While Savigny et al. suggested that STING plays a protective role in the bleomycin model by limiting pulmonary fibrosis, Zhang et al. reported a less severe fibrotic phenotype in response to bleomycin in STING-deficient mice compared to WT mice (Savigny et al. Front Immunol 11:588799, 2021; Zhang et al. Nat Cell Biol 24(5)766-782, 2022). Administration of STING inhibitors also improved 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). In addition, cGAS-STING signaling induces pulmonary inflammation in response to cigarette smoke exposure (a major cause of chronic obstructive pulmonary disease (COPD)) and silica particles (Nascimento et al. Sci Rep 9(1)14848, 2019; Benmerzoug et al. Nat Com 9(1)5226, 2018).

[0346] Myocardial infarction (MI) results in ischemic cell death of the heart, releasing fragments of the dying cells. The released cardiomyocyte DNA is phagocytosed by infiltrating macrophages, leading to cGAS-STING-mediated type I IFN production. Genetic or pharmacological blockade of the cGAS-STING pathway prevents MI-induced adverse ventricular remodeling, improves systolic function, and increases survival after myocardial infarction (King et al. Nat Med 23(12)1481-1487, 2017; Cao at al. Circulation 137(24)2613-2634, 2018; Lai et al. J Am Heart Assoc 10(15)e020754, 2021; Rech et al. Life Sci 291:120263, 2022). In addition, cGAS-STING knockdown blunts pressure overload-induced cardiac hypertrophy and improves cardiac function in a mouse transverse aortic constriction (TAC) model (Hu et al. Am J Physiol Heart circ Physiol 318(6)H1525-H1537, 2020). Activation of the cGAS-STING pathway is also associated with the development of atherosclerosis and ischemic stroke brain injury (Pham et al. Eur Heart J 42(42)4336-4348, 2021; Li et al., EMBO Mol Med 12(4)e11002, 2020).

[0347] Excessive cGAS-STING signaling leads to acute and chronic inflammation in multiple tissues, and in addition to the above diseases, the cGAS-STING pathway is also associated with 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 11:571334, 2020), and sepsis (Hu et al., EBioMedicme 41:497-508, 2019).

[0348] In the last five years, several studies have shown 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)1061-1070, 2017). Senescent cells have a unique secretory phenotype (senescence-associated secretory phenotype), which is defined as changes in the expression of pro-inflammatory cytokines, chemokines, extracellular matrix components, and matrix metalloproteinases (MMPs). The senescence-associated secretory phenotype is thought to contribute to many age-related chronic diseases, including atherosclerosis and cardiovascular disease, arthritis, type 2 diabetes, neurodegenerative diseases, and others. Inhibition of cGAS can reduce chronic inflammation and provide benefits in many indications relevant to the elderly patient population.

[0349] Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19 disease. It has been reported that the interaction of SARS-CoV-2 with host cells activates the cGAS-STING pathway through non-canonical pathways (Neufeldt et al. 2022, Commun Biol 5(1)45, 2022; Di Domizio et al. Nature 603(7899)145-151, 2022). The fusion of SARS-CoV-2 with host cells results in cytosolic micronuclei that bind and activate cGAS to induce an interferon response (Liu et al. Sci Signal 5(729)eabg8744, 2022). Although activation of the cGAS-STING pathway during SARS-CoV-2 infection produces cytokines that can inhibit viral replication, overactivation leads to uncontrolled immune responses caused by COVID-19 immunopathology (Di Domizio et al. Nature 603(7899)145-151, 2022). Pharmacological inhibition of the cGAS-STING pathway is expected to modulate the immune response after infection and may thus alleviate the immunopathology associated with disease symptoms. SARS-CoV-2-infected mice treated with a STING antagonist two days after infection showed reduced pathology in their lungs and decreased levels of type I IFN and other cytokines (Di Domizio et al. Nature 603(7899)145-151, 2022). Activation of the cGAS-STING pathway is also associated with a variety of other viral and bacterial pathogens.

[0350] Multiple laboratories have investigated the role of the cGAS-STING pathway in cancer. Many cancer cells exhibit genomic instability, which leads to the formation of micronuclei and cGAS activation. Induced cGAS-STING signaling can result in anti-tumor or pro-tumorigenic processes, depending on the specific context. On the one hand, for more effective tumor surveillance, cytokines (such as type I IFN) produced by the activated cGAS-STING pathway enhance natural killer (NK) cell responses and initiate CD8+ T cell responses (Marcus et al. Immunity 9(4)754-763, 2018; Woo et al. Immunity 41(5)830-842, 2014). On the other hand, activation of the cGAS-STING pathway is associated with metastasis and immune evasion. It has been proposed that tumor cells with high genomic instability, which is a hallmark of metastatic tumors, utilize the cGAS-STING pathway to promote cell invasion (Bakhoum et al. Nature 553(7689)467–472, 2018). In addition, cGAS and STING shape the immunosuppressive tumor microenvironment by recruiting regulatory T cells and myeloid-derived 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).

[0351] In embodiments, the present invention relates to compounds, compositions containing them, and their use in treating various disorders, particularly autoimmune, autoinflammatory, or immune-mediated conditions such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjögren'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), particularly systemic lupus erythematosus, cutaneous lupus erythematosus, and lupus nephritis.

[0352] In embodiments, the present invention relates to compounds, compositions containing them, and their use in treating various disorders, particularly autoimmune, autoinflammatory, or immune-mediated conditions, such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjögren'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.

[0353] In one aspect of the invention, there is provided a method of treating an autoimmune, autoinflammatory, or immune-mediated condition in a person in need thereof, which comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof.

[0354] In a further aspect, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for use in therapy.

[0355] In a further aspect, there is provided a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for treating an autoimmune, autoinflammatory, or immune-mediated condition.

[0356] 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 the compound or a tautomer thereof, in the manufacture of a medicament for treating an autoimmune, autoinflammatory, or immune-mediated condition.

[0357] In embodiments, the autoimmune, autoinflammatory, or immune-mediated condition is selected from systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, Sjögren's syndrome, dermatomyositis, and scleroderma, particularly systemic lupus erythematosus.

[0358] In embodiments, the autoimmune, autoinflammatory, or immune-mediated condition is systemic lupus erythematosus (SLE). In embodiments, the systemic lupus erythematosus is characterized as moderate to severe.

[0359] In embodiments, the autoimmune, autoinflammatory, or immune-mediated condition is lupus nephritis.

[0360] In embodiments, the autoimmune, autoinflammatory or immune-mediated disorder is selected from 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).

[0361] In embodiments, a method of treating systemic lupus erythematosus in a person in need thereof is provided, which comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof.

[0362] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for use in treating systemic lupus erythematosus is provided.

[0363] In embodiments, the systemic lupus erythematosus is characterized as moderate to severe.

[0364] Accordingly, in embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for use in treating moderate to severe systemic lupus erythematosus is provided.

[0365] In embodiments, the systemic lupus erythematosus is characterized as active systemic lupus erythematosus.

[0366] In embodiments, the systemic lupus erythematosus is active, moderate to severe systemic lupus erythematosus.

[0367] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for use in treating lupus nephritis is provided.

[0368] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for use in treating lupus nephritis identified by biopsy is provided.

[0369] In embodiments, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, for use in treating cutaneous lupus erythematosus is provided. In embodiments, the cutaneous lupus erythematosus is subacute or chronic.

[0370] In a further embodiment, use of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, in the manufacture of a medicament for treating systemic lupus erythematosus is provided.

[0371] 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 preparation of a medicament for the treatment of lupus nephritis.

[0372] 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 preparation of a medicament for the treatment of cutaneous lupus erythematosus.

[0373] In an embodiment, 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

[0374] which is used for the treatment of systemic lupus erythematosus.

[0375] In an embodiment, 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

[0376] which is used for the treatment of lupus nephritis.

[0377] In an embodiment, 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

[0378] which is used for the treatment of cutaneous lupus erythematosus.

[0379] In an embodiment, 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

[0380] which is used for the treatment of systemic lupus erythematosus.

[0381] In an embodiment, 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

[0382] which is used for the treatment of lupus nephritis.

[0383] In an embodiment, 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

[0384] which is used for the treatment of cutaneous lupus erythematosus.

[0385] Pharmaceutical composition / Route of administration / Dose

[0386] Although the compounds of the invention may be administered as the raw chemical for treatment, the active ingredient is generally presented as a pharmaceutical composition.

[0387] In a further aspect, the 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 tautomer; and (b) a pharmaceutically acceptable excipient. An excipient must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to its recipient.

[0388] The pharmaceutical composition may be adapted for administration by any suitable route, such as by oral (including buccal or sublingual), rectal, inhalation, intranasal, topical (including buccal, sublingual or transdermal), ocular (including topical, intravitreal, subconjunctival, episcleral, sub-Tenon's), 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 together the active ingredient with the excipient(s).

[0389] In one embodiment, the pharmaceutical composition is presented for oral administration, for example as a tablet or capsule. Other suitable compositions for oral administration may be powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or water-in-oil liquid emulsions or oil-in-water liquid emulsions.

[0390] The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer may be used alone or in combination with other therapeutic agents. Thus, combination therapy according to the invention comprises administering at least one compound of formula (I) or a pharmaceutically acceptable salt or tautomer thereof, and using at least one other therapeutic active agent. The compound of formula (I) or a pharmaceutically acceptable salt or tautomer thereof, and the other therapeutic active agent may be formulated and administered together in a single pharmaceutical composition, or may be formulated and administered separately. When formulated and administered separately, the administration may be simultaneous or sequential in any order.

[0391] The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer may be used in combination with one or more other therapeutic agents useful for treating autoimmune, autoinflammatory or immune-mediated disorders.

[0392] Thus, in a further aspect of the 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 tautomer; and (ii) an immunomodulator.

[0393] In an embodiment, the immunomodulator is belimumab, also known as BENLYSTA.

[0394] In an embodiment, the present 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, and an immunomodulator.

[0395] In an embodiment, the present invention provides a combination therapy of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, and an immunomodulator for treating autoimmune, autoinflammatory or immune-mediated disorders, particularly systemic lupus erythematosus.

[0396] In an embodiment, the present invention provides a method for treating autoimmune, autoinflammatory or immune-mediated disorders, which comprises administering a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, together with an immunomodulator.

[0397] In an embodiment, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, can be used in combination with one or more other therapeutic agents (such as antimalarials, steroids and immunosuppressants) for the standard of care for treating systemic lupus erythematosus.

[0398] In an embodiment, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, can be used to treat SLE patients who do not respond to the standard of care.

[0399] In an embodiment, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, can be used to treat patients with SLE who are receiving the standard of care and do not respond to at least one immunosuppressant.

[0400] In an embodiment, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, can be used to treat patients with active, moderate to severe SLE who are receiving the standard of care and do not respond to at least one immunosuppressant.

[0401] In an embodiment, a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, can be used to treat patients with SLE that cannot be controlled by treatment with the standard of care alone. Examples

[0402] General synthetic method

[0403] The compounds of the present invention can be prepared using the synthetic procedures shown in the following reaction schemes and the knowledge of skilled organic chemists. The syntheses provided in these schemes are applicable to the production of the compounds of the present invention with various different substituents using appropriate precursors (which can be appropriately protected if necessary) to achieve compatibility with the reactions outlined herein. Deprotection is then carried out when needed to obtain the compounds with the generally disclosed properties. 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; examples thereof can be found in “Greene’s Protective Groups in Organic Synthesis’ (Peter G.M. Nuts, 5th edition, J.Wiley and Sons, 2014). Intermediates (compounds used to prepare the compounds of the present invention) can also exist as salts.

[0404] General Method 1 (Scheme 1)

[0405] An appropriately protected halo-ketone triazole compound (A) and a pyrimidin-2-amine (B) are mixed and heated in an appropriate solvent (e.g., EtOH) to provide the resulting imidazopyrimidine (C). The imidazopyrimidine is halogenated with an appropriate reagent (e.g., N-bromosuccinimide) to give (D), where X is a halogen. The (D) is subjected to a catalyst-mediated coupling with an appropriate reagent (e.g., a borate ester (E)) to give a substituted imidazopyrimidine (F), where -G-Z is R protected with an appropriate protecting group. 3 The triazole protecting group (Y) and any other potential protecting groups are removed by any appropriate method (e.g., acid hydrolysis) to give the desired 1H-triazole of formula (I).

[0406]

[0407] Scheme 1

[0408] General Method 2 (Scheme 2)

[0409] A bromoimidazopyrimidine (H) that can be prepared by General Method 1 (where R 5 is Br) is coupled with an appropriate partner through a catalyst-mediated coupling (i.e., with a photocatalytic alkyl halide) to give J, where -G-Z is R protected with an appropriate protecting group. 3 The triazole protecting group (Y) and any other potential protecting groups are removed by an appropriate method (e.g., acid hydrolysis) to give the desired 1H-triazole of formula (I).

[0410]

[0411] Scheme 2

[0412] General method 3 (Scheme 3)

[0413] The imidazopyrimidine (K) having a suitably protected functional group (PG = protecting group) on R 4 , R 5 or R 6 (R as shown in the figure 5 ) prepared by Method 1 can be selectively deprotected to give L, which is then further functionalized (e.g., by electrophilic alkylation) to give M. Removal of the remaining protecting groups (Y and Z) gives the compound of formula (I).

[0414]

[0415] Scheme 3

[0416] General method 4 (Scheme 4)

[0417] The imidazopyrimidine (N) having a primary alcohol at any one (or more) of the positions bearing R 4 , R 5 or R 6 (R as shown in the figure 5 ) synthesized by Method 1 is converted to a leaving group (e.g., mesylate) and replaced by a suitable nucleophile to give P. Before removing the remaining protecting groups (Y and Z), it can be further purified to give the compound of formula (I).

[0418]

[0419] Scheme 4

[0420] General method 5 (Scheme 5)

[0421] Method 5 is an extension of Method 1, with an additional functionalization step after imidazopyrimidine formation. When R 5a can be further functionalized (e.g., by catalyst-mediated coupling or electrophilic alkylation to introduce new substituents), the reaction gives a substituted imidazopyrimidine (R). This group can be further modified by known methods to give the desired R 5 group. Subsequently, the imidazopyrimidine is halogenated with a suitable reagent (e.g., N-bromosuccinimide) to give (S). Catalyst-mediated coupling of (S) with a suitable reagent (e.g., borate ester (E)) gives a substituted imidazopyrimidine (T). Removal of the triazole protecting group (Y) and any other potential protecting groups (e.g., Z) by any appropriate method (e.g., acidic hydrolysis) gives the 1H-triazole compound of formula (I). This method is also applicable to molecules where the groups at the R4 or R6 positions can be modified as described above.

[0422]

[0423] Scheme 5

[0424] General method 6 (Scheme 6)

[0425] General method 6 employs a synthetic strategy involving late-stage triazole formation. Imidazopyrimidine (W) is formed by the reaction of U and V. Amide formation occurs, and subsequent halogenation of the imidazopyrimidine with a suitable reagent (e.g., N-bromosuccinimide) gives X. Catalyst-mediated coupling of X with a suitable reagent (e.g., boronate ester E) gives the substituted imidazopyrimidine Y. Two-step triazole formation is carried out by condensation with a reagent (AA) containing R 1 to form an amidine, followed by condensation with hydrazine and cyclization to the triazole (BB). Removal of the protecting group Z can be achieved in this step or with a separate deprotection step to give the 1H-triazole compound of formula (I).

[0426]

[0427] Scheme 6

[0428] General method for prodrug preparation (Scheme 7)

[0429] The triazole (I) that can be prepared by one of the general methods reacts with a suitable reagent to give a prodrug of formula (I) that may contain additional protecting groups (PM = prodrug moiety). If a protecting group is present, removal of the protecting group by a suitable method in step 6 will complete the synthesis. The prodrug moiety can also be added at an early stage of the synthesis.

[0430] From general method 1

[0431]

[0432] Scheme 7

[0433] Mass spectrometry-directed automated preparative HPLC (MDAP)

[0434] The compounds of the present invention are prepared using mass spectrometry-directed automated preparative HPLC, and the conditions are given below. UV detection is the average signal at wavelengths from 210 nm to 350 nm, and mass spectrometry is recorded on a mass spectrometer using alternating scan positive and negative mode electrospray ionization.

[0435] MDAP method A

[0436] Method A is carried out at ambient temperature on an Xselect CSH C 18 column (typically 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0437] A = 0.1% v / v solution of trifluoroacetic acid in water

[0438] B = 0.1% v / v trifluoroacetic acid in acetonitrile solution.

[0439] The gradient used is:

[0440] Time (min) Flow rate (mL / min) ％A ％B 0 40 95 5 3 40 95 5 12 40 65 35 12.5 40 1 99 17 40 1 99

[0441] MDAP Method B

[0442] Method B is carried out at ambient temperature on an Xselect CSH C 18 column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0443] A = 0.1% v / v formic acid in water solution

[0444] B = 0.1% v / v formic acid in acetonitrile solution.

[0445] The gradient used is:

[0446] Time (min) Flow rate (mL / min) ％A ％B 0 40 85 15 1 40 85 15 10 40 45 55 10.5 40 1 99 15 40 1 99

[0447] MDAP Method C

[0448] Method C is carried out at ambient temperature on an Xselect CSH C 18 column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0449] A = 0.1% v / v formic acid in water solution

[0450] B = 0.1% v / v formic acid in acetonitrile solution.

[0451] The gradient used is:

[0452] Time (min) Flow rate (mL / min) ％A ％B 0 40 95 5 3 40 95 5 22 40 65 35 22.5 40 1 99 27 40 1 99

[0453] MDAP Method D

[0454] Method D is carried out at ambient temperature on an Xselect CSH C 18 column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0455] A = 0.1% v / v formic acid in water solution

[0456] B = 0.1% v / v formic acid in acetonitrile solution.

[0457] The gradient used is:

[0458] Time (min) Flow rate (mL / min) ％A ％B 0 40 95 5 3 40 95 5 12 40 65 35 12.5 40 1 99 17 40 1 99

[0459] MDAP Method E

[0460] Method E is carried out at ambient temperature on Xselect CSH C 18 column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0461] A = 0.1% v / v solution of trifluoroacetic acid in water

[0462] B = 0.1% v / v solution of trifluoroacetic acid in acetonitrile.

[0463] The gradient employed is:

[0464] Time (min) Flow rate (mL / min) ％A ％B 0 40 85 15 1 40 85 15 10 40 45 55 10.5 40 1 99 15 40 1 99

[0465] MDAP Method F

[0466] Method F is carried out at ambient temperature on Xselect CSH C 18 column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0467] A = 0.1% v / v solution of formic acid in water

[0468] B = 0.1% v / v solution of formic acid in acetonitrile.

[0469] The gradient employed is:

[0470] Time (min) Flow rate (mL / min) ％A ％B 0 40 70 30 1 40 70 30 10 40 15 85 10.5 40 1 99 15 40 1 99

[0471] MDAP Method G

[0472] Method G is carried out at ambient temperature on Xselect CSH C 18 column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used are:

[0473] A = 0.1% v / v solution of formic acid in water

[0474] B = 0.1% v / v solution of formic acid in acetonitrile.

[0475] The gradient employed is:

[0476] Time (min) Flow rate (mL / min) ％A ％B 0 40 50 50 1 40 50 50 10 40 1 99 10.5 40 1 99 15 40 1 99

[0477] MDAP Method H

[0478] Method H is carried out at ambient temperature on Xselect CSH C 18Performed on a column (usually 150 mm x 30 mm i.d. 5 μm packing diameter). The solvents used were:

[0479] A = 0.1% v / v solution of trifluoroacetic acid in water

[0480] B = 0.1% v / v solution of trifluoroacetic acid in acetonitrile.

[0481] The gradient employed was:

[0482] Time (min) Flow rate (mL / min) ％A ％B 0 40 70 30 1 40 70 30 10 40 15 85 10.5 40 1 99 15 40 1 99

[0483] Unless otherwise stated, the starting materials used for the preparation of the intermediates and examples are commercially available from, for example, PharmaTech and Sigma Aldrich.

[0484] Intermediate 1

[0485] 1-(3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-2-chloroethanone

[0486]

[0487] Step 1: 3,5-Dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole

[0488] To a solution of 3,5-dibromo-1H-1,2,4-triazole (200 g, 882 mmol) in AcCN (300 mL) at room temperature was added DIEA (308 mL, 176 mmol), 1-(chloromethyl)-4-methoxybenzene (143 mL, 1058 mmol) and KI (14.63 g, 88 mmol). 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 Na 2 SO 4 dried and concentrated. The residue was dissolved in DCM (250 mL) and adsorbed on silica gel (100 g), then purified by column chromatography (100 - 200 mesh silica gel [1 kg]) eluting with a hexane solution of 5 - 10% EtOAc to give the title compound (190 g, 531 mmol, 60% yield), which was a off-white solid. LCMS: [M+H] + = 347.92

[0489]

[0490] Step 2: 1-(3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-2-chloroethanone

[0491] At -40 °C, isopropylmagnesium chloride lithium (1 M in THF) (559 mL, 559 mmol) was added to a solution of 3,5-dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole (100 g, 280 mmol) in THF (800 mL). 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 NH 4 Cl aqueous solution (500 mL), and extracted with EtOAc (2 × 1 L). The combined organic extracts were washed with brine (500 mL), dried over Na 2 SO 4 and concentrated. The residue was adsorbed onto silica gel (100 g) and purified by column chromatography (silica gel 100 - 200 mesh [400 g]) eluting with a hexane solution of 10 - 20% EtOAc to give the title compound (23.45 g, 66.5 mmol, 24% yield), which was a pale grey solid. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.33 - 7.41 (m, 2H), 6.83 - 6.90 (m, 2H), 5.66 (s, 2H), 4.87 (s, 2H), 3.78 (s, 3H). LCMS: [M + H] + = 345.92

[0492] Intermediate 2

[0493] N,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide

[0494]

[0495] 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 min, then treated with a solution of 4,4'-di-tert-butyl-2,2'-bipyridine (1.50 g, 5.59 mmol) in THF (50 mL). After 20 min, 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 h, the reaction was concentrated and the resulting residue was triturated with pentane to give the title compound (32.2 g, 102 mmol, 89% yield), which was a brown solid. 11H NMR (400 MHz, CDCl 3 ) δ ppm 8.02 (d, J = 1.01 Hz, 1H), 7.73 (d, J = 1.01 Hz, 1H), 2.89 (s, 6H), 1.39 (s, 12H). LCMS: [M+H] + = 220.1 (boric acid)

[0496] Intermediate 3

[0497] 2-Chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one

[0498]

[0499] Step 1: 1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazole

[0500] To a stirred mixture of (4-methoxybenzyl)hydrazine hydrochloride (50.0 g, 265 mmol) in methanol (500 mL) was added sodium methoxide (60.0 g, 278 mmol) as 25 wt% in methanol. After the white suspension was stirred for 15 minutes, methyl 2,2,2-trifluoroacetate (36.0 g, 281 mmol) was added dropwise over 30 minutes. The reaction was stirred for an additional 2 hr. (LCMS showed a new peak at t RET 0.75 min at 92% (UV). For the acylated PMB hydrazine, a weak M+Na + 271.2 was seen. The PMB hydrazine SM t RET 0.33 min. MS (ES) [M+H] + 121.0.) The reaction was treated with formamidine acetate (30.0 g, 288 mmol), heated to reflux at 85 °C, and stirred for 24 hr. (LCMS showed a new peak at t RET 0.95 min at 47% (UV), with a weak MS (ES) [M+H] + 258.2) The reaction was evaporated to dryness, dissolved in EtOAc, washed with aqueous NaHCO 3 solution, dried (Na 2 SO 4), filter and evaporate to dryness. Purify by silica gel chromatography (Isco RediSep Rf Gold 330 g, 0% for 4 minutes, to 30% in 2 minutes, then to 70% in 15 minutes, heptane solution of EtOAc). Combine the pure fractions and evaporate to dryness to give the product 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (45.4 g), which is a yellow oil that solidifies 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 HNMR(400MHz,CDCl 3 )δ8.06(s,1H),7.35 - 7.30(m,2H),6.97(d,J=8.9Hz,2H),5.36(s,2H),3.87(s,3H).LCMS m / z 258.2[M + H] +

[0501]

[0502] Step 2

[0503] The following reaction was carried out twice on a half scale and then combined after purification.

[0504] 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) at -10 °C (ice, NaCl) under nitrogen, add dropwise 1.0 N 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (400 mL, 400 mmol) over 30 minutes. Stir the reaction for 30 min, then treat with a solution of 2-chloro-N-methoxy-N-methylacetamide (58.0 g, 422 mmol) in tetrahydrofuran (THF) (140 mL). Stir the reaction for 1 hr, then carefully quench with 1 N aq. HCl (500 mL) (pH ~ 4). Extract the reaction with EtOAc (300 mL), wash with brine, dry (Na 2 SO 4 ),filter and concentrate in vacuo. Purify by silica gel chromatography (Isco RediSep Rf Gold 330 g, 25 to 60% CH 2 Cl 2A heptane solution; the solid was purified by loading 30 g of Isolute HM-N. The 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, yield 64.1%), which was a white solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0505] Intermediate 4

[0506] 2-Chloro-1-(3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)ethan-1-one

[0507]

[0508] Step 1

[0509] 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 dropwise 2,2-difluoroacetic anhydride (25 mL, 201 mmol) over 30 min. The reaction was stirred for 30 min and then diluted with EtOAc (300 mL) and water (500 mL). The ethyl acetate phase was removed, washed with brine, dried (Na 2 SO 4 ), 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 h, and acetic acid (75 mL, 1310 mmol) was added after 4 h. The reaction was cooled to rt and evaporated in vacuo. The residue was dissolved in EtOAc, washed with an aqueous solution of NaHCO 3 aqueous solution, dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification by silica gel chromatography (Isco RediSep Rf Gold 220 g, heptane solution of 20 to 80% EtOAc) gave 3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (26 g, yield 75%), which was a pale yellow oil. 11H 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] +

[0510] Step 2

[0511] At -10 °C (ice, NaCl) under nitrogen, a stirred solution of 3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (25 g, 105 mmol) in tetrahydrofuran (200 mL) was added dropwise over 30 min with 1.0 N THF / toluene solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (180 mL, 180 mmol). The reaction mixture was stirred for 30 min 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 hr and then carefully quenched with 1 N aq. HCl (450 mL) (pH ~ 4). The reaction was extracted with EtOAc (300 mL), washed (brine), dried (Na 2 SO 4 )), filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (Isco RediSep Rf Gold 330 g, heptane solution of 10 to 50% EtOAc). The desired fractions were combined and concentrated in vacuo to afford 2-chloro-1-(3-(difluoromethyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (19.6 g, yield 59.4%), which was a white solid. 1 1H 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).

[0512] Intermediate 5

[0513] 6-Bromo-2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine

[0514]

[0515] 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 saturated NaHCO 3 aqueous solution, filtered, washed with water and dried under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (Isco RediSep Rf Gold 120 g, DCM solution with 0 to 20% EtOAc). 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), which was a light brownish solid. 1 1H 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] +

[0516] Intermediate 6

[0517] 2-(2-aminopyrimidin-4-yl)-2,2-difluoroethan-1-ol

[0518]

[0519] Step 1

[0520] 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 hr. The reaction was cooled to rt, diluted with EtOAc (200 mL), neutralized with saturated NH 4 Cl aqueous solution (200 mL) and stirred for 15 minutes. The mixture was filtered to remove insolubles 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 (Na 2 SO 4) Filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography (Isco RediSep Rf Gold 80 g, CH 2 Cl 2 solution). The desired fractions were combined and concentrated in vacuo to afford ethyl 2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetate (2.3 g, 44.5% yield), which was a grayish-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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] +

[0521] Step 2

[0522] Sodium borohydride (400 mg, 10.57 mmol) was added portionwise 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. The reaction was stirred at 0 °C for 30 min and then warmed to rt. The reaction was stirred for 1.5 h and then quenched slowly with 1 N aqueous HCl (25 mL). The reaction was concentrated to near dryness in vacuo, basified with saturated NaHCO 3 and filtered to remove insolubles. The product remained in the aqueous filtrate. The aqueous solution was evaporated to dryness in vacuo. The resulting solid was triturated with CHCl 3 solution (100 mL) of 20% methanol, filtered and rinsed with CHCl 3 solution of 20% methanol. The filtrate was evaporated to dryness in vacuo to give the crude product, which was a yellow solid. The crude was purified by silica gel chromatography (Isco RediSep Rf Gold 80 g, DCM solution of 0 to 20% MeOH). The desired fractions were combined and evaporated in vacuo to afford 2-(2-aminopyrimidin-4-yl)-2,2-difluoroethan-1-ol (1.1 g, 64.8% yield), which was a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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 / z176.1 [M+H] +

[0523] Intermediate 7

[0524] 4-(Difluoromethyl)pyrimidin-2-amine

[0525]

[0526] Step 1

[0527] At -70 °C (CO 2 , iPrOH), 2,2-Difluoroacetic anhydride (25.8 mL, 208 mmol) was added dropwise to a stirred solution of ethyl vinyl ether (15.99 mL, 167 mmol) and pyridine (16.4 mL, 203 mmol) in DCM (160 mL). The reaction was warmed to rt and stirred overnight. The reaction was quenched with water. The organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give (E)-4-Ethoxy-1,1-difluorobut-3-en-2-one (25.4 g, 87% yield), which was an orange oil. 1 1H 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] +

[0528] Step 2

[0529] A mixture of guanidine hydrochloride (19.6 g, 205 mmol) and ethanol (80 mL) was stirred for 1 hr, then treated with sodium hydroxide (8.0 g, 200 mmol) and stirred overnight. 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 to the stirred suspension over 1 hr. The mixture was stirred for 2 hr 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 in vacuo to give 4-(Difluoromethyl)pyrimidin-2-amine (14.02 g, 55.0% yield), which was a white solid. 1 1HNMR (400 MHz, DMSO-d 6)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] +

[0530] Intermediate 8

[0531] tert-Butyl 2-amino-8,8-difluoro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0532]

[0533] Step 1

[0534] Mix tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (855 mg, 3.63 mmol) with 1,1-dimethoxy-N,N-dimethylmethanamine (10 mL, 74.7 mmol), and heat the mixture at 100 °C for 16 h. Cool the reaction to rt and slowly neutralize with saturated aqueous sodium bicarbonate. Extract the mixture with EtOAc (6x), and wash the combined organic layers (brine), dry (MgSO 4 )), filter, and concentrate in vacuo to give crude (E)-5-((dimethylamino)methylene)-3,3-difluoro-4-oxopiperidine-1-carboxylate (1055 mg, 100% yield). LCMS m / z 291.2 [M+H] +

[0535] Step 2

[0536] Suspend (E)-5-((dimethylamino)methylene)-3,3-difluoro-4-oxopiperidine-1-carboxylate (1050 mg, 3.62 mmol), guanidine hydrochloride (930 mg, 9.74 mmol), and K 2 CO 3 (1353 mg, 9.79 mmol) in N-methyl-2-pyrrolidone (NMP) (15 mL), and heat at 75 °C for 3 h. Cool the solution to rt, then slowly neutralize with saturated aqueous sodium bicarbonate. Extract the mixture with EtOAc (4x), and wash the combined organic layers (brine), dry (MgSO 4) Filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (Isco RediSep Rf Gold 80 g, heptane solution of 0 - 100% EtOAc). The desired fractions were concentrated in vacuo to afford 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] +

[0537] Example 1

[0538] 5-[3-(1H-Imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0539]

[0540] Step 1

[0541] 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) were heated in EtOH (80 mL) at 90 °C overnight. The reaction was cooled to rt and the resulting precipitate was collected by filtration and washed with EtOH to afford 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] +

[0542] Step 2

[0543] 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 Na 2 S 2 O 3 (aqueous solution) / saturated NaHCO 3 (aqueous solution) and brine, dried over MgSO 4Dry and concentrate. Grind the residue with a hexane solution of 10% DCM, and wash the resulting solid with hexane to obtain 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, yield 93%), which is a white solid. 1 H NMR(400MHz,CDCl 3 )δppm8.76(dd,J=4.1,2.0Hz,1H),8.61(dd,J=6.8,2.0Hz,1H),7.48(d,J=8.8Hz,2H),7.18(dd,J=7.0,4.2Hz,1H),6.86(d,J=8.9Hz,2H),6.17(s,2H),3.79(s,3H).LCMS m / z 455.3[M+H] +

[0544] Step 3

[0545] 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 2 (dppf)-CH 2 Cl 2 -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. Concentrate the reaction, and partition the residue between saturated aqueous NaHCO 3 and DCM. Separate the organic layer, wash with brine, dry over MgSO 4 and concentrate. The residue was purified by silica gel chromatography (ISCO 330 g RediSepRf column, eluting with a hexane solution of 20 - 100% [3:1 EtOAc:EtOH]) to obtain 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(400MHz,CDCl 3) 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] +

[0546] Step 4

[0547] 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), saturated NaHCO 3 aqueous solution was adjusted to pH = 7, and stirred in a mixture of EtOAc (200 mL) and saturated NaHCO 3 aqueous solution 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 and suspended again in EtOH at 100 °C for 1 hr 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 1H NMR (400 MHz, DMSO-d 6 ) 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] +

[0548] Example 2

[0549] 5-[6-Fluoro-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0550]

[0551] Step 1

[0552] In each of nine separate containers, a solution 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 in a microwave reactor at 170 °C for 4 h. 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, hexane solution of 10 - 80% [3:1:0.01 EtOAc / EtOH / Et 3 N]). The fractions were combined and concentrated in vacuo to afford 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), which was a yellow solid. 1 1H NMR (400 MHz, chloroform-d) δ ppm 8.72 (d, J = 2.9 Hz, 1H), 8.55 - 8.43 (m, 1H), 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] +

[0553] Step 2

[0554] 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 rt for 3 h. The reaction mixture was partitioned between 1:1 saturated Na 2 S 2 O 3 aqueous solution / saturated NaHCO 3 aqueous solution and DCM. The organic layer was washed with brine, dried over MgSO 4 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 / Et 3Purified with a hexane solution of [N], to obtain 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, yield 68%), which is a yellow solid. 1 1H 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] +

[0555] Step 3

[0556] 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 2 (dppf)-CH 2 Cl 2 adduct (0.998 g, 1.222 mmol) in DME (5 mL) was heated under N 2 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 IscoRediSep Rf Gold column, 20-80% 3:1 EtOAc:EtOH / hexane with 2% NH 4 OH) to obtain 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, yield 70%). 11H 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, J = 8.8 Hz, 2H), 6.21 (s, 2H), 3.79 (s, 3H), 3.02 (s, 6H). LCMS m / z 566.1 [M+H] +

[0557] Step 4

[0558] 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 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 15.75 (br s, 1H), 12.73 (br s, 1H), 10.30 (dd, J = 5.0, 3.1 Hz, 1H), 8.93 (d, J = 2.9 Hz, 1H), 8.64 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H). LCMS: t RET = 0.41 min (gradient from 1 - 100% of a 0.1% v / v solution of TFA in acetonitrile to a 0.1% v / v solution of TFA in water over 1.85 min), m / z 339.2 [M+H] +

[0559] Example 3

[0560] 5-[3-(1H-Imidazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0561]

[0562] Step 1

[0563] In CH 32-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) in CN (20 mL), 4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 6.13 mmol), and sodium bicarbonate (0.515 g, 6.13 mmol) were heated in a capped vessel at 115 °C overnight. Another portion of 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (500 mg) was added and heating was continued for another night, then more 2-chloro-1-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethan-1-one (500 mg) was added. The temperature was raised to 120 °C and the reaction was stirred for another night and cooled. The resulting precipitate was removed by filtration and washed with aqueous citric acid and MeOH. The filtrate was concentrated until only the aqueous phase remained, which was extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , concentrated, and purified by silica gel chromatography (120 g Isco RediSep Rf Gold column, eluting with a hexane solution of 0 - 50% EtOAc) to give the crude product. The material was sonicated with MeOH and filtered. The filtrate was treated with water until a solid precipitated. The solid was collected by filtration and washed with hexane, then with a 10% Et 2 O hexane solution 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%), which was a tan solid. 1 1H NMR (400 MHz, DMSO-d 6 ) 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] +

[0564] Step 2

[0565] 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 rt for 90 min, at 55 °C for 1 h, and then at 45 °C overnight. The reaction was concentrated, dissolved in DCM, washed with saturated NaHCO 3 aqueous solution, dried over Na 2 SO 4 and concentrated. The resulting residue was triturated with 1:4 Et 2 O:hexane 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 1H NMR (400 MHz, DMSO-d 6 ) 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] +

[0566] Step 3

[0567] 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 a few minutes. Water (400 μL), PdCl 2 (dppf)-CH 2 Cl 2- The adduct (107 mg, 0.131 mmol) and potassium phosphate (232 g, 1.09 mmol) were taken, 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 separated, concentrated and purified by silica gel chromatography (120 g Isco RediSep Rf Gold column, eluting with a hexane solution of 5 - 55% EtOAc) 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%), which was a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.98 (d, J = 7.3 Hz, 1H), 8.55 (dd, J = 20.0, 1.4 Hz, 2H), 7.77 (d, J = 7.3 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 6.90 - 6.98 (m, 2H), 5.96 (s, 2H), 3.73 (s, 3H), 2.88 (s, 6H). LCMS m / z 616.3 [M+H] +

[0568] Step 4

[0569] 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). The fractions containing the desired product were treated with sodium citrate buffer and concentrated until only the aqueous phase remained. The resulting solid was collected by filtration and washed with water and hexane to afford 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%), which was a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δppm 15.88(br s,1H),12.81(br s,1H),10.48(d,J=7.4Hz,1H),8.68(s,1H),8.08(d,J=1.0Hz,1H),7.69(d,J=7.4Hz,1H).LCMS m / z389.1[M+H] +

[0570] Examples 4 - 12 were synthesized in a similar manner to Example 2.

[0571]

[0572]

[0573]

[0574] The following examples were prepared in a similar manner to Example 2, except that additional steps 3a and 3b were carried out after step 3.

[0575] Example 13

[0576] 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

[0577]

[0578] Step 3a

[0579] Dissolve 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) in THF (4 mL). Add HCl (2 mL, 8.00 mmol, 4N in dioxane) and stir the reaction at rt for 3 h. Since no reaction had been observed so far, six drops of 6N aqueous HCl were added and the reaction was stirred at rt for 20 h, then at 60 °C for 4 h. Cool the reaction and concentrate in vacuo. Partition the resulting residue between saturated NaHCO 3 aqueous solution and EtOAc. Wash the organic layer with brine and dry (MgSO 4) was filtered and concentrated to obtain 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, yield 74%), which was a crude yellow residue and was used in the next step without purification. LCMS m / z 483.2 [M+H] +

[0580] Step 3b

[0581] 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 4 (9.36 mg, 0.24 mmol) was added, and the reaction mixture was stirred at rt for 4 h. The reaction was quenched by adding 0.5 mL of saturated NaHCO 3 aqueous solution. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO 4 )), filtered and concentrated in vacuo to obtain 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, yield 98%), which was used in the next step without purification. LCMS m / z 485.2 [M+H] +

[0582] Step 4

[0583] 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 h. The reaction mixture was cooled and concentrated to a yellow residue. The residue was dissolved in 2 mL of THF, and 6 drops of 16N aqueous NaOH were added. The mixture was stirred for 1 h and then concentrated to a yellow residue. The residue was purified by preparative HPLC (Xselect CSH C 18Column (150 mm x 30 mm i.d., 5 μm packing diameter), purified with 30 - 85% 10 mM ammonium bicarbonate / water with acetonitrile). The desired fraction was 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), which is a yellow solid. 1 H NMR (400 MHz, methanol-d 4 ) 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] +

[0584] The following examples were prepared in a similar manner to Example 2, except that Step 4a was carried out after Step 3.

[0585] Example 14

[0586] 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

[0587]

[0588] Step 4a

[0589] 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 h. The reaction mixture was cooled and the mixture was concentrated to a brown residue. The residue was purified by reverse phase HPLC (Xselect CSH C 18 Column (150 mm x 30 mm i.d., 5 μm packing diameter), 15 - 50% acetonitrile / water, each with 0.1% formic acid). The desired fraction was 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), which is a yellow solid.1 1H NMR (400 MHz, methanol-d 4 ) δ ppm 9.82 (d, J = 7.3 Hz, 1H), 8.39 (s, 1H), 8.00 (d, J = 0.98 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 2.79 (s, 3H). LCMS m / z 363.1 [M+H] +

[0590] Examples 15 - 17 were synthesized in a similar manner to Example 2, except that an additional Step 3c was carried out after Step 3.

[0591] Example 15

[0592] 5-[6-(Cyclohexylmethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole, trifluoroacetate

[0593]

[0594] Step 2

[0595] 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 rt for 2 h. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography (220 g column, 2:1, PE:EtOAc) to give 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), which was a yellow solid. LCMS m / z 578.9 [M+H] +

[0596] Step 3c

[0597] In N 2 under stirring to 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(CF 3 )ppy] 2 (dtbbpy)PF 6 (8.96 mg, 7.98 μmol), NiCl2 A solution of ethylene glycol dimethyl ether (3.51 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (4.28 mg, 0.02 mmol) and LiOH (7.65 mg, 0.32 mmol) in DME (10 mL) was added to (Me 3 Si) 3 SiH (0.05 mL, 0.16 mmol) and (bromomethyl)cyclohexane (42.4 mg, 0.24 mmol). The reaction was stirred at rt with a 37 W blue LED for 3 h. 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), which was a yellow solid. LCMS m / z 644.2 [M+H] +

[0598] Step 4

[0599] 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 rt and concentrated to remove TFA. The residue was dissolved in DMF (2.0 mL), filtered, and purified by preparative HPLC (SunFire C18 OBD preparative column, 5 μm, 19 mm X 250 mm; mobile phase A: water [0.05% TFA], mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 28% B to 45% B in 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 (9.4 mg, 0.018 mmol, 14% yield), which was a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)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] +

[0600] Example 16

[0601] 5-[6-Cyclopentyl-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole, trifluoroacetate

[0602]

[0603] Step 3c

[0604] Under N 2 With stirring, to a solution of 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(CF 3 )ppy] 2 (dtbbpy)PF 6 (8.96 mg, 7.98 μmol), NiCl 2 ethylene glycol dimethyl ether (3.51 mg, 0.02 mmol), 4,4-di-tert-butyl-2,2-bipyridine (4.28 mg, 0.02 mmol) and LiOH (7.65 mg, 0.32 mmol) in DME (8 mL) was added (Me 3 Si) 3 SiH (0.05 mL, 0.160 mmol) and bromocyclopentane (0.03 mL, 0.24 mmol). The reaction was stirred at rt with a 37 W blue LED for 3 h. 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), which is a yellow solid. LCMS m / z 616.15 [M+H] +

[0605] Step 4

[0606] 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 preparative column, 5 μm, 19 mm X 250 mm; mobile phase A: water [0.05% TFA], mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 20% B to 33% B in 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 (10.4 mg, 0.020 mmol, 31% yield), which was a white solid. 1 1H NMR (400 MHz, DMSO-d 6 ) 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] +

[0607] Example 17

[0608] 5-[6-(Cyclopentylmethyl)-3-(1H-imidazol-5-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole, trifluoroacetate

[0609]

[0610] Step 3c

[0611] At rt under N 2 To 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(CF 3 )ppy] 2(dtbbpy)PF 6 (13.43 mg, 0.012 mmol), NiCl 2 A solution of ethylene glycol dimethyl ether (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) in DME (14 mL) was added to (bromomethyl)cyclopentane (0.044 mL, 0.359 mmol) and (Me 3 Si) 3 SiH (0.074 mL, 0.239 mmol). The reaction was stirred at rt with a 34 W blue LED for 3 h. 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), which was a yellow solid. LCMS m / z 630.3 [M + H] +

[0612] Step 4

[0613] 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 rt and concentrated to remove TFA. The residue was dissolved in DMF (2.0 mL), filtered, and purified by preparative HPLC (SunFire C18 OBD preparative column, 5 μm, 19 mm X 250 mm; mobile phase A: water [0.05% TFA], mobile phase B: MeCN; flow rate: 25 mL / min; gradient: from 30% B to 35% B in 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 (8.9 mg, 0.017 mmol, 14% yield), which was a yellow solid. 1 H NMR (400 MHz, DMSO - d 6)δ9.30(s,1H),8.64(s,1H),8.57(s,1H),8.30(s,1H),2.64(d,J=7.6Hz,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] +

[0614] The following examples were synthesized in a similar manner to Example 2, except that an additional step 3d and 3e were carried out after step 3.

[0615] Example 18

[0616] 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

[0617]

[0618] Step 3d

[0619] 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)-carboxylic acid tert-butyl ester (90 mg, 0.122 mmol) was dissolved in DCM (15 mL), and then TFA (2 mL, 26.0 mmol) was added. The solution was stirred at rt for 5 h. The solution was concentrated in vacuo. The resulting product was dissolved in (MeOH, 5 mL), neutralized with aqueous NH 4 OH (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] +

[0620] Step 3e

[0621] 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 min. Sodium triacetoxyborohydride (48 mg, 0.226 mmol) was added. The reaction mixture was stirred for a few minutes, and 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 min. The reaction was diluted with EtOAc. Saturated NaHCO 3 aqueous solution was added, and the combined mixture was extracted with EtOAc (3x). The combined organics were washed with brine, dried (MgSO 4 ), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (Isco RediSep Rf Gold 24 g column, heptane solution of 25 - 100% EtOAc). 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] +

[0622] Step 4

[0623] 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 rt, concentrated in vacuo, and then evaporated from DCM / EtOAc / MeOH (3x). The residue was suspended in IPA (5 mL), and NH 4Neutralize the OH aqueous solution and then concentrate. The resulting solid is purified by ISCO reverse-phase preparative HPLC (30 - 100%, aqueous solution of MeCN, +0.1% TFA in each solvent, Gemini Prep C18 5 μM, 50x30 mm, AXIA packed column). The product fractions are concentrated in vacuo and then lyophilized to give 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 (3.4 mg, 6.30 μmol, 15% yield), which is a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.23 - 9.22 (m, 1H), 9.21 - 9.20 (m, 1H), 8.22 - 8.20 (m, 1H), 4.28 (s, 2H), 2.84 (s, 3H), 2H obscured by solvent. LCMS m / z 426.2 [M+H] +

[0624] The following examples were synthesized in a similar manner to Example 2, except that an additional step 1a was carried out after step 1.

[0625] Example 19

[0626] 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

[0627]

[0628] Step 1a

[0629] 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% sodium hydride dispersion (100 mg, 2.50 mmol) at 0 °C for 15 min. Iodomethane (170 μL, 2.72 mmol) was added and the reaction was stirred at 0 °C for 15 min, then allowed to warm to rt and then quenched with water. The reaction was extracted with EtOAc and the organic layer was washed with Na 2 S 2 O 3 aqueous solution, dried (Na 2 SO4 ) Filter and concentrate in vacuo. Purify the crude material by silica gel chromatography (80 g Isco RediSep Rf Gold column, CH 2 Cl 2 solution). Combine the desired fractions and concentrate in vacuo to afford 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), which is a grayish-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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] +

[0630] 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] +

[0631] The following examples were synthesized in a similar manner to Example 2, except that Step 1b was carried out instead of Step 2.

[0632] Example 20

[0633] 3-(1H-Imidazol-5-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl methanesulfonate

[0634]

[0635] Step 1b

[0636] 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 min. NBS (0.082 g, 0.461 mmol) was added and the reaction was stirred for 1 h. The reaction was partitioned between DCM and saturated aqueous sodium carbonate. The organic layer was concentrated under reduced pressure to afford the crude material. The crude material was purified by silica gel chromatography (Combiflash, DCM solution of 0 - 30% [3:1 EtOAc:EtOH]). 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), which was 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] +

[0637] 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: 1 H NMR (400 MHz, DMSO-d 6 ) 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] +

[0638] The following examples were synthesized in a similar manner to Example 2, except that Step 5 was carried out instead of Step 1.

[0639] Example 21

[0640] 5-[3-(1H-imidazol-5-yl)-7-(methylthio)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0641]

[0642] Step 5

[0643] To a stirred solution of 4-chloropyrimidin-2-amine (1.0 g, 7.72 mmol) in DMF (20 mL) was added sodium methylthiolate (0.55 g, 7.85 mmol) portionwise over 10 min. The reaction was stirred at room temperature for 1 h. 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 h. The mixture was triturated with saturated NaHCO 3 aqueous solution, filtered, washed with water and dried in vacuo 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), which was a beige solid. 1 1H NMR (400 MHz, DMSO-d 6 ) 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] +

[0644] Step 4

[0645] 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 saturated NaHCO 3Adjust to pH close to 7. Treat the mixture with ammonium citrate buffer (0.2 M), then grind and filter. Wash the resulting filtered solid with water, then wash with a small volume of EtOH and dry. Next, wash the solid with DCM and dry under vacuum to obtain 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%), which is a pale orange solid. 1 H NMR(400MHz,DMSO-d 6 )δppm15.60(br s,1H),12.72(br s,1H),9.84(d,J=7.3Hz,1H),8.57(s,1H),8.03(s,1H),7.14(d,J=7.3Hz,1H),2.62(s,3H).LCMS m / z 367.1[M+H] +

[0646] The following examples were synthesized in a similar manner to Example 2, except that Step 1c was carried out after Step 1 and Step 3f was carried out after Step 3.

[0647] Example 22

[0648] 5-[3-(1H-imidazol-5-yl)-6-(methylsulfonyl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0649]

[0650] Step 1c

[0651] Under nitrogen, sodium methanethiolate (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). 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 2 SO 4) It was filtered and evaporated in vacuo. The crude material was purified by silica gel chromatography (Isco RediSep Rf Gold 120 g column, heptane solution of 30 - 100% EtOAc). The fractions were combined and concentrated in vacuo to afford 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), which was a light brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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] + 。

[0652] Step 3f

[0653] 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) at 0 °C in an ice bath was added mCPBA 77 wt% (470 mg, 2.72 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was washed with an aqueous Na 2 CO 3 solution, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Isco RediSep Rf Gold 40 g, CH 2 Cl 2 solution of 0 to 60% EtOAc). The 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), which was a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)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] + 。

[0654] Step 4

[0655] 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). Saturated NaHCO 3 aqueous solution was added, the pH of the mixture was adjusted to 7, and then it was treated with ammonium citrate (0.2 M) buffer solution (50 mL). The resulting solid was filtered and 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%), which is a light yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.27 (br s, 1H), 10.45 (d, J = 2.5 Hz, 1H), 9.13 (d, J = 2.5 Hz, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 3.48 (s, 3H), 1H not observed. LCMS m / z 399.0 [M + H] +

[0656] Example 23

[0657] 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]butyric acid

[0658]

[0659] Step 1

[0660] 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 sonicated briefly and then stirred for 15 minutes. The solvent was evaporated and the residue was dried overnight under high vacuum.

[0661] The dried Cs-salt was dissolved in DMF (55.00 mL), bromochloromethane (72.8 mL, 1119 mmol) was added, and the solution was stirred overnight at RT. 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 (1x) and brine (2x), 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-d 6 ) δ ppm 5.86 (s, 2H), 2.58 - 2.66 (m, 2H), 2.48 - 2.53 (m, 2H), 1.39 (s, 9H).

[0662] Step 2

[0663] 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 overnight at room temperature. The major product was separated 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 lyophile. LCMS m / z 507.4 [M+H] +.1 H NMR (400 MHz, DMSO-d 6)δ15.66(br s,1H),10.00(dd,J=2.01,7.03Hz,1H),8.74(dd,J=2.01,4.02Hz,1H),8.67(d,J=1.26Hz,1H),8.18(d,J=1.25Hz,1H),7.26(dd,J=4.02,7.03Hz,1H),6.13(s,2H),2.54-2.61(m,2H),2.44-2.49(m,2H),1.29(s,9H).

[0664] Step 3

[0665] 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 afford 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)butyric acid (41 mg, 0.091 mmol, yield 100%), which was a pale yellow solid. LCMS m / z 451.2 [M+H] +.1 H NMR(400MHz,DMSO-d 6 )δppm 15.71(br s,1H),12.26(br s,1H),9.98(dd,J=2.03,7.10Hz,1H),8.74(dd,J=2.03,4.06Hz,1H),8.65(d,J=1.27Hz,1H),8.19(d,J=1.27Hz,1H),7.26(dd,J=4.06,7.10Hz,1H),6.13(s,2H),2.55-2.65(m,2H),2.45-2.50(m,2H).

[0666] Example 24

[0667] (2S)-2-Amino-3-methylbutyric acid (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 ester, 2 trifluoroacetate

[0668]

[0669] Step 1

[0670] 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) was added cesium carbonate (2.249 g, 6.90 mmol), and the mixture was stirred until the carbonate dissolved and gas evolution ceased (about 15 minutes). The solvent was evaporated, and the residue was dried overnight in high vacuum.

[0671] 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 RT 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 (1x), brine (1x), dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (80 g Isco RediSepRf Gold column, eluted with 0 - 20% (hexane solution of EtOAc)) to give (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (2.817 g, 10.60 mmol, 77% yield), which was a clear oil. LCMS m / z 288 [M+Na] +.1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0672] Step 2

[0673] 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), (tert-butoxycarbonyl)-L-valine chloromethyl ester (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 h. More (tert-butoxycarbonyl)-L-valine chloromethyl ester (5.74 mg, 0.022 mmol) and DBU (0.003 mL, 0.022 mmol) were added, and the mixture was stirred for 28 h. More (tert-butoxycarbonyl)-L-valine chloromethyl ester (22.96 mg, 0.086 mmol) and DBU (0.013 mL, 0.086 mmol) were added and the mixture was stirred over the weekend (~2.5 days). The product was isolated by preparative HPLC (MDAP method G) to give (tert-butoxycarbonyl)-L-valine (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 ester (32 mg, 0.041 mmol, 47.5% yield) as an off-white lyophilate. LCMS m / z 779.3 [M+H] + .

[0674] Step 3

[0675] To a solution of (tert-butoxycarbonyl)-L-valine (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 ester (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 hr and then evaporated to dryness. The residue was dissolved in 5 mL of water and lyophilized to give L-valine (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 ester, 2-trifluoroacetate (30 mg, 0.037 mmol, yield 97%) as a light yellow lyophilizate. LCMS m / z 579.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)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).

[0676] Example 25

[0677] 2-(Methylamino)acetic acid {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 ester, hydrochloride

[0678]

[0679] Step 1

[0680] 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), N-(tert-butoxycarbonyl)-N-methylglycine (2-(((1-chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl ester (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 separated by preparative HPLC (MDAP method E) to give N-(tert-butoxycarbonyl)-N-methylglycine (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 ester (64 mg, 0.091 mmol, yield 39.1%). LCMS m / z 700.5 [M+H] + .

[0681] Step 2

[0682] To a solution of N-(tert-butoxycarbonyl)-N-methylglycine (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 ester (64 mg, 0.091 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol), and the mixture was stirred for 15 minutes. The solvent was evaporated, and the product was separated by preparative HPLC (MDAP method A) to give 24 mg of an off-white lyophilized solid. The lyophilized solid was dissolved in the minimum volume of ACN, 4M HCl in dioxane solution (0.114 mL, 0.457 mmol) was added and the solvent was evaporated. The HCl treatment was repeated once, and then the residue was dissolved in 3 mL of water and lyophilized to give methylglycine (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 ester, hydrochloride (20 mg, 0.031 mmol, yield 34.4%), which was an off-white lyophilized solid. LCMS m / z 600.2 [M+H] + The structure was confirmed by 2D NMR (HMBC).

[0683] Example 26, Example 27 and Example 28

[0684] 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

[0685] [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

[0686] {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

[0687]

[0688] Step 1

[0689] To a cold 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 dropwise chloroformyl chloride (0.500 mL, 5.63 mmol) over 1 min. The mixture was stirred overnight at room temperature. 1N HCl (20 mL, 20.00 mmol) was added and the mixture was stirred vigorously for 2 min and then partitioned. The aqueous layer was further extracted with DCM (2 x 5 mL), and the combined organic layers were washed with saturated aqueous sodium bicarbonate (1x), brine (1x), 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), which was a colorless oil. The product was contaminated with 33% starting material (by 1 H-NMR), but was used in the next step without further purification.

[0690] 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)

[0691] Step 2

[0692] 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) were stirred overnight at room temperature. The mixture was filtered and the product was separated by preparative HPLC (MDAP method H) to give

[0693] (2-((((5-(3-(1H-Imidazol-5-yl)imidazo[1,2-a]pyrimidine-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.

[0694] 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, yield 13.9%). LCMS m / z 552.09 [M+H] + The structure was confirmed after deprotection in Step 3

[0695] tert-Butyl methyl (2-((((3-(trifluoromethyl)-5-(3-(1-(7,10,10-trimethyl-3,8-dioxo-2,4,9-trioxa-7-azoundecyl)-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, yield 14.3%). LCMS m / z 783.28 [M+H] + The structure was confirmed after deprotection in Step 4. Step 3

[0696] 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 (Example 26) (26 mg, 0.038 mmol, yield 88%). LCMS m / z 452.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0697] Step 4

[0698] A solution of tert-butyl methyl (2-((((3-(trifluoromethyl)-5-(3-(1-(7,10,10-trimethyl-3,8-dioxo-2,4,9-trioxa-7-azoundecyl)-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 trifluoroacetates (Example 27) (37 mg, 0.046 mmol, yield 102%). LCMS m / z 583.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0699] Step 5

[0700] 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 minutes. The mixture was evaporated to dryness, and the residue was dissolved in water (a small amount of ACN was needed) 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 trifluoroacetates (Example 28) (21 mg, 0.031 mmol, yield 77%).

[0701] LCMS m / z 452.3 [M+H] +.1 1H NMR (400 MHz, DMSO-d 6 ) 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 Hz, 1H), 6.81 (s, 2H), 4.35 - 4.42 (m, 2H), 3.22 - 3.30 (m, 2H), 2.54 - 2.60 (m, 3H). The structure was confirmed by 2D NMR (HMBC, 15N HMBC).

[0702] Example 29 and Example 30

[0703] {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

[0704] {4-Oxo-4-[(5-{3-[1-({[4-(phosphonyloxy)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

[0705]

[0706] Step 1

[0707] The solution of methyl 4-hydroxybutyrate (1.170 g, 9.90 mmol) and di-tert-butyl diisopropylphosphoramidite (4.69 mL, 14.86 mmol) in DCM (20 mL) was evaporated to dryness and dried under high vacuum for 30 minutes. The mixture was azeotroped with acetonitrile (20 mL), then dissolved in acetonitrile (60.00 mL) and evaporated to about half of its volume. A solution of 0.45 M 1H-tetrazole in acetonitrile (44.0 mL, 19.81 mmol) was added. The formation of a white precipitate started immediately. The mixture was stirred at room temperature for 1.5 hr, then cooled to 0 °C and mCPBA (5.55 g, 24.76 mmol) (purity 77%) was introduced. The mixture was stirred at 0 °C for 10 minutes and then at room temperature for 1 hr. Sodium sulfite (3.12 g, 24.76 mmol) dissolved in 40 mL of water was added to quench the excess mCPBA; the acetonitrile was distilled off. The residue was partitioned between water (30 mL) and EtOAc (50 mL), and the organic phase was washed with water (1x), saturated aqueous sodium bicarbonate (2x), water (1x), brine (1x), dried over sodium sulfate and evaporated to give the crude product, which was 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 RfGold column, eluted with 0 - 20% (hexane solution of EtOAC / EtOH 3 / 1)) to give methyl 4-((di-tert-butoxyphosphoryl)oxy)butyrate (1.043 g, yield 33.9%). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0708] Step 2

[0709] To a stirred cold solution of methyl 4-((di-tert-butoxyphosphoryl)oxy)butyrate (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 hr. A solution of 6 M aqueous HCl (1.680 mL, 10.08 mmol) was added, then MeOH was distilled off. The residue was extracted with EtOAc (2x), the organic phase was washed with brine (1x), dried over sodium sulfate and evaporated to give 4-((di-tert-butoxyphosphoryl)oxy)butyric acid (876 mg, 2.96 mmol, 88% yield), which was a colorless oil. 1 H NMR (400 MHz, DMSO-d6 ) δ 12.11 (broad singlet, 1H), 3.88 (quartet, J = 6.53 Hz, 2H), 2.31 (triplet, J = 7.28 Hz, 2H), 1.81 (quintet, J = 6.84 Hz, 2H), 1.41 (singlet, 18H). 31 ³¹P NMR (162 MHz, DMSO-d 6 ) δ -9.89 (broad triplet, J = 5.87 Hz, 1P).

[0710] Step 3

[0711] To a solution of 4-((di-tert-butoxyphosphoryl)oxy)butyric 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 (about 15 min). The solvent was evaporated, and the residue was dried overnight in high vacuum to give cesium 4-((di-tert-butoxyphosphoryl)oxy)butyrate (976 mg, 2.279 mmol, 99% yield), which was a colorless oil.

[0712] The dried Cs-salt was dissolved in DMF (9 mL), bromochloromethane (9.70 mL, 149 mmol) was added, and the solution was stirred at RT 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 (1x), brine (1x), dried over sodium sulfate and evaporated to give methyl 4-((di-tert-butoxyphosphoryl)oxy)butyrate chloride (723 mg, 2.097 mmol, 91% yield), which was a colorless oil; 1 ¹H NMR (400 MHz, DMSO-d 6 ) δ 5.86 (singlet, 2H), 3.89 (quartet, J = 6.36 Hz, 2H), 1.80 - 1.93 (multiplet, 2H), 1.41 (multiplet, 20H).

[0713] Step 4

[0714] 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), methyl 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 a suspension in DMF (1 mL) were stirred overnight at RT. The mixture was filtered and separated by preparative HPLC (MDAP method H) to give 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 ester (78 mg, 0.124 mmol, yield 39.7%), which was a pale yellow oil. LCMS m / z 629.3 [M+H] + and methyl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (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 ester (53 mg, 0.057 mmol, yield 18.12%), which was a pale yellow oil. LCMS m / z 937.4 [M+H] + .

[0715] Step 5

[0716] 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 ester (78 mg, 0.124 mmol) was dissolved in TFA (2 mL, 26.0 mmol), allowed to stand for 10 minutes, then evaporated, co-evaporated with 3 mL ACN (2x) and dried. The residue was dissolved in water and lyophilized to give methyl 4-(phosphoryloxy)butanoate (4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl)-1H-imidazol-1-yl)methyl ester, trifluoroacetate (Example 29) (66 mg, 0.105 mmol, yield 33.5%), which was an off-white lyophilizate. LCMS m / z 517.2 [M+H] + .1HNMR(400MHz,DMSO-d 6 ) 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 (quin, J = 6.91 Hz, 2H). Two phosphoric acid Hs were not observed. The structure was confirmed by 2D NMR (ROESY).

[0717] Step 6

[0718] Dissolve 4 - ((di - tert - butoxyphosphoryl)oxy)butyric acid (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 ester (53 mg, 0.057 mmol) in TFA (2 mL, 26.0 mmol), let stand for 10 minutes, then evaporate, co - evaporate with 3 mL ACN (2x) and dry. Dissolve the residue in water and lyophilize to obtain 4 - (phosphoryloxy)butyric acid (5 - (3 - (1 - (((4 - (phosphoryloxy)butanoyl)oxy)methyl)-1H - imidazol - 4 - yl)imidazo[1,2 - a]pyrimidin - 2 - yl)-3 - (trifluoromethyl)-1H - 1,2,4 - triazol - 1 - yl)methyl ester, trifluoroacetate (Example 30) (39 mg, 0.047 mmol, yield 15.11%), which is a beige lyophilized product. LCMS m / z 713.05 [M + H] +.1 H NMR(400MHz,DMSO-d 6 ) 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). Four phosphoric acid Hs were not observed. The structure was confirmed by 2D NMR (ROESY, HMBC, 15NHMBC).

[0719] Example 31, Example 32 and Example 33

[0720] 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

[0721] 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

[0722] 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 trifluoroacetates

[0723]

[0724] Step 1

[0725] To a cold solution of tert-butyl 3-hydroxypropionate (1 g, 6.84 mmol) and pyridine (0.609 mL, 7.52 mmol) in DCM (25 mL) was added dropwise chloroformylmethyl chloroformate (0.608 mL, 6.84 mmol) over about 1 min. The mixture was stirred overnight at room temperature. 1N aqueous HCl solution (20 mL, 658 mmol) was added, and the mixture was stirred vigorously for 2 minutes and then 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 3-(((chloromethoxy)carbonyl)oxy)propionate (1.468 g, 6.15 mmol, 90% yield), which was a colorless oil.

[0726] 1 1H 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).

[0727] Step 2

[0728] 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)propionate (93 mg, 0.390 mmol), and potassium carbonate (64.7 mg, 0.468 mmol) in DMF (2 mL) was stirred overnight. The mixture was filtered and the product was separated by preparative HPLC (MDAP method H) to give

[0729] 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)propionate (14 mg, yield 8.6%). MS ES+ m / z 523.1 [M+H] + . The structure was confirmed after deprotection in Step 5.

[0730] 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)propionate (73 mg, yield 32.3%). MS ES+ m / z 725.2 [M+H] + . The structure was confirmed after deprotection in Step 3.

[0731] 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)propionate (25 mg, yield 15.3%). MS ES+ m / z 523.1 [M+H] + . The structure was confirmed after deprotection in Step 4.

[0732] Step 3

[0733] 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)propionate (73 mg, 0.101 mmol) and a solution of TFA (2 mL, 26.0 mmol) in DCM (2 mL) were stirred at room temperature for 1 hr. The mixture was evaporated to dryness, the residue was dissolved in water (a small amount of ACN was needed) 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 (Example 31) (75 mg, 0.103 mmol, 100% yield). LCMS m / z 613.1; 1 H NMR (400 MHz, DMSO-d 6 ) 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). The two carboxylic acid protons were not observed.

[0734] Step 4

[0735] 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)propionate (25 mg, 0.048 mmol) and a solution of TFA (2 mL, 26.0 mmol) in DCM (2 mL) were stirred at room temperature for 1 hr. The mixture was evaporated to dryness, the residue was dissolved in water (a small amount of ACN was needed) 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 (Example 32) (25 mg, 0.047 mmol, 97% LCMS m / z 467.2 [M+H] +.1 H NMR (400 MHz, DMSO-d 6) 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.

[0736] Step 5

[0737] 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)propionate (14 mg, 0.027 mmol) and TFA (2 mL, 26.0 mmol) in DCM (2 mL) was stirred at room temperature for 1 hr. The mixture was evaporated to dryness, the residue was dissolved in water (a small amount of ACN was needed) 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)propionic acid, 2 trifluoroacetate (Example 33) (14 mg, 0.020 mmol, yield 75%). LCMS m / z 467.16 [M+H] + ; 1 1HNMR (400 MHz, DMSO-d 6 ) 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 and imidazole H were observed.

[0738] Example 34

[0739] ({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

[0740]

[0741] Step 1

[0742] 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 h. The mixture was cooled, poured into ice, and then carefully neutralized with potassium carbonate to ~pH 7.

[0743] 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 Na 2 SO 4 ) and evaporated onto HM-N adsorbent and purified by flash chromatography ([[]] RF using a 330 g Redisep RF silica gel column, dichloromethane solution of 0 - 10% ethyl acetate) to give the crude product.

[0744] It was triturated with TBME (200 mL) to give a tan solid, which was collected and washed with TBME and hexane 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).

[0745] LCMS electrospray, m / z 273.1 (M + H + ); 1 1H NMR (400 MHz, DMSO-d6) δ ppm 15.76 (br s, 1H) 9.32 (dd, J = 4.40, 2.93 Hz, 1H) 8.90 (d, J = 2.93 Hz, 1H) 8.55 (s, 1H).

[0746] Step 2

[0747] 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 h. The mixture was filtered through a porcelain filter with a paper filter using vacuum filtration, and the filter 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, 1H) 9.32 (dd, J = 3.91, 2.93 Hz, 1H) 8.96 (d, J = 2.45 Hz, 1H); LCMS m / e 351.0.

[0748] Step 3

[0749] 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 stirred vigorously at 55 °C, and di-tert-butyl (chloromethyl) phosphate (15.54 mL, 66.1 mmol) was added, and the mixture was stirred overnight.

[0750] 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 Na 2 SO 4 and evaporated.

[0751] The product was adsorbed onto HM-N adsorbent and purified by flash chromatography ([[]] RF, using a 330 g Redisep RF silica gel column, dichloromethane solution of 0 - 30% ethyl acetate) 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 1H NMR (400 MHz, chloroform-d) δ ppm 8.71 (d, J = 2.93 Hz, 1H) 8.51 (t, J = 2.93 Hz, 1H) 6.69 - 6.75 (m, 2H) 1.45 (s, 18H); LCMS: [M+H] +573.0, 575.0 Br mode.

[0752] Step 4

[0753] A mixture of (5-(3-bromo-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyldi-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 2 (dppf) (192 mg, 0.26 mmol) in 1,2-dimethoxyethane (DME) (15 mL) was sealed in a 45 mL microwave vial, stirred and heated by thermal method at 130 °C for 90 min.

[0754] This reaction was carried out 7 more times, then the reaction mixtures were combined and purified as shown below.

[0755] The reaction mixture was filtered through a pad, washed with ethyl acetate and evaporated in vacuo. The residue was dissolved in dichloromethane (50 mL) and adsorbed onto a silica gel (35 g) pre-column. Flash chromatography ([[]] RF, using 40 g Redisep RF silica gel column, dichloromethane solution of 0 - 40% ethyl acetate) gave di-tert-butyl ((5-(3-(1-(N,N-dimethylaminosulfonyl)-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).

[0756] 1 H NMR (400 MHz, chloroform-d) δ ppm 9.94 (dd, J = 4.40, 2.93 Hz, 1H) 8.77 (d, J = 1.47 Hz, 1H) 8.72 (d, J = 2.94 Hz, 1H) 8.09 (d, J = 1.47 Hz, 1H) 6.78 (s, 1H) 6.76 (s, 1H) 3.00 (s, 6H) 1.42 (s, 18H); LCMS: m / e 668.2 (M+H + )

[0757] Step 5

[0758] 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) was treated with a solution of 4 M HCl in dioxane (25 mL, 100 mmol). The flask was stoppered and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was neutralized to ~pH 7 with 20% aqueous potassium carbonate and the mixture was evaporated in vacuo and azeotroped twice with ethanol to give a crude solid.

[0759] The solid was desalted by preparative HPLC as shown below.

[0760]

[0761] The product was lyophilized 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).

[0762] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.98 (dd, J = 4.89, 2.93 Hz, 1H) 8.96 (d, J = 2.93 Hz, 1H) 8.16 (d, J = 0.98 Hz, 1H) 8.11 (s, 1H) 6.44 (d, J = 10.76 Hz, 2H) (2OH and 1NH not observed); LCMS: t RET = 0.41 min (gradient from 1 - 100% of a solution of 0.1% v / v formic acid in acetonitrile to a solution of 0.1% v / v formic acid in water in 1.85 min), m / e 449.1 (M+H + ).

[0763] Example 35 and Example 36

[0764] Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate

[0765] Methyl 2-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidine-7-carboxylate

[0766]

[0767] Step 1: Methyl 2-aminopyrimidine-4-carboxylate

[0768] A mixture of 2-aminopyrimidine-4-carboxylic acid (5.3 g, 38.1 mmol), 4M HCl in dioxane solution (20.0 mL, 80 mmol), and methanol (80.0 mL) was heated to 64 °C for 4 h. The reaction mixture was cooled to rt, and then an excess of diethyl ether was added to the reaction mixture. The resulting precipitate was collected by filtration and then dried in a vacuum oven to obtain the desired product, which was the HCl salt. This material was stirred and sonicated in 160 mL of saturated NaHCO 3 aqueous solution for 20 min. Gas evolution was observed. The suspended solid was collected by filtration and washed with deionized water. The solid was dried overnight in a vacuum oven at 50 °C to obtain 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

[0769] Step 2: Methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrimidine-7-carboxylate

[0770] 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 in a sealed reaction tube at 115 °C overnight. The reaction showed very little conversion to the desired product. Another portion of methyl 2-aminopyrimidine-4-carboxylate (462 mg, 3.02 mmol) was added to the reaction mixture. The mixture was heated in a sealed reaction tube at 115 °C overnight. The reaction mixture was cooled to rt and the resulting precipitate was collected by filtration and washed with acetonitrile. The solid was stirred vigorously in a 1:1 mixture of EtOAc / aqueous 1N HCl for 20 min 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).

[0771] Step 3: Methyl 2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine-7-carboxylate

[0772] 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 at 60 °C for 1 h. The reaction mixture was cooled to rt 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 NaHCO 3 aqueous solution and brine. The organic layer was dried over Na 2 SO 4Dry, filter and concentrate to a residue. Purify the residue over silica gel, eluting with a DCM solution of 0 - 50% EtOAc to afford 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 peak).

[0773] 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

[0774] 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 2 (dppf)-CH 2 Cl 2 adduct (27.8 mg, 0.034 mmol), K 3 PO 4 (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 a mixture of DMF (9 mL) and water (3 mL) were sonicated in a microwave vial for 3 min and heated at 75 °C in a Biotage microwave apparatus for 8 min. Add EtOAc (10 mL) to the reaction mixture and wash the mixture with water and brine. The organic layer was dried over Na 2 SO 4Dry and concentrate. The residue was purified by silica gel (12 g column) and eluted with hexane solution of 10–50% EtOAc 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, monitored by LCMS. The reaction was cooled to RT 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(600MHz,DMSO-d 6 )δ ppm 15.23(br.s.,1H),13.42(br.s.,1H),8.98–9.07(m,1H),8.25(br.s.,2H),7.57–7.66(m,1H),3.96(s,3H).LCMS:[M+H] + =389.0,391.0(Br isotope peak)

[0775] 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

[0776] 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 2 (dppf)-CH 2 Cl 2 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 then heated at 130 °C in a Biotage microwave apparatus for 40 min. The reaction mixture was cooled to rt, diluted with EtOAc and then washed with water. The organic layer was dried over Na 2 SO 4Dry and concentrate, and purify the residue over silica gel (24 g column), eluting with hexane solution of 35–40% EtOAc. Concentrate 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, and recrystallize the residue 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). Suspend this material in TFA (4 mL), and heat the reaction mixture to 61 °C for 16 h. Concentrate the reaction mixture to a residue. Suspend the residue in DCM, and collect the partially pure product by filtration. Stir the collected solid in refluxing EtOH for five minutes, and collect by filtration to give the title compound (Example 36) (14 mg, 0.036 mmol, 17%), which is a pale yellow 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 peaks)

[0777] Example 37

[0778] 3-Bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole, trifluoroacetate

[0779]

[0780] Step 2: 2-(3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-3-iodoimidazo[1,2-a]pyrimidine

[0781] 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 rt, 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 peaks)

[0782] 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

[0783] 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), PdCl2(dppf)-CH2Cl2 adduct (33.9 mg, 0.041 mmol) in DME (9 mL) was sonicated thoroughly for 5 min and then heated at 130 °C for 20 min using an Anton-Parr microwave apparatus. The reaction mixture was cooled to rt, 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 Na 2 SO 4Dry, filter and concentrate to a residue. The residue was purified by silica gel and eluted with a DCM solution of 15%–70% 3:1 EtOAc-EtOH 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 peak).

[0784] Step 4: 3-Bromo-5-[3-(1H-imidazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-1H-1,2,4-triazole, trifluoroacetate

[0785] 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 the reaction was complete as determined by LCMS. The reaction mixture was concentrated and the residue was suspended in warm DCM and sonicated. The resulting solid was collected by filtration but still showed traces of the protected intermediate. The material was treated with TFA and heated to 64 °C for 4 h to complete deprotection. The reaction mixture was concentrated and the residue was suspended in DCM and sonicated. The solid was collected by filtration to give the title compound (50.0 mg, 0.112 mmol, 59%), which was 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). The 2NH proton was not observed. LCMS: [M+H] + = 331.0, 333.0 (Br isotope peak)

[0786] Example 38

[0787] 5-[6-Fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0788]

[0789] 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

[0790] 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), and potassium phosphate (203 mg, 0.955 mmol) in dioxane (2 mL) was added PdCl 2 (dppf)-CH 2 Cl 2 adduct (26.0 mg, 0.032 mmol). The reaction mixture was heated in a microwave vial in an Anton-Parr microwave apparatus at 120 °C for 10 min. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated to a brown residue. The residue was purified by Isco Combiflash (20%-100% (3:1 EtOAc / EtOH) / hexane; 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.

[0791] Step 4: 5-[6-Fluoro-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-2-yl]-3-(trifluoromethyl)-1H-1,2,4-triazole

[0792] 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 hr. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (Xselect CSHC 18The column (150 mm x 30 mm i.d., 5 μm packing diameter) was eluted and purified with an aqueous solution of 15 - 55% CH3CN (each containing 0.1% formic acid) to obtain the title compound (35.5 mg, 0.105 mmol, 39%). 1 HNMR (400 MHz, DMSO-d 6 ) δ ppm 15.62 (brs, 1H), 13.38 (br s, 1H), 9.10 (dd, J = 4.4, 2.9 Hz, 1H), 8.90 (d, J = 2.9 Hz, 1H), 8.44 (s, 1H), 8.11 (s, 1H). LCMS: [M+H] + = 339.1.

[0793] Examples 39 - 165 were prepared using methods similar to those described herein and knowledge known in the art. The following table shows the general synthetic methods for preparing these compounds, as well as their theoretical and measured molecular weights.

[0794]

[0795]

[0796]

[0797]

[0798]

[0799] Solubility data

[0800] The solubility of certain compounds in FASSIF (fasting state simulated intestinal fluid) was measured and listed in Table 2 below.

[0801] After equilibration at room temperature for 4 h, the solubility of the solid compound was determined in FaSSIF at pH 6.5. 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 solid compound in a 4 mL vial. The resulting suspension was shaken at 900 rpm at room temperature for 4 h, then transferred to a Multiscreen HTS 96-well solubility filtration plate. Residual solids were removed by filtration. The supernatant was quantified by HPLC-UV using a single-point calibration of a compound of known concentration in DMSO. The dynamic range measured was 1 - 1000 μg / mL.

[0802] Table 2

[0803] Example number FASSIF solubility (μg / mL) 1 4 2 5 23 455 24 324 25 >1000 27 298 28 208 29 >1000 34 >1000

[0804] Biological data

[0805] Production of recombinant human CGAS.

[0806] Human cGAS (157-522) was purified from Escherichia coli (BL21(DE3)*) expressing an amino-terminal His-MBP-tev tag 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 inhibitor (Roche complete without EDTA)) and eluted stepwise with 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 Superdex 75 equilibrated in 20 mM HEPES, pH 7.5, 400 mM NaCl, 1 mM TCEP, 1 mM PMSF.

[0807] RapidFire 300 mass spectrometry (RF-MS 300) assay.

[0808] The compound was resuspended in DMSO at a 10 mM stock concentration and tested using the RapidFire mass spectrometry assay to determine its IC50 value against human CGAS (157 - 522). The compound was serially diluted 2-, 3-, or 4-fold in pure DMSO to generate an 11-point dose-response curve, and then 250 nL of the compound or DMSO solution was transferred into 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 synthesis 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, 19 - 24 of the plate using a Combi liquid handler (ThermoFisher). A low-control solution of 12.5 μL / well containing 150 μM ATP, 150 μM GTP, and 20 μM pppGpA in assay buffer was added to column 18 using a Combi. Then, 12.5 μL / well of a 10 - 100 nM human CGAS (157 - 522) solution in assay buffer was added to all wells of the plate. The plate was centrifuged to mix the solutions and then incubated at room temperature for 1 - 2 hr. 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 diUMP (ci-di-UMP; Invivogen catalog #tlrl-cdu) (as an internal standard (IS)). The plate was centrifuged for 1 min and then the quenched reaction was analyzed using an RF-MS300 system operating in the multiple reaction monitoring (MRM) detection mode.

[0809] The sample (10 μL injection volume) was analyzed for the analyte (2’3’-cyclic guanosine monophosphate adenosine monophosphate (2’3’-cGAMP), the product of the biochemical reaction) / pppGpA / c-di-UMP IS adsorption through a silica C18 / C solid-phase extraction (SPE) column. The adsorbed sample was desalted for 3000 ms using 100% water eluent A / desalting solution. Subsequently, the desalted sample was directly eluted into a Sciex 4000, 5000, or 5500 triple quadrupole mass spectrometer (QQQ-MS) using 0.5% TFA in 20% / 80% acetonitrile / water eluent B / elution solution 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: 12 relative settings; 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 (for 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 (for all analytes); interface heater (Sciex 4000 / 5000 only): on; Q1 resolution: unit (for all analytes); Q3 resolution: unit (for all analytes). The RapidFire Integrator software application was used to calculate the AUC-2’3’-cGAMP / AUC-c-di-UMP intensity ratio to obtain the area under the curve (AUC) for all analytes. The % product formation was calculated by comparison with the response in column 6 (high control) / column 18 (low control). The % product inhibition was calculated as follows:

[0810] % Inhibition = 100 x [(Sample - Average low control) / (Average high control - Average low control)]

[0811] The following equation was used for curve fitting:

[0812] where A is the minimum response, B is the maximum response, C is log 10 *XC50, D is the slope factor, and x is log in ABAS XE10 Compound concentration [M].

[0813] CGAS Whole Blood Cytokine Release Assay

[0814] Blood collection: Collect blood into tubes containing 10% sodium heparin (5 ml / 45 ml blood final volume).

[0815] Protocol for CGAS Whole Blood Cytokine Release Assay: Provide compounds serially diluted 1:3 at 150 nL per well in 384-well polypropylene microplates (Catalog 781280; Greiner Bio-One, Frickenhausen, Germany). Dispense 5 μL of PBS / 20% Null BacMam into all wells except the 18th column on a Multidrop Combi (Thermo Scientific, Waltham, MA). Dispense 5 μL of PBS into the 18th column. Transfer 45 μL of donor-derived blood into the compound plates using Bravo (Agilent, Santa Clara, CA). The Bravo protocol mixes the blood and compound / PBS five times. Incubate the plates at 37 °C, 5% CO2 for 6 hours. At the 6-hour mark, remove the plates and centrifuge at 3000 RPM for 10 minutes. Transfer 3 μL of the supernatant from the plates into 384-well NBS microplates (Catalog 4513; Corning Life Sciences, Corning, NY). Seal these plates with adhesive foil and store in an -80 freezer until ready for analysis.

[0816] For cytokine detection, human IP-10 BD flow cytometric bead array (CBA) beads (BD Biosciences, Franklin Lakes, NJ) were used. The capture bead solution was prepared by diluting the stock solution of IP-10 capture beads 1:50 in BD diluent for serum / plasma (Catalog 51-9003991, BD Biosciences, Franklin Lakes, NJ). 2 μL of this solution was added to each well of the assay microplate, which was then sealed with adhesive foil and incubated for 2 h at room temperature in the dark. The detection reagent was further prepared by diluting the stock solution of the detection reagent 1:50. 2 μL of the detection reagent was added to each well, and the microplate was sealed with adhesive foil and incubated for 1 h at room temperature in the dark. After incubation for 1 h, 3 μL of BD CBA wash buffer was added to each well of the microplate. Data were obtained on an iQue Screener flow cytometer. The inhibition of IP-10 present in the sample wells was quantified by fluorescence detection using iQue. A sip time of 1 s was used for each sample. A blue laser excited at 488 nm and an emission filter of 585 / 40 nm were used to capture the mean and median of IP-10, with the detector in logarithmic mode (FL2-H).

[0817] All data analysis was performed in IDBS ActivityBase XE. The percent inhibition was determined using the formula 100 - (100(U - C2) / (C1 - C2)), where U is the unknown value, C1 is the mean high control response of the mixture in DMSO only, and C2 is the mean of the minimum responses of the control without BacMam stimulation in column 18.

[0818] Curve fitting was performed using the following equation:

[0819] where A is the minimum response, B is the maximum response, C is log 10 *XC50, D is the slope factor, and x is log 10 compound concentration [M] in ABAS XE.

[0820] Table 3 below shows the biological data of the compound RF-MS 300 assay and the whole blood (hWB) cytokine release assay.

[0821] Table 3.

[0822]

[0823]

[0824]

[0825] It is believed that for prodrug compounds, the activity in RF-MS assays is due to the parent compound from impurities in the sample. For hWB assays, some prodrugs are unstable under the assay conditions, and thus the activity of the prodrug may be due to the parent compound from impurities or due to the removal of the prodrug moiety.

[0826] Additional data

[0827] Certain compounds disclosed in WO 2022 / 137082 and WO 2022 / 137085 were tested, and the biological data of the RF-MS 300 assays and whole blood (hWB) cytokine release assays of the compounds are shown in Table 4 below. Exemplary compounds of the present invention showed improved properties relative to certain compounds disclosed in WO 2022 / 137082 and WO 2022 / 137085.

[0828] The whole blood (hWB) cytokine release assay was performed as follows.

[0829] Human whole blood from healthy individual donors was collected into 60 ml syringes containing sodium heparin (5 ml of sodium heparin per syringe; Cat#309653, Becton-Dickinson, NJ, US). In a biosafety cabinet, 140 ul of the collected blood was transferred to each well of a 96-well flat bottom plate (Cat#167008, VWR, PA, US). The DMSO stock solution (10 mM stock solution) of the small molecule cGAS inhibitor was diluted in PBS to prepare a 10x solution (3-fold dilution), and 20 ul of the prepared 10x solution was added to the appropriate wells. The plate was shaken at room temperature for 5 minutes and then incubated at 37 °C for 30 minutes. The stock solution of purified Bacmam was diluted with PBS + 0.1% BSA to prepare a 4% (v / v) solution (10x). To activate the cGAS pathway, 20 uL of Bacmam was added to the blood, and the plate was shaken at room temperature for 10 minutes. PBS was added to reach a final volume of 200 ul. Then the plate was incubated at 37 °C for 6 hours.

[0830] The plate was removed from the incubator, and 100 uL / well of PBS was added. The plate was gently shaken at room temperature for 10 minutes and centrifuged (3000 rpm, 10 minutes). The plasma layer was removed and transferred to a separate 96-well plate and kept at -80 °C.

[0831] The IP-10 levels of the plasma samples were measured using an IP-10 detection (U-plex or V-plex) plate (Cat#K151-UFK-4; Cat#K151-NVD-4; Meso-Scale Discovery, Inc.).

[0832] Table 4.

[0833]

Claims

1. A compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 1 is hydrogen or a prodrug moiety; R 2 Selected from hydrogen, halogen, 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 , wherein C 1-3 alkyl, halo(C 1-3 )alkyl and halo(C 1-3 )alkoxy are optionally substituted by hydroxyl or -NR 7 R 8 ; R 3 is a 5- or 6-membered heteroaryl, which is optionally substituted by C 1-3 alkyl, -C(O)R 8 or a prodrug moiety; Each R 4 , R 5 and R 6 is independently -L-Y; Each L is independently selected from 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 -; each n or m is independently 1, 2 or 3; Each R a and R b is independently selected from hydrogen, halogen, and methyl; Each Y is independently selected from hydrogen, halogen, hydroxy, 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 one, two or three heteroatoms independently selected from N, O and S, wherein the C 3-7 cycloalkyl, phenyl, heteroaryl and heterocycloalkyl groups are optionally substituted by one, two or three substituents independently selected from halogen, hydroxy, -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- to 8-membered monocyclic or bicyclic ring, which optionally contains one or two heteroatoms independently selected from N, O, and S, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 ; R 7 and R 8 are independently selected from hydrogen and C 1-4 alkyl; R 9 independently selected from hydrogen, C 1-4 alkyl, -C(O)C 1-4 alkyl, and halo(C 1-4 )alkyl; and R 10 independently selected from hydrogen and C 1-6 alkyl; or wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo.

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

3. The compound according to claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein R 3 is a 5-membered nitrogen-containing heteroaryl.

4. A compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 1 is hydrogen or a prodrug moiety; R 2 selected from hydrogen, halogen, 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 , wherein C 1-3 alkyl, halo(C 1-3 )alkyl and halo(C 1-3 )alkoxy are optionally substituted by hydroxy or -NR 7 R 8 ; R 3 is an imidazolyl or pyrazolyl group, wherein R 3 is optionally substituted with C 1-3 alkyl, -C(O)R 8 or a prodrug moiety; Each R 4 、R 5 and R 6 is independently -L-Y; Each L is independently selected from 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 -; 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 selected from hydrogen, halogen, hydroxy, 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, a 5- or 6-membered heteroaryl, and a 4- to 10-membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O and S, wherein the C 3-7 cycloalkyl, phenyl, heteroaryl and heterocycloalkyl groups are optionally substituted by one, two or three substituents independently selected from halogen, hydroxy, -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 atom(s) to which they are attached form a 5- to 8-membered monocyclic or bicyclic ring, which optionally contains one or two heteroatoms independently selected from N, O and S, wherein said ring is optionally substituted by one, two or three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 ; R 7 and R 8 are independently selected from hydrogen and C 1-3 alkyl; R 9 independently selected from hydrogen, C 1-4 alkyl, -C(O)C 1-4 alkyl and halo(C 1-4 )alkyl; and R 10 independently selected from hydrogen and C 1-6 alkyl; or wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with oxo.

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

6. A compound according to any one of the preceding claims, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each prodrug moiety is independently selected from -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 -heteroaryl-CH 2 O-C(O)-CH 2 -NR d R e ; wherein R d and R e are each independently hydrogen or C 1-6 alkyl; each heterocycloalkyl is 4- to 6-membered and contains one or two heteroatoms independently selected from N, O and S; and each heteroaryl is 5- or 6-membered and contains one or two heteroatoms independently selected from N, O and S.

7. A compound according to claim 6 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein each prodrug moiety is independently selected from -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 .

8. The compound or tautomer thereof according to claim 6, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each prodrug moiety is independently selected from 9. The compound or tautomer thereof according to claim 8, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each prodrug moiety is independently selected from 10. A compound according to any one of claims 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each prodrug moiety is -CH 2 O-P(O)(OR d )(OR e ).

11. The compound or tautomer thereof according to claim 10, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each prodrug moiety is 12. A compound or a tautomer thereof according to any one of the preceding claims, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 3 is an imidazolyl group.

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

14. The compound according to claim 13 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein R 1 is 15. A compound according to any one of claims 1 to 4, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein R 1 is hydrogen and R 3 is imidazolyl.

16. A compound or a tautomer thereof according to any one of the preceding claims, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, wherein R 2 is selected from Br, cyano, -C(O)NH 2 , -CF 2 CH 2 NH 2 , -CF 2 CH 2 , -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 .

17. The compound according to claim 16, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or a tautomer thereof, wherein R 2 is -CF 3 .

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

19. A compound according to claim 18 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein each Y is independently selected from hydrogen, halogen, 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 one or two heteroatoms independently selected from N, O and S, wherein said heterocycloalkyl and C 3-7 cycloalkyl are optionally substituted with up to three substituents independently selected from halogen, hydroxy, -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- to 8-membered monocyclic or bicyclic ring, which optionally contains one or two heteroatoms independently selected from N, O and S, wherein said ring is optionally substituted with up to three substituents independently selected from halogen, C 1-4 alkyl, oxo, -C(O)R 10 and -SO 2 R 10 .

20. A compound or a tautomer thereof according to any one of the preceding claims, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein each Y is independently selected from hydrogen, halogen, CO 2 R 10 and halo(C 1-4 )alkyl.

21. A compound or a tautomer thereof according to any one of the preceding claims, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein R 6 is hydrogen.

22. A compound according to any one of the preceding claims, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein R 4 and R 6 is hydrogen and R 5 is fluorine.

23. A compound or tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, selected from: 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]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]-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.

24. The compound according to claim 1 or claim 4, which is or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or its tautomer.

25. The compound according to claim 1 or claim 4, which is a prodrug of the following: or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or its tautomer.

26. The compound according to claim 25, which is wherein R 1 is a prodrug moiety; or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or its tautomer.

27. The compound according to claim 26, which is or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or its tautomer.

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

29. A pharmaceutical composition, which comprises: (a) a compound as defined in any one of claims 1 to 28 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or its tautomer; and (b) a pharmaceutically acceptable excipient.

30. A method for treating an autoimmune, autoinflammatory or immune-mediated disorder in a person in need thereof, comprising administering to the person a therapeutically effective amount of a compound or a tautomer thereof as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt of the compound or the tautomer thereof.

31. A compound or a tautomer thereof as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, for use in therapy.

32. A compound or a tautomer thereof as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, for treating an autoimmune, autoinflammatory or immune-mediated disorder.

33. Use of a compound or a tautomer thereof as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, in the manufacture of a medicament for treating an autoimmune, autoinflammatory or immune-mediated disorder.

34. The treatment method, compound used or use according to any one of claims 30, 30 or 31, wherein the disorder is selected from 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. The method, compound used or use according to claim 34, wherein the disorder is systemic lupus erythematosus or lupus nephritis.

36. A combination, the combination being (i) a compound or a tautomer thereof as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt of the compound or the tautomer thereof; and (ii) an immunomodulator.

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