Pyrimidine SGC stimulators

Abstract

The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts thereof, and pharmaceutical formulations containing them, and their uses, alone or in combination with one or more additional agents, for treating various diseases in which an increase in the concentration of nitric oxide (NO) and / or an increase in the concentration of cyclic guanosine monophosphate (cGMP), or both, or upregulation of the NO pathway, is desired. In some embodiments, the compound is of Formula I or a pharmaceutically acceptable salt thereof. (I) TIFF2025536343000075.tif3865

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 417,180, filed October 18, 2022. The entire contents of the prior application are expressly incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present disclosure relates to stimulators of soluble guanylate cyclase (sGC) and pharmaceutically acceptable salts thereof. It also relates to pharmaceutical preparations and dosage forms containing them, and their use, alone or in combination with one or more additional agents, for treating various diseases. The diseases are those that benefit from sGC stimulation or from increasing the concentration of nitric oxide (NO) and / or cyclic guanosine monophosphate (cGMP). [Background technology]

[0003] sGC is the primary receptor for NO in vivo. Upon binding to sGC, NO activates its catalytic domain, leading to the conversion of guanosine-5'-triphosphate (GTP) to the second messenger cGMP. Elevated levels of cGMP then regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels. In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by the sequential reduction of inorganic nitrate. Experimental and clinical evidence indicates that reduced NO concentrations, reduced NO bioavailability, and / or reduced responsiveness to endogenously produced NO contribute to the development of many diseases. sGC stimulators are heme-dependent agonists of the sGC enzyme that act synergistically with various amounts of NO to increase its enzymatic conversion of GTP to cGMP. sGC stimulators are clearly distinct from and structurally unrelated to another class of NO-independent, heme-independent agonists of sGC known as sGC activators.

[0004] Therapies that improve or restore sGC function offer considerable advantages over current alternative therapies that either target the NO-sGC-cGMP pathway or benefit from its upregulation. There is an urgent need to develop new and safe therapies for patients with a dysfunctional NO-sGC-cGMP pathway. Summary of the Invention [Means for solving the problem]

[0005] In a first aspect, the compounds of the present invention have the formula I:

[0006] [ka]

[0007] [In the formula, X is N or C(J C1 ) and J C is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J C1 is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; n is an integer selected from 0, 1, 2, or 3; each J Bis a halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J D1 is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J D2 is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; R is each independently selected from C optionally substituted with 1 to 3 independently selected halogen atoms. 1~4 is alkyl, J D2 is hydrogen and n is 1, 2, or 3, J C , J C1 , J D1 , and J. B at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 halogen atoms; 3~5C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 is alkyl, J D2 is hydrogen and n is 0, J C , J C1 , and J. D1 at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 alkyl] or a pharmaceutically acceptable salt thereof, provided that the compound is:

[0008] [ka]

[0009] It's not one of them. In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier. In one embodiment of the second aspect, the present invention relates to a pharmaceutical dosage form comprising said pharmaceutical composition.

[0010] In a third aspect, the present invention relates to a method of treating a disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination therapy, wherein the disease would benefit from sGC stimulation or from increased concentrations of NO and / or cGMP. DETAILED DESCRIPTION OF THE INVENTION

[0011] Reference will now be made in detail to certain specific embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined in the claims. The invention is not limited to the methods and materials described herein, but includes all methods and materials similar or equivalent to those described herein that may be used in the practice of the invention. In the event that one or more of the incorporated references, patents, or similar materials, including but not limited to defined terms, term use, described techniques, etc., differs from or contradicts this application, this application controls.

[0012] Compound definitions and general terminology For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Edition, 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Edition, Smith, M.B. and March, J., eds., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entireties.

[0013] In general, the term "substituted" refers to the replacement of one or more hydrogen radicals of a given structure with another specific radical substituent different from hydrogen (some non-limiting examples are hydroxy, phenyl, or alkyl radicals). When a structure is "optionally substituted," it may be substituted or unsubstituted. When a structure is substituted, a substituent is allowed at any substitutable atom. A "substitutable atom" is any atom (e.g., carbon, nitrogen, oxygen, or sulfur) bonded to at least one hydrogen atom. It will be understood that when a particular ring is optionally substituted, it may be substituted at one, some, or all of its substitutable ring atoms, depending on the number of possible substituents. A "substitutable ring atom" is any ring atom (e.g., carbon or nitrogen) bonded to at least one hydrogen atom, and does not include ring atoms that are already bonded to one or more moieties or substituents other than hydrogen and where the structure indicates that hydrogen is no longer available for substitution.

[0014] When one or more positions of a structure can be substituted with one or more substituents selected from a particular group or list, the one or more substituents at each position are "independently selected" and can be equal or the same at each occurrence at each position, unless otherwise specified. For example, R 100 Each R is replaced by 100 is independently selected from halogen and methyl, this means that each occurrence of R 100 are independently selected from halogen or methyl, e.g., one R 100 may be fluoro and one may be methyl, or both may be chloro, or one may be fluoro and the other may be chloro, or both may be methyl, etc. Similarly, when a substitutable atom is bonded to two or more hydrogens (e.g., CH or NH), the substituents are "independently selected" and can be equal to or the same as each occurrence of hydrogen, unless otherwise specified. For example, when there are two methyls (e.g., CH), R 100 Each R is replaced by 100 is independently selected from halogen and methyl, this means that each occurrence of R 100are independently selected from halogen or methyl, e.g., one R 100 (i.e., one of the hydrogens attached to C in the CH3 group) can be replaced with fluoro, one with methyl (e.g., CHF(CH3)), or both with chloro (e.g., CHCl2), etc.

[0015] The selection and combination of substituents envisioned in this disclosure are only those that result in the formation of stable or chemically feasible compounds. Such selection and combination are obvious to those skilled in the art and can be determined without undue experimentation. The term "stable" as used herein refers to a compound that is not substantially altered when subjected to conditions that allow its production, detection, and in some embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein. A chemically feasible compound is a compound that can be prepared by a person skilled in the art based on the disclosures herein, supplemented as necessary with relevant knowledge in the art.

[0016] The phrase "at most," as used herein, refers to zero or any integer less than or equal to the number following the phrase. For example, "at most 3" means either 0, 1, 2, or 3.

[0017] As used herein, a specified numerical range for an atom or substituent includes any integer therein. For example, a group having 1 to 4 atoms may have 1, 2, 3, or 4 atoms. When any variable occurs more than once at any position, its definition at each occurrence is independent of every other occurrence. When a moiety is substituted with zero instances of a particular variable, this means that the moiety is unsubstituted (i.e., has only hydrogen radicals attached to any substitutable atom).

[0018] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are also within the scope of the invention, regardless of how a particular compound is designated. In one embodiment, the present invention provides a method for converting hydrogen to deuterium (i.e. 2H), which may be preferred in some circumstances because it may provide certain therapeutic benefits resulting in better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Deuterium-labeled compounds of the present invention may generally be prepared by substituting a deuterated reagent for a non-deuterated reagent according to procedures similar to those disclosed in the following schemes and / or examples herein.

[0019] The term "alkyl," as used herein, as well as "alkyl chain" or "alkyl group," refers to a saturated, unbranched (e.g., straight) or branched-chain monovalent hydrocarbon radical. x Alkyl is an alkyl chain containing x carbon atoms, where x is an integer different from 0. x~y An "alkyl" is an alkyl chain containing x to y (inclusive) number of carbon atoms, where x and y are two different integers and both are different from 0. For example, C 1~6 Alkyl is an alkyl as defined above containing any number of carbon atoms from 1 to 6. Examples of alkyl groups include, but are not limited to, methyl (i.e., a C1 alkyl), ethyl (i.e., a C2 alkyl), n-propyl (a C3 alkyl), isopropyl (a different C3 alkyl), n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and the like.

[0020] The term "cycloalkyl," as used herein, and similarly "cycloalkyl ring" or "cycloalkyl group," refers to a ring system formed solely by carbon and hydrogen atoms that is fully saturated. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. A cycloalkyl ring is also referred to as the term "C x~y The term "cycloalkyl" refers to a group consisting of "a cycloalkyl group" and "a cycloalkyl group," where x and y are the minimum and maximum numbers of carbon atoms forming the cycloalkyl ring.

[0021] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I. The compounds of the invention are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0022] For example, J C , J C1 , J B , and J. D Substituents such as are generally defined when introduced and retain that definition throughout the specification and in all independent claims unless otherwise specified.

[0023] The compounds of the invention are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0024] Compound / Composition Embodiments The present invention is based on the discovery that the compounds disclosed herein are sGC stimulators.Compounds with similar structural features, particularly 4-OH substituents on pyrimidine ring, have only been known as synthetic intermediates that can be used for the preparation of sGC stimulators with 4-amino substituents on the pyrimidine ring.Unexpectedly, it has been found that the compounds disclosed herein have strong sGC promoting activity, and therefore have the potential to be useful in the treatment of diseases that can benefit from stimulating NO-sGC-cGMP pathway.

[0025] In a first embodiment of the first aspect, the compound of the invention has formula I:

[0026] [ka]

[0027] [In the formula, X is N or C(J C1 ) and J C is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J C1 is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; n is an integer selected from 0, 1, 2, or 3; each J B is a halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J D1 is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J D2 is hydrogen, halogen, C 1~6 Alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3~5 cycloalkyl, C 3~5 Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; 1~6 the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; R is each independently selected from C optionally substituted with 1 to 3 independently selected halogen atoms. 1~4 is alkyl, J D2 is hydrogen and n is 1, 2, or 3, J C , J C1 , J D1 , and J. B at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or up to three halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 is alkyl, J D2 is hydrogen and n is 0, J C , J C1 , and J. D1 at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or up to three halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 alkyl] or a pharmaceutically acceptable salt thereof, provided that the compound is:

[0028] [ka]

[0029] It's not one of them. In a second embodiment, the compound of formula I has formula IA:

[0030] [ka]

[0031] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I; J D2 is hydrogen and n is 1, 2, or 3, J C , J C1 , J D1 , and J. B at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 is alkyl, J D2 is hydrogen and n is 0, J C , J C1 , and J. D1 at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 It is alkyl.

[0032] In a third embodiment, for a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof, J C1 is hydrogen, halogen, C 1~3 is selected from the group consisting of alkyl, -CN, -SH, -SR, -OR, and -C(O)R;1~3 The alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and —OR, and the remainder of the variables are as defined in the first or second embodiment.

[0033] In a fourth embodiment, J is substituted or unsubstituted with a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof. C1 is selected from the group consisting of hydrogen, -F, -Cl, -CN, -CH, -CHF, -SH, -CHOH, -CHOCH, -SCH, -CH(OH)CH, -C(O)CH, and -OCH, and the remaining variables are defined in the first, second, or third embodiment.

[0034] In a fifth embodiment, J is substituted or unsubstituted with a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof. C1 is hydrogen, halogen, and C 1~3 alkyl, C 1~3 The alkyl is optionally substituted with 1 to 3 independently selected halogen substituents, and the remaining variables are defined in the first, second, third, or fourth embodiment.

[0035] In a sixth embodiment, J is substituted or unsubstituted with a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof. C1 is selected from the group consisting of hydrogen, —F, —Cl, —CH 3 , and —CH 2 F, and the remaining variables are defined in the first, second, third, fourth, or fifth embodiment.

[0036] In a seventh embodiment, for a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof, J C1 is hydrogen or -F, and the remaining variables are defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0037] In an eighth embodiment, the compound of formula IB has the formula IB:

[0038] [ka]

[0039] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I; J D2 is hydrogen and n is 1, 2, or 3, J C , J D1 , and J. B at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 halogen atoms; 3~5 a cycloalkyl ring or a C substituted with 1 to 3 substituents independently selected from the group consisting of -OH, -OR, -SR and -C(O)R 1~6 is alkyl, J D2 is hydrogen and n is 0, J C and J. D1 at least one of which is independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 halogen atoms; 3~5 a cycloalkyl ring or a C substituted with 1 to 3 substituents independently selected from the group consisting of -OH, -OR, -SR and -C(O)R 1~6 Although it is an alkyl, However, the compound is as follows:

[0040] [ka]

[0041] It's not one of them. In a ninth embodiment, for a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In some embodiments, n is 2. In other embodiments, n is 3.

[0042] In a tenth embodiment, for compounds of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 0 or 1, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In some embodiments, n is 1. In other embodiments, n is 0.

[0043] In an eleventh embodiment, for a compound of Formula I, IA or Formula IB, or a pharmaceutically acceptable salt thereof, each J B are halogens, -CN, -OH, -OR, -SR, -C(O)R and C 1~3 alkyl, independently selected from the group consisting of C 1~3 The alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, —OH, and —OR, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0044] In a twelfth embodiment, for a compound of Formula I, IA or Formula IB, or a pharmaceutically acceptable salt thereof, J B are independently selected from the group consisting of -F, -Cl, -Br, -CN, -CH, -CF, -CHF, -CHFCH, -CHCHF, -C(O)CH, -CH(OH)CH, -CHCH, -SCH, -OCH, -OH, -CHOCH, and -CHOH, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0045] In a thirteenth embodiment, for compounds of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3, and each J B are halogens, -OR, -CN, -OH, and C 1~3 alkyl, independently selected from the group consisting of C 1~3The alkyl is optionally substituted with 1 to 3 independently selected halogen substituents, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or eleventh embodiment.

[0046] In a fourteenth embodiment, for compounds of Formula I, IA or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3, and each J B are independently selected from the group consisting of -F, -Cl, -CH3, -CF3, -CN, -OH, and -OCH3, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, or thirteenth embodiment.

[0047] In a fifteenth embodiment, for compounds of Formula I, IA or IB, or a pharmaceutically acceptable salt thereof, n is 2 and each J B are independently selected from the group consisting of -F, -CH3, and -CF3, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, thirteenth, or fourteenth embodiment. In some embodiments, one J B is —CH or —CF, and the other is —F. In other embodiments, both J B is -F.

[0048] In a sixteenth embodiment, for compounds of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 3 and each J B are independently selected from the group consisting of -F, -OH, -CH3, -CH2F, and -CF3, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, or thirteenth embodiment. In some embodiments, one J B is -F, and the second J B is -CH3 or -CH2F, and the other is -F, -OH, -CH3 or -CH2F.

[0049] In a seventeenth embodiment, for compounds of Formula I, IA or IB, or a pharmaceutically acceptable salt thereof, n is 1 and J B is C optionally substituted with halogen, —OR, and 1 to 3 independently selected halogen substituents; 1~3 alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth, or eleventh embodiment.

[0050] In an eighteenth embodiment, for compounds of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 1 and J B is C optionally substituted with -F, -OR, and 1 to 3 independently selected halogen substituents; 1~3 alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth, or eleventh embodiment.

[0051] In a nineteenth embodiment, for compounds of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 1 and J B is selected from the group consisting of -F, -CH3, -CF3, and -OCH3, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth, or eleventh embodiment.

[0052] In a twentieth embodiment, for compounds of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 0, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0053] In a twenty-first embodiment, for a compound of formula I, IA or IB, or a pharmaceutically acceptable salt thereof, J D2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —OH, —OR, —SR, —C(O)R, and halogen, —OH, —OR, and —C(O)R; 1~3and alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0054] In a twenty-second embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J D2 is selected from the group consisting of hydrogen, -F, -Cl, -Br, -CH, -SCH, -OH, -CHF, -CHOCHCH, -OCH, -CHOCH, and -CHCHOH, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0055] In a twenty-third embodiment, for a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J D2 is C optionally substituted with 1 to 3 substituents independently selected from hydrogen, halogen, —OR, and halogen and —C(O)R; 1~3 and alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment. D2 is selected from the group consisting of hydrogen, -F and -Cl. D2 is hydrogen or -F. In yet other embodiments, J D2 is hydrogen.

[0056] In a twenty-fourth embodiment, for a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J C is C optionally substituted with 1 to 3 substituents independently selected from hydrogen, halogen, —OR, —SR, —C(O)R, —CN, and halogen, —OR, and —OH;1~3 alkyl, and R is C optionally substituted with 1 to 3 fluoro. 1~3 alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0057] In a twenty-fifth embodiment, for a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J C is selected from the group consisting of hydrogen, -F, -Cl, -CH, -CHF, -OCH, -SCH, -C(O)CH, -CHOCH, -CHOH, and -CN; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment. In some embodiments, J C is selected from the group consisting of hydrogen, —F, —Cl, —CH 3 and —CH 2 F.

[0058] In a 26th embodiment, for compounds of formula I or IA, the compound has formula IIA:

[0059] [ka]

[0060] or one of its pharmaceutically acceptable salts, the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-fourth, or twenty-fifth embodiment; When n is 1, 2, or 3, J C , J C1 , J D1 , and J. Bat least one of which is optionally independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 independently selected halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 is alkyl, If n is 0, J C , J C1 , and J. D1 at least one of which is optionally independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 independently selected halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 It is alkyl.

[0061] In a 27th embodiment, for compounds of formula I or IB, the compound has formula IIB:

[0062] [ka]

[0063] or one of its pharmaceutically acceptable salts, all other variables are as described in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-fourth, or twenty-fifth embodiment; When n is 1, 2, or 3, J C , J D1 , and J. B at least one of which is optionally independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 independently selected halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 is alkyl, If n is 0, J C and J. D1 at least one of which is optionally independently substituted with -OH, -OR, -SH, -SR, -CN, -C(O)R, or 1 to 3 independently selected halogen atoms; 3~5 C substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, -OH, -OR, -SR, and -C(O)R 1~6 Although it is an alkyl, However, the compound is as follows:

[0064] [ka]

[0065] It's not one of them. In a twenty-eighth embodiment, for a compound of formula I, IA, IB, IIA or IIB, or a pharmaceutically acceptable salt thereof, J D1 is C optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CN, —OH, —OR, —SR, —C(O)R, and halogen, —OH, and —OR; 1~3 and alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiment.

[0066] In a twenty-ninth embodiment, for a compound of formula I, IA, IB, IIA or IIB, or a pharmaceutically acceptable salt thereof, J D1is selected from the group consisting of hydrogen, -F, -CH, -CN, -SCH, -CHF, -OCH, -C(O)CH, -CH(OH)CH, or -CHCHOH; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0067] In a thirtieth embodiment, for a compound of formula I, IA, IB, IIA or IIB, or a pharmaceutically acceptable salt thereof, J D1 is C optionally substituted with 1 to 3 substituents independently selected from hydrogen, halogen, —OR, and halogen and —C(O)R; 1~3 and alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment. D1 is selected from the group consisting of hydrogen, —F, and —Cl. D1 is a halogen. In another embodiment, J D1 is -F.

[0068] In a thirty-first embodiment, for compounds of formula I, IA, IB, IIA, or IIB, or a pharmaceutically acceptable salt thereof, R is each individually and independently C 1~4 alkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtyth embodiment. In some embodiments, R is each individually and independently C 1~2 In some embodiments, R is methyl.

[0069] In a thirty-second embodiment, the present invention is directed to the sGC stimulator compounds of Table I, and their pharmaceutically acceptable salts thereof.

[0070] [Table 1-1]

[0071] [Table 1-2]

[0072] [Table 1-3]

[0073] [Table 1-4]

[0074] [Table 1-5]

[0075] [Table 1-6]

[0076] A thirty-third embodiment of the present invention is a compound of Table II or a pharmaceutically acceptable salt thereof.

[0077] [Table 2-1]

[0078] [Table 2-2]

[0079] [Table 2-3]

[0080] [Table 2-4]

[0081] In a thirty-fourth embodiment, the compound of the invention is selected from the compounds of Table III, or a pharmaceutically acceptable salt thereof.

[0082] [Table 3-1]

[0083] [Table 3-2]

[0084] In a thirty-fifth embodiment, the compound of the invention is selected from the compounds of Table IV, or a pharmaceutically acceptable salt thereof.

[0085] [Table 4]

[0086] Pharmaceutically acceptable salts of the present invention "Pharmaceutically acceptable salts" of the compounds described herein include those derived from the compounds when mixed with an inorganic or organic acid or base. In some embodiments, salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments, salts can be prepared from the free form of the compounds in a separate synthetic step. The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of the compounds of Table I are those that can be used in medicine. However, non-pharmaceutically acceptable salts may be useful in the preparation of the compounds of Table I or their pharmaceutically acceptable salts.

[0087] When a compound described herein (e.g., a compound in Tables I-IV or a compound represented by Formula I, or Formula IA, IIA, IB, or IIB) is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particular embodiments include ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts prepared from primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N, N 1- Including salts of dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0088] In some embodiments, the compounds of the present invention have an acidic OH group that can react with a base (e.g., a pharmaceutically acceptable non-toxic base) to form a salt (e.g., a pharmaceutically acceptable salt). In some embodiments, the salt is an ammonium, calcium, magnesium, potassium, or sodium salt. In some embodiments, the salt is a sodium salt.

[0089] When a compound described herein (e.g., a compound of Tables I-IV or a compound represented by Formula I, IA, IIA, IB, or IIB) is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetate, acetic acid, acid citrate, acid phosphate, ascorbate, benzenesulfonic acid, benzenesulfonate, benzoic acid, benzoate, bromide, hydrogen sulfate, hydrogen tartrate, camphorsulfonic acid, chloride, citrate, citric acid, ethanesulfonate, ethanesulfonic acid, formate, fumarate, fumaric acid, gentisinate, gluconate, gluconic acid, glucuronate, glutamate, glutamic acid, hydrobromide, hydrochloric acid, iodide, isethionate, isothiocyanate, and the like. Acids include nicotinate, lactate, lactic acid, maleate, maleic acid, malic acid, mandelic acid, methanesulfonic acid, methanesulfonate, mucic acid, nitrate, nitric acid, oleate, oxalate, pamoic acid, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), pantothenic acid, pantothenate, phosphate, phosphoric acid, saccharate, salicylate, succinic acid, succinate, sulfuric acid, sulfate, tannate, tartrate, tartaric acid, p-toluenesulfonate, p-toluenesulfonic acid, etc. Particular embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0090] The compounds described herein, as well as their pharmaceutically acceptable salts, can also be utilized in compositions to treat or prevent the diseases identified herein. Pharmaceutical Compositions and Methods of Administration In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound described herein (e.g., a compound of Tables I-IV or a compound represented by Formula I, IA, IIA, IB, or IIB, or a pharmaceutically acceptable salt thereof), and at least one pharmaceutically acceptable excipient or carrier.

[0091] In some embodiments of the second aspect, the pharmaceutical composition of the invention comprises a compound described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0092] The compounds disclosed herein and their pharmaceutically acceptable salts thereof can be formulated as pharmaceutical compositions or "formulations." A typical formulation is prepared by mixing a compound described herein (e.g., a compound in Tables I-IV or a compound represented by Formula I, IA, IB, IIA, or IIB, or a pharmaceutically acceptable salt thereof) with a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent, or excipient used will depend on the means and purpose for which the compound described herein (e.g., a compound in Tables I-IV or a compound represented by Formula I, IA, IB, IIA, or IIB, or a pharmaceutically acceptable salt thereof) is being formulated. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS: Generally Regarded as Safe) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulation may also include other types of excipients, such as one or more buffers, stabilizers, antiadherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or sustained-release), preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavors, flavoring agents, and other known additives, that provide a quality presentation of the drug (i.e., a compound of Tables I-IV, a compound represented by Formula I, IA, IB, IIA, or IIB, or a pharmaceutical composition thereof) or aid in manufacturing a pharmaceutical product (i.e., a medicament).

[0093] Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin. , gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be encapsulated in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, for example, in hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively; colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21st ed., edited by University of the Sciences in Philadelphia, 2005 (hereinafter "Remington's").

[0094] The formulations may be prepared using conventional dissolution and mixing procedures. The term "therapeutically effective amount," as used herein, means an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician. The therapeutically effective amount of the compound administered is determined by such considerations and is the minimum amount necessary to ameliorate, cure, or treat a disease or one or more of its symptoms.

[0095] The terms "administer," "administering," or "administration," with reference to a compound, composition, or dosage form of the invention, mean introducing the compound, composition, or dosage form into the system of a subject or patient in need of treatment. When the compound of the invention is provided in combination with one or more other active agents, "administration" and variations thereof are each understood to include simultaneous and / or sequential introduction of the compound, composition, or dosage form and the other active agent(s).

[0096] The compounds described herein can be administered systemically or locally, for example orally (in solid dosage forms including hard or soft capsules (e.g., gelatin capsules), tablets, pills, powders, sublingual tablets, troches, lozenges, and granules; and by inhalation (e.g., aerosols, gases, inhalers, nebulizers, etc.), otically (e.g., using ear drops), topically (e.g., in the form of creams, gels, inhalants, liniments, lotions, ointments, patches, pastes, powders, solutions, The compositions may be administered parenterally, including, but not limited to, liquid dosage forms including, but not limited to, pharmaceutically acceptable emulsions, microemulsions, aqueous or oily solutions, suspensions, syrups, and elixirs, or parenterally, such as via sprays, transdermal patches, ophthalmic solutions (e.g., eye drops, eye gels, eye ointments), rectally (e.g., enemas or suppositories), nasally, bucally, vaginally (e.g., douches, intrauterine devices, suppositories, vaginal rings, or tablets), ear drops, or via an implanted reservoir. The term "parenteral," as used herein, includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0097] Formulations of compounds intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. In solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, jasmine, maltodextrin, niacin ... The tablet is mixed with potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.The tablet can be uncoated or coated by known techniques, including microencapsulation, to mask unpleasant tastes or delay disintegration and absorption in the digestive tract, thereby providing a sustained effect over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used alone or with wax.Water-soluble taste-masking materials such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose can be used.

[0098] In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and perfumes.

[0099] Oral compositions (either solid or liquid) may also contain excipients and adjuvants, such as dispersing or wetting agents, for example, naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate); emulsifying and suspending agents, for example, sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; sweetening agents, flavorings, and fragrances; and / or one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example, sucrose or saccharin.

[0100] Pharmaceutical compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants. Formulations suitable for pulmonary or nasal administration have particle sizes ranging, for example, from 0.1 to 500 microns (including particles ranging between 0.1 and 500 microns in increments of microns, such as 0.5, 1, 30, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or through the mouth to reach the alveolar sacs.

[0101] The pharmaceutical compositions described herein can also be administered locally, especially when the target of treatment comprises areas or organs that are easily accessible by topical application, including diseases of the eye, ear, skin or lower intestinal tract.Suitable topical formulations can be easily prepared for each of these areas or organs.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any necessary preservative or buffer.

[0102] For topical application, pharmaceutical compositions can be formulated with a suitable ointment containing active ingredients suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, pharmaceutical compositions can be formulated with a suitable lotion or cream containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[0103] Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base.Optionally, the aqueous phase of the cream base can contain polyhydric alcohols, i.e., alcohols with two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400), and mixtures thereof.Topical formulations desirably contain a compound that improves the absorption or penetration of the active ingredient through the skin or other affected areas.Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0104] The oily phase of the emulsion prepared using the compounds of the present invention can be composed of known ingredients in a known manner. While the phase may contain only an emulsifier (also known as an excretion enhancer), it is desirable to include a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier, which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of a cream formulation. Excretion enhancers and emulsion stabilizers suitable for use in the formulation of the compounds of the present invention include Tween™-60, Span™-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0105] In addition, the present invention contemplates the use of transdermal patches, which have the added benefit of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0106] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in pH-adjusted isotonic sterile saline, or preferably as a solution in pH-adjusted isotonic sterile saline, with or without a preservative, such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, such as the mouth and skin, the formulation may be applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w / w. When formulated in an ointment, the active ingredient may be utilized with either an oil-based paraffinic or water-miscible ointment base.

[0107] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers, such as cocoa butter, beeswax, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, so that they melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays.

[0108] Sterile injectable forms of the compositions described herein (e.g., for parenteral administration) may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents (including those described in the preceding paragraphs). Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable solutions, including natural pharmaceutically acceptable oils, such as vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, especially their polyoxyethylated versions, or mineral oils such as liquid paraffin. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for the purpose of injectable formulations. Oil suspensions may contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those described above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

[0109] In another embodiment of the second aspect, the compound of the present invention or its pharmaceutically acceptable salt can be formulated into a veterinary composition containing a veterinary carrier. The veterinary carrier is a material that is useful for administering the composition and can be a solid, liquid, or gaseous material that is otherwise inert. In the veterinary field, it is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or by any other desired route.

[0110] Treatment method In a third aspect, the present invention also provides a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, IA, IIA, IB, or IIB, or a compound of Tables I-IV, or a pharmaceutically acceptable salt thereof, alone or in combination therapy, wherein the disease would benefit from sGC stimulation, or from increased concentrations of NO or cGMP, or both, or from upregulation of the NO-sGC-cGMP pathway. In another embodiment of the third aspect, the present invention also provides a method of treating a disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition or dosage form comprising a compound of Formula I, IA, IB, IIA, IIB, or Tables I-IV, or a pharmaceutically acceptable salt thereof, alone or in combination therapy, wherein the disease would benefit from sGC stimulation, or from increased concentrations of NO or cGMP, or both, or from upregulation of the NO-sGC-cGMP pathway.

[0111] In a fourth aspect, the present invention provides the use of a compound of Formula I, IA, IB, IIA, IIB, Tables I-IV or any of the compounds of the first to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising a compound of Formula I, IA, IB, IIA, IIB or Tables I-IV or any of the compounds of the first to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, in the treatment of one of the diseases disclosed herein in a subject in need of such treatment.

[0112] In a fifth aspect, the present invention provides the use of a compound of Formula I, IA, IB, IIA, IIB, Tables I-IV or any of the first to thirty-five embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising a compound of Formula I, IA, IB, IIA, IIB or Tables I-IV or any of the compounds of the first to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating one of the diseases disclosed herein in a subject in need thereof.

[0113] The present invention further provides a method of making or manufacturing a medicament useful for treating one of the diseases disclosed herein, comprising the step of using a compound of Formula I, IA, IIA, IB, IIB, Tables I-IV or any of the compounds of the first to thirty-five embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising a compound of Formula I, IA, IB, IIA, IIB or Tables I-IV or any of the compounds of the first to thirty-five embodiments, or a pharmaceutically acceptable salt thereof.

[0114] Embodiments of the third through fifth aspects of the present invention are methods of treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein (e.g., a compound described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment or a pharmaceutically acceptable salt thereof). 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 embodiment thereof), or a pharmaceutical composition comprising a compound described herein (e.g., a compound described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment or a pharmaceutically acceptable salt thereof) to a subject in need of treatment.

[0115] In some embodiments of the third through fifth aspects, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases characterized by an undesirable decrease in NO bioavailability and / or sensitivity to NO, such as those associated with states of oxidative or nitrative stress.

[0116] Increasing cGMP levels through the NO-sGC-cGMP pathway results in vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive, antiremodeling, antiapoptotic, anti-inflammatory, antifibrotic, metabolic, neuronal signaling, and mitochondrial effects. Therefore, sGC stimulators can be used to treat and / or prevent a range of diseases.

[0117] Specific diseases or disorders that may be treated and / or prevented by administering an sGC stimulator of the invention according to the third to fifth aspects (e.g., a compound of Formula I, IA, IB, IIA, IIB, Tables I-IV, or a compound of any of the first to thirty-fifth embodiments and pharmaceutically acceptable salts thereof) include, but are not limited to, the following: abetalipoproteinemia, achalasia (e.g., esophageal achalasia), acute respiratory distress syndrome (ARDS), adhesive capsulitis, age-related learning and memory impairment, age-related memory loss, alcoholism, alopecia or hair loss, severe disability, Alzheimer's disease (including pre-Alzheimer's disease, mild to moderate Alzheimer's disease, or moderate to severe Alzheimer's disease), amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), anal fissure, aneurysm, angina pectoris (e.g., stable or unstable angina, variant angina, Prinzmetal's angina, mild small vessel angina), anxiety or anxiety disorders, argininosuccinic aciduria, arterial and venous thrombosis, arthritis, Asperger's syndrome, asthma and asthma disorders, ataxia, telangiectasia, atherosclerosis (e.g., atherosclerosis associated with internal injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration), atrophic vaginitis, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), autism and disorders on the autism spectrum, benign prostatic hyperplasia (BPH) or hypertrophy or dilation, bipolar disorder, bladder outlet cerebral aneurysm, cerebral hypoxia, cancer metastasis, cerebral amyloid angiopathy (CAA) or congophilic angiopathy, cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL or CADASIL syndrome), cerebral perfusion, cerebral small vessel disease, cerebral vasospasm, chemobrain, childhood disintegrative disorder, chronic bronchitis, chronic fatigue, chronic traumatic encephalopathy (CTE), ciliopathies, cirrhosis (e.g., cirrhosis, cirrhosis associated with chronic liver disease, primary biliary cirrhosis), CNS disease-related dysfunction, CNS disease-related sleep disorders, cognitive impairment associated with Huntington's disease, cognitive impairment, cognitive disorders (e.g., vascular cognitive impairment, mild cognitive impairment, cognitive impairment associated with diabetes, cognitive impairment associated with multiple sclerosis, cognitive impairment associated with obstructive sleep apnea, cognitive impairment associated with schizophrenia (CIAS), cognitive impairment associated with sickle cell disease, concussion, congenital myasthenic syndrome, connective tissue disease, consequences of cerebral infarction (stroke), preservation of blood substitutes in trauma patients, CREST syndrome, Crohn's disease, cystic fibrosis (CF),Delusional disorder, dementia (e.g., vascular dementia, post-stroke dementia, dementia with Lewy bodies, dementia with frontal lobar degeneration, dementia with frontotemporal lobar degeneration, dementia with corticobasal degeneration, Creutzfeldt-Jakob dementia, HIV dementia, multi-infarct dementia, post-operative dementia, strategic single-lesion dementia, HIV-associated dementia (asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), HIV-associated dementia (HAD, also known as AIDS dementia complex [ADC] or HIV encephalopathy), presenile dementia (mild cognitive impairment, MCI), mixed dementia dementia, Binswanger dementia (subcortical arteriosclerotic encephalopathy), Parkinsonism-related dementia), demyelinating diseases, depression, depressive disorders, dermatomyositis, diabetic angiopathy, diabetic macular edema, diabetic microangiopathy, diabetic ulcers or wounds (e.g., diabetic foot ulcers), diseases related to or associated with metabolic syndrome (e.g., obesity, diabetes, insulin resistance, elevated fasting glucose, elevated fasting insulin, elevated lipids), diseases involving downregulated neurotransmitters, diseases involving impaired cerebral blood flow, diseases involving neurodegenerative disorders, diseases involving synaptic dysfunction, Diseases involving neuroinflammation, diseases involving neurotoxicity, diseases of the genitourinary system in both sexes (benign and malignant), concentration disorders in children with learning and memory problems, Down's syndrome, drug addiction, drug-induced psychosis, dry eye syndrome, Duchenne muscular dystrophy, Dupuytren's contracture, dyskinesias (e.g. acute dyskinesia, chronic or tardive dyskinesia, non-motor dyskinesia, levodopa-induced dyskinesia (LID)), dysmenorrhea (e.g. primary dysmenorrhea, secondary dysmenorrhea), dyspareunia, dysphagia, dystonia (e.g. generalized dyskinesia) dystonia, focal dystonia, segmental dystonia, sexual dystonia, intermediate dystonia, acute dystonic reaction, hereditary or primary dystonia), edema, electrolyte disturbances (e.g., hyperkalemia, hyponatremia), emphysema, endometriosis, endothelial dysfunction or injuries and diseases related to endothelial dysfunction, erectile dysfunction, esophageal achalasia, Fabry disease, female sexual dysfunction (e.g., female sexual arousal failure), fibromyalgia, fibrosis (e.g., endomyocardial fibrosis, atrial fibrosis, cardiac interstitial fibrosis, cardiac fibrosis, pulmonary fibrosis, ocular fibrosis, dermal fibrosis, intestinal fibrosis,Renal fibrosis or kidney fibrosis (renal fibrosis, kidney fibrosis, interstitial renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis of the lung, hepatic fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, arthrofibrosis, myelofibrosis, bone marrow fibrosis, bone marrow fibrosis, radiation-induced fibrosis, pancreatic fibrosis), fragile X, functional dyspepsia, gastroparesis, Gaucher disease, generalized disorder of concentration, general psychosis, glaucoma, glioblastoma, glomerulopathy (e.g., glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis), granuloma, head injury, hearing impairment (e.g., Heart disease (e.g., partial hearing loss, complete hearing loss, partial hearing loss, complete hearing loss, noise-induced hearing loss), heart disease (e.g., left ventricular myocardial remodeling, left ventricular systolic dysfunction, ischemic cardiomyopathy, dilated cardiomyopathy, alcoholic cardiomyopathy, storage cardiomyopathy, congenital heart dysfunction, reduced coronary artery blood flow, diastolic or systolic dysfunction, coronary insufficiency, acute coronary syndrome, coronary artery disease, arrhythmias, reduced ventricular preload, cardiac hypertrophy, right ventricular hypertrophy, atrial and ventricular rhythm disorders and cardiac conduction disorders, atrioventricular block class I to III (AVB) I-III), supraventricular tachyarrhythmias, ventricular premature contractions, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsades de pointes tachycardia, atrial and ventricular premature contractions, AV junctional premature contractions, sick sinus node syndrome, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, myocardial insufficiency, chronic, acute or viral myocarditis, cardiogenic shock, cardiac remodeling), heart failure (HF; e.g., heart failure with preserved ejection fraction (HFPEF), heart failure with reduced ejection fraction (HFREF), acute heart failure, chronic heart failure, acute phase of pre-existing chronic heart failure (worsening HF), transient heart failure, acute heart failure All heart failure, systolic heart failure, diastolic heart failure, congestive heart failure, acute decompensated heart failure, right ventricular failure, complete heart failure, high-output heart failure, heart failure with valve defects, diabetic heart failure, heart failure / cardiorenal syndrome, right heart failure), high levels of plasminogen activator inhibitor 1 (PA-1), high levels of fibrinogen and low density DLD, histiocytosis X, Huntington's disease or chorea (HD), hyperammonemia and related conditions, hypertension (e.g. arterial hypertension, treatment-resistant hypertension, diabetic hypertension, idiopathic hypertension, essential hypertension, secondary hypertension, pregnancy-induced hypertension, portal hypertension, systemic hypertension, preeclampsia,acute and chronic coronary artery blood pressure elevation), hypertonia, hypertrophic scarring, hypoactive sexual arousal disorder, hypoperfusion, impotence, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), inflammation due to cerebral malaria, inflammation due to infection, inflammatory response in perioperative care, platelet aggregation, intellectual disability, intermittent claudication, interstitial cystitis (IC), dialysis hypotension, ischemia (e.g., cerebral ischemia, myocardial ischemia, thromboembolic ischemia, critical limb ischemia), keloids, renal disease (e.g., chronic kidney disease, acute and chronic renal failure, sequelae of renal failure, renal insufficiency related to pulmonary enemas, HF) Renal insufficiency related to uremia or anemia, primary renal disease, congenital renal disease, progressive polycystic kidney disease, renal transplant rejection, immune complex-induced kidney disease, abnormally low creatinine and / or water excretion, abnormally high blood levels of urea, nitrogen, potassium, and / or creatinine, altered activity of renal enzymes (e.g., glutamyl synthetase), altered urine osmolality or volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, vascular kidney disease, renal cysts, renal edema due to HF ), Korsakoff psychosis, leukocyte activation, levodopa-induced addictive behavior, lichen sclerosus, lipid-related disorders (e.g., excess adiposity, excess subcutaneous fat, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL cholesterol) levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver disease, hepatic steatosis or abnormal lipid accumulation in the liver, heart, kidney, or muscle, sitosterolemia) , xanthomatosis, Tangier's disease), liver disease (e.g., vascular liver disease, hepatic stellate cell activity, hepatic fibrous collagen and total collagen accumulation, necrotic and / or immunological inflammatory liver disease, cholestatic liver disease associated with granulomatous liver disease, cholestatic liver disease associated with hepatic malignancy, cholestatic liver disease associated with intrahepatic cholestasis of pregnancy, cholestatic liver disease associated with hepatitis, cholestatic liver disease associated with sepsis, cholestatic liver disease associated with drugs or toxins, cholestatic liver disease associated with graft-versus-host disease, cholestatic liver disease associated after liver transplantation,Cholestatic liver disease associated with choledocholithiasis, cholestatic liver disease associated with bile duct tumors, cholestatic liver disease associated with pancreatic cancer, cholestatic liver disease associated with Mirizzi syndrome, cholestatic liver disease associated with AIDS, cholangiopathy, cholestatic liver disease associated with parasites, cholestatic liver disease associated with schistosomiasis, hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic vaso-occlusive disease (VOD), hepatic sinusoidal obstruction syndrome (SOS), hepatic encephalopathy, focal thrombosis, lower urinary tract syndrome (LUTS), lumbar spinal stenosis disease, lupus nephritis, lupus or systemic lupus erythematosus, microalbuminuria, microcirculatory abnormalities, migraine, mild neurocognitive disorder (MND), morphea, moyamoya disease, multiple lacunar infarctions, multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), multiple sclerosis (including MS, clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS)), multiple system atrophy (MSA), myocardial infarction or heart attack (e.g. ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, previous myocardial infarction), recent Ocular choroidal neovascularization, nevi, opioid dependence, nephropathy (e.g., diabetic nephropathy, non-diabetic nephropathy, nephritis, toxin-induced nephropathy, contrast-induced nephropathy, diabetic or non-diabetic nephrosclerosis, nephrotic syndrome, pyelonephritis, nephrogenic fibrosis), neurodegenerative diseases, neurogenic bladder and incontinence, neuroinflammation, neurological diseases associated with decreased nitric oxide production, neuromuscular diseases (e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, peripheral myopathies, myotonic dystrophies type I and type II, facioscapulohumeral muscular dystrophy) muscular dystrophy, autosomal and X-linked Emery-Dreifuss muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy (SMA), neuromyelitis optica, neuropathies (e.g. peripheral neuropathies, autonomic neuropathies, central nervous system neuropathies, chemotherapy-induced neuropathies, diabetic neuropathy, painful neuropathy, neuropathic pain, non-painful neuropathy, painful diabetic neuropathy, non-painful diabetic neuropathy, neuropathies associated with CNS diseases (e.g. multiple sclerosis, MS),Radiation-induced neuropathy), neuropathic pain associated with herpes zoster, neuropathic pain associated with spinal surgery), obsessive-compulsive disorder (OCD), thromboangiitis obliterans, obstructive uropathy, eosinophilic fasciitis, osteoporosis, overactive bladder, pain (e.g., acute pain, central pain syndrome, inflammatory pain, postoperative pain, tension pain, visceral pain, claudication pain), rare pain indications (e.g., acetazolamide-responsive myotonia, autologous red blood cell sensitization syndrome, autosomal dominant, Charcot-Marie-Tooth disease type 2V, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, channelopathy-associated congenital insensitivity to pain, chronic pain requiring intrathecal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital insensitivity to pain with hyperhidrosis, congenital insensitivity to pain with severe intellectual disability, congenital insensitivity to pain-hydrophidrosis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome with predominant lower limb involvement, predominantly upper body Familial paroxysmal pain syndromes with involvement, hereditary painful calluses, hereditary sensory and autonomic neuropathy type 4, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, interstitial cystitis, painful orbital and systemic neurofibromatosis-Marfanoid body syndrome, paroxysmal excruciating pain, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, Tolosa-Hunt syndrome), pancreatitis, panic disorder, Parkinson's disease, Parkinsonism plus, Parkinsonian dysphagia, pathological eating disorders, pelvic pain, peripheral vascular disease (e.g. peripheral arterial disease, peripheral Arterial occlusive disease, peripheral vascular embolism, peripheral perfusion disorder), peritonitis, pervasive developmental disorder, Peyronie's disease, Pick's syndrome, polychondritis, polymyositis, post-herpetic neuralgia, post-traumatic head injury, post-traumatic stress disorder (PTSD), premature ejaculation, progressive nuclear palsy, prostatic hyperplasia, pulmonary disease (e.g., multifactorial pulmonary arteriopathy, bronchoconstriction or pulmonary bronchoconstriction, pulmonary vascular disease, chronic obstructive pulmonary disease (COPD), pulmonary capillary hemangiomatosis, lymphangiomatosis and compressed pulmonary vessels (e.g., due to adenopathy, tumor or fibrosing mediastinitis), pulmonary vascular remodeling, pulmonary muscle hypertonia), pulmonary hypertension (PH, e.g., For example, pulmonary arterial hypertension (PAH), primary PH, secondary PH, idiopathic PH, precapillary PH, idiopathic PH, PH associated with left ventricular disease, PH associated with HIV, PH associated with SCD, PH associated with thromboembolism (chronic thromboembolic PH or CTEPH), PH associated with sarcoidosis, PH associated with chronic obstructive pulmonary disease, PH associated with acute respiratory distress syndrome (ARDS), PH associated with acute lung injury, PH associated with alpha-1-antitrypsin deficiency (AATD), PH associated with emphysema (e.g., smoking-induced emphysema), PH associated with lung disease,PH associated with hypoxemia, PH associated with scleroderma, PH associated with cystic fibrosis (CF), PH associated with left ventricular dysfunction, PH associated with hypoxemia, PH (WHO groups I, II, III, IV and V), PH associated with mitral valve disease, PH associated with pericarditis, PH associated with constrictive pericarditis, PH associated with aortic stenosis, PH associated with dilated cardiomyopathy, PH associated with hypertrophic cardiomyopathy, PH associated with restrictive cardiomyopathy, PH associated with mediastinal fibrosis, PH associated with pulmonary fibrosis, PH associated with anomalous pulmonary venous return, PH associated with pulmonary veno-occlusive disease, PH associated with pulmonary vasculitis, PH associated with collagen vascular disease, PH associated with congenital heart disease, PH associated with pulmonary venous hypertension, interstitial lung disease PH associated with disease, PH associated with sleep-disordered breathing, PH associated with chronic airflow obstruction, PH associated with obstructive sleep apnea, PH associated with central sleep apnea, PH associated with mixed sleep apnea, PH associated with alveolar hypoventilation, PH associated with chronic exposure to high altitude, PH associated with neonatal lung disease, PH associated with alveolar-capillary dysplasia, PH associated with sickle cell disease, PH associated with other coagulation disorders, PH associated with chronic thromboembolic disorders), radiculopathy, Raynaud's disease, Raynaud's syndrome (primary or secondary), refractory epilepsy, Rempenning syndrome, reperfusion injury (e.g., ischemia-reperfusion injury, ischemia-reperfusion associated with organ transplantation), restenosis (e.g., restenosis occurring after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation, or bypass surgery), retinopathies (e.g., diabetic retinopathy, non-diabetic retinopathy, non-proliferative diabetic retinopathy, proliferative vitreoretinopathy, peripheral retinal degeneration, retinal vein occlusion), Rett's syndrome, rheumatoid or rheumatic diseases (e.g., arthritis, rheumatoid arthritis), sarcoidosis, rheumatoid arthritis, ... coid, schistosomiasis, schizoaffective disorder, schizophrenia, schizophrenia with dementia, scleroderma (e.g., localized or localized scleroderma, systemic sclerosis), sclerosis (e.g., nephrosclerosis, progressive sclerosis, hepatic sclerosis, primary sclerosing cholangitis, sclerosis of the gastrointestinal tract, hippocampal sclerosis, focal sclerosis, primary lateral sclerosis, osteosclerosis, otosclerosis, atherosclerosis, tuberous sclerosis, systemic sclerosis), sepsis or septic shock or anaphylactic shock, sickle cell anemia, sickle cell disease, Sjogren's syndrome, sleep-wake disorders,Sneddon syndrome, spasticity (e.g., coronary vasospasm, vasospasm, peripheral arterial spasm), spinal cord injury, spinal muscular atrophy, spinal subluxation, spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), stroke, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, syncope, tauopathy, tension, thalamic degeneration, thromboembolic or thrombogenic disorders, transient ischemic attack (TIA), traumatic brain injury, tubulointerstitial disease, ulcers, uterine fibroids, vagina Atrophy, valve defects (e.g., mitral stenosis, mitral regurgitation, insufficiency or insufficiency, aortic stenosis, aortic regurgitation, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, mixed valvular disease), vascular disorders due to cerebrovascular disease, cardiac and renal complications, vascular leakage or permeability, vasculitis (e.g., thromboangiitis, thromboangiitis obliterans, Kawasaki disease, arteritis, aortitis), vaso-occlusive stroke, Venus graft failure, wet age-related macular degeneration and Williams syndrome.

[0118] In a specific embodiment, the disease that can be treated with an sGC stimulator of the invention (e.g., a compound of any one of Formula I, IA, IB, IIA, IIB, or Tables I-IV, or any of the first through thirty-five embodiments) is a CNS (central nervous system) disease. In another embodiment, the disease is a mitochondrial disease.

[0119] In one embodiment of the third through fifth aspects, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by increased neuroinflammation. One embodiment of the present invention is a method of reducing neuroinflammation in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0120] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by increased neurotoxicity. One embodiment of the present invention is a method of reducing or compensating for the negative effects of neurotoxicity in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through 35 embodiments, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0121] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by impaired nerve regeneration. One embodiment of the present invention is a method of restoring nerve regeneration in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through 35 embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0122] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by synaptic dysfunction. One embodiment of the present invention is a method of restoring synaptic function in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through 35 embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0123] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by downregulated neurotransmitters. One embodiment of the present invention is a method of normalizing neurotransmitters in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through 35 embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0124] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by impaired cerebral blood flow. One embodiment of the present invention is a method of restoring cerebral blood flow in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising them.

[0125] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by increased neurodegeneration. One embodiment of the present invention is a method of reducing neurodegeneration in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through 35 embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0126] In another embodiment of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by cognitive impairment. One embodiment of the present invention is a method of improving cognition in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first through 35 embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same. In some embodiments, the treatment improves memory. In other embodiments, the treatment improves attention. In other embodiments, the treatment improves executive function.

[0127] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that are neuroprotective. In particular, the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the compounds of the first to 35th embodiments, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions or dosage forms comprising them, may be useful for protecting neurons in subjects in need thereof.

[0128] In another embodiment of the third to fifth aspects of the invention, the CNS disease, condition or disorder is selected from the group consisting of Alzheimer's disease (AD), vascular dementia (VD), vascular cognitive impairment, mixed dementia, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal lobar degeneration or dementia (FTD), asymptomatic neurocognitive impairment (ANI), subjective cognitive impairment or decline (SCD), cognitive aging, mild neurocognitive impairment (MND), HIV-associated dementia (HAD) (also called AIDS dementia complex [ADC] or HIV encephalopathy), dementia with Lewy bodies, presenile dementia or mild cognitive impairment (MCI).

[0129] In another embodiment of the third to fifth aspects of the invention, the disease, condition or disorder is a CNS disorder or condition selected from the group consisting of sleep-wake disorders and neurological abnormalities associated with Sneddon syndrome.

[0130] In another embodiment of the third to fifth aspects of the invention, the disease, condition or disorder is a CNS disorder or condition selected from the group consisting of Alzheimer's disease or pre-Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease.

[0131] In another embodiment of the third to fifth aspects of the invention, the CNS disease is selected from the group consisting of glaucoma, Huntington's disease (or Huntington's chorea, HD), multiple sclerosis (MS), multiple system atrophy (MSA), Parkinson's disease (PD), parkinsonism plus, spinocerebellar ataxia (SCA), Steel-Richardson-Olszewski disease (progressive supranuclear palsy), amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), or Down's syndrome.

[0132] In another embodiment of the third to fifth aspects of the invention, the CNS disease is selected from the group consisting of attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD). In another embodiment of the third to fifth aspects of the invention, the CNS disorder is selected from the group consisting of a traumatic (closed or open) penetrating brain injury, a traumatic brain injury (TBI), a non-traumatic stroke (particularly an ischemic stroke), an aneurysm, hypoxia, or other injury to the brain.

[0133] In other embodiments of the third to fifth aspects of the invention, the CNS disorder is a psychiatric, mental, mood or affective disorder selected from the group consisting of bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorder, anxiety disorder, panic disorder, or post-traumatic stress disorder (PTSD).

[0134] In other embodiments of the third to fifth aspects of the invention, the CNS disease or disorder is selected from the group consisting of dystonia, including, for example, generalized, focal, segmental, sexual, intermediate, hereditary / primary dystonia or acute dystonic reaction; or dyskinesia, including, for example, acute, chronic / tardive, and non-motor and levodopa-induced dyskinesia (LID).

[0135] In other embodiments of the third through fifth aspects, the CNS disease or disorder is selected from a disorder characterized by a relative reduction in synaptic plasticity and synaptic processing, including, for example, Fragile X, Rett syndrome, Williams syndrome, Rempenning syndrome, autism spectrum disorder (ASD), autism, Asperger's syndrome, pervasive developmental disorder, or childhood disintegrative disorder.

[0136] In other embodiments of the third through fifth aspects, the CNS disorder is selected from the group consisting of chemobrain, levodopa-induced addictive behavior, alcoholism, narcotic addiction (including but not limited to amphetamines, opiates or other substances), and substance abuse.

[0137] In one embodiment of the third to fifth aspects, the CNS disease is a cognitive impairment or dysfunction resulting from brain injury, psychiatric disorder, neurodevelopmental disorder or neurodegenerative disorder. In some embodiments of the third through fifth aspects, the cognitive impairment, either MCI or dementia, is associated with Alzheimer's disease (AD), vascular dementia, mixed dementia, AD with vascular pathology (ADv), cerebral infarction, cerebral ischemia, stroke, brain injury, traumatic brain injury, learning disability, autism, attention deficit disorder, depression, spinocerebellar ataxia, dementia with Lewy bodies, dementia with frontal lobar degeneration, Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelinating diseases, multiple sclerosis (MS), thalamic degeneration, Creutzfeldt-Jakob dementia, HIV dementia, schizophrenia, Korsakoff psychosis, post-operative cognitive decline in the elderly, bipolar disorder, or mitochondrial disease. In other embodiments, the cognitive impairment is associated with sickle cell disease.

[0138] In some embodiments of the third through fifth aspects, the MCI, dementia, subclinical cognitive impairment, or SCD is associated with cognitive aging, post-surgical cognitive decline, a medication side effect, a metabolic imbalance, a hormonal problem, a vitamin or nutrient deficiency, delirium, a psychiatric illness, damage to brain neurons due to injury (e.g., in stroke or other cerebrovascular disease or due to traumatic brain injury), the early stages of a neurodegenerative process, exposure to a toxin, or a viral or bacterial infection.

[0139] In other embodiments of the third through fifth aspects, the compounds disclosed herein are sGC stimulators that may be useful for the prevention and / or treatment of rare pain indications. One embodiment of the present invention is a method of treating rare pain indications in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IA, IB, IIA, IIB, Tables I-IV, or any of the compounds of the first through thirty-fifth embodiments of the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising same.

[0140] In particular, rare pain indications include acetazolamide-responsive myotonia, autosomal dominant Charcot-Marie-Tooth disease type 2V, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, channelopathy-associated congenital insensitivity to pain, chronic pain requiring intrathecal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital insensitivity to pain with hyperhidrosis, congenital insensitivity to pain with severe intellectual disability, congenital insensitivity to pain-hydrophidrosis syndrome, painful turtle The present invention relates to a cutaneous keratoderma with clefts, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome with predominantly lower limb involvement, familial paroxysmal pain syndrome with predominantly upper body involvement, hereditary painful calluses, hereditary sensory and autonomic neuropathy type 4, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, interstitial cystitis, painful orbital and generalized neurofibromatosis-Marfanoid body syndrome, paroxysmal excruciating pain syndrome, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, and Tolosa-Hunt syndrome.

[0141] In other embodiments, the CNS disorder is neuropathic pain. In some embodiments, the pain is neuropathic pain associated with a CNS disease. In further embodiments, the disease or condition is selected from acute pain, central pain syndrome, chemotherapy-induced neuropathy, diabetic neuropathy, fibromyalgia, inflammatory pain, painful diabetic peripheral neuropathy, post-operative pain, tension pain, and visceral pain.

[0142] In other embodiments of the third through fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that may be useful for the prevention and / or treatment of high altitude sickness (mountain sickness), cerebral small vessel disease, cerebral vasculitis, cerebral vasospasm, hepatic encephalopathy, moyamoya disease, Parkinson's dysphagia, ataxia-telangiectasia, autism spectrum disorder, chronic fatigue, chronic traumatic encephalopathy (CTE), cognitive impairment associated with diabetes, cognitive impairment associated with multiple sclerosis, cognitive impairment associated with obstructive sleep apnea, cognitive impairment associated with schizophrenia (CIAS), cognitive impairment associated with sickle cell disease, concussion, retinopathy, diabetic retinopathy (including proliferative and non-proliferative), and dysphagia.

[0143] In other embodiments of the third through fifth aspects, the compounds disclosed herein are sGC stimulators that may be useful for the prevention and / or treatment of ocular fibrosis, Fabry disease, Gaucher disease, glioblastoma, brain inflammation due to cerebral malaria (SoC), brain inflammation due to infection, intellectual disability, myopic choroidal neovascularization, neuromyelitis optica, neuropathic pain associated with multiple sclerosis, neuropathic pain associated with shingles (herpes zoster), neuropathic pain associated with spinal surgery, Parkinson's dementia, peripheral and autonomic neuropathies, peripheral retinal degeneration, post-traumatic stress syndrome, post-herpetic neuralgia, post-operative dementia, proliferative vitreoretinopathy, radiation-induced cerebral fibrosis, radiculopathy, refractory epilepsy, retinal vein occlusion, spinal cord injury, spinal muscular atrophy, spinal cord subluxation, tauopathy, and wet age-related macular degeneration.

[0144] CNS disorders that may benefit from treatment with the sGC stimulators of the present invention are those in which increased concentrations of NO or increased concentrations of cGMP, or both, or upregulation of the NO-sGC-cGMP pathway, are desirable.

[0145] The compounds described herein, as well as pharmaceutically acceptable salts thereof, are useful as stimulators of sGC that can cross the blood-brain barrier (BBB) ​​and are useful in the prevention and / or treatment of CNS diseases, conditions, and disorders that can benefit from sGC stimulation in the brain.

[0146] In some embodiments of the third through fifth aspects, the compounds of the present invention can stimulate sGC in the brain without causing a significant drop in blood pressure (BP) in patients. In some embodiments, the compounds reduce a patient's BP by an average of less than 5 mmHg for a dose that produces the desired CNS effect. In other embodiments, the reduction is less than an average of 10 mmHg. In other embodiments, the reduction in a patient's BP is not clinically significant. In still other embodiments, the methods and uses of the present invention do not result in a significant incidence of adverse events (AEs) related to symptomatic hypotension when a patient is treated for a CNS disorder.

[0147] In some embodiments of the third through fifth aspects, the compounds of the invention are useful for treating mitochondrial diseases of genetic origin. Specific mitochondrial diseases that can be treated and / or prevented by administering an sGC stimulator of the present invention (e.g., an sGC stimulator of any of Formulas I, IA, IB, IIA, IIB, Tables I-IV, or embodiments 1-35 of the first aspect, or a pharmaceutically acceptable salt thereof) include, but are not limited to, the following: Alpers disease, autosomal dominant optic atrophy (ADOA), Barth syndrome / LIC (fatal infantile cardiomyopathy), beta-oxidation deficiency, primary systemic carnitine deficiency, long-chain fatty acid transport deficiency, carnitine palmitoyltransferase deficiency, carnitine / acylcarnitine translocase deficiency, carnitine palmitoyltransferase I (CPT I) deficiency, carnitine palmitoyltransferase II (CPT II) deficiency II) deficiency, very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), multiple acyl-CoA dehydrogenase deficiency (MAD / glutaric aciduria type II), mitochondrial trifunctional protein deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase deficiency (SCAD), glutaric aciduria type II, (SCHAD) deficiency, short-chain / medium-chain 3-Hydroxyacyl-CoA dehydrogenase (S / MCHAD), medium-chain 3-ketoacyl-CoA thiolase deficiency, 2,4-dienoyl-CoA reductase deficiency, mitochondrial enoyl-CoA reductase protein-associated neurodegeneration (MEPAN), carnitine deficiency, creatine deficiency syndrome, coenzyme Q10 deficiency, complex I, II, III, IV, V deficiency, chronic progressive external ophthalmoplegia (CPEO), Friedreich's ataxia, Kearns-Sayre syndrome, leukodystrophy, Leigh's disease or syndrome, LHON, LHON Plus, Luft disease, MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial recessive ataxia syndrome (MIRAS), mitochondrial cytopathies, mitochondrial DNA depletion, mitochondrial encephalopathy, mitochondrial myopathy, multiple mitochondrial dysfunction syndrome, MNGIE (Myoneurogenic gastrointestinal encephalopathy), NARP (Neuropathy, ataxia, retinitis pigmentosa, and ptosis), Pearson syndrome, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency or pyruvate dehydrogenase complex deficiency (PDCD / PDH), and POLG mutations.

[0148] In one embodiment, the mitochondrial disease is selected from Alpers, carnitine-acyl-carnitine deficiency, carnitine deficiency, complex I, II, III, IV deficiency, CPEO, CPT II deficiency, creatine deficiency syndrome, KSS, LCHAD, Leigh syndrome, leukodystrophy, LHON, MELAS, MEPAN, MERRF, MIRAS, mitochondrial DNA depletion, MNGIE, NARP, Pearson syndrome, and POLG mutations.

[0149] Definitions and general terminology for usage The term "disease," as used herein, refers to any deviation from or disruption of the normal structure or function of any body part, organ, or system, manifested by a characteristic set of symptoms and signs, the etiology, pathology, and prognosis of which may be known or unknown. The term disease encompasses disorders and conditions (or medical conditions) and other related terms, such as syndromes, and is defined as a combination of symptoms resulting from a single cause or causes that commonly occur together to form a distinct clinical picture. In some embodiments, the term disease refers to sGC-, cGMP-, and / or NO-mediated medical or pathological disorders.

[0150] "Treate," "treating," or "treatment," in reference to a disorder, disease, condition, symptom, or syndrome, refers to arresting or ameliorating the cause and / or effects (i.e., improvement in symptoms, physiological, physical, psychological, emotional, or any other clinical manifestation, observation, or measurement, or pathological assessment) of the disorder, disease, condition, or syndrome.

[0151] As used herein, the terms "treat," "treatment," or "treating" also refer to the delay, amelioration, or prevention of progression (i.e., known or expected progression of the disease), the severity and / or duration of the disease, or the delay, amelioration, or prevention of the progression of one or more symptoms, clinical manifestations, observations, or measurements, or the prevention or slowing of the negative progression of a pathological assessment (i.e., "managing" without "curing" the condition), resulting from the administration of one or more therapies.

[0152] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird such as a chicken, quail, or turkey, or a mammal), and specifically, "mammal" includes non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice), as well as primates (e.g., monkeys, chimpanzees, and humans), and more specifically, humans. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., horses, cows, pigs, and sheep), or a companion animal or pet (e.g., a dog, cat, mouse, rat, hamster, gerbil, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0153] The term "biological sample," as used herein, refers to an in vitro or ex vivo sample, including, but not limited to, a cell culture or an extract thereof; a biopsy obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, lymph, ocular fluid, vitreous humor, cerebrospinal fluid (CSF), or other bodily fluid or an extract thereof.

[0154] In another embodiment, the present invention provides a method for stimulating sGC activity in a biological sample, comprising contacting the biological sample with a compound or composition of the present invention.The use of sGC stimulating agents in biological samples is useful for various purposes known to those skilled in the art.Examples of such purposes include, but are not limited to, biological assays and biological specimen storage.

[0155] Combination therapy The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment of diseases mediated, modulated, or affected by sGC, cGMP, and / or NO.

[0156] As used herein, the terms "in combination" (as in the sentence "combination therapy") or "co-administration" can be used interchangeably to refer to the use of two or more therapies. The use of the terms does not restrict the order in which the therapies are administered to a subject.

[0157] The compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents.For the combined treatment with two or more active agents, when active agents are in separate dosage formulations, active agents can be administered separately or in combination.In addition, the administration of one element can be administered before, simultaneously with, or after the administration of other agents.

[0158] When used in combination therapy with other drugs, the "therapeutically effective amount" of the compounds and pharmaceutical compositions described herein and one or more other drugs depends on the type of drug used.Suitable dosages are known for approved drugs and can be adjusted by those skilled in the art according to the subject's condition, the type of condition to be treated, and the amount of the compounds described herein used.If the amount is not clearly indicated, an effective amount should be assumed.

[0159] In some embodiments, co-administration or combination therapy includes administration of a first and a second amount of a compound in an essentially simultaneous manner, for example, in a single pharmaceutical composition, such as a capsule or tablet having a fixed ratio of the first and second amounts, or in multiple separate capsules or tablets for each. In addition, such co-administration also includes use of each compound in a sequential manner, in any order.

[0160] When co-administration involves separate administration of a first amount of a compound of Formula I, IA, IB, IIA, IIB, Tables I-IV, or any of the first through thirty-five embodiments of the first aspect, and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period between each administration capable of producing the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound, such as efficacy, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the compound of Formula I, IA, IB, IIA, IIB, Tables I-IV, or any of the first through thirty-five embodiments of the first aspect, and the second therapeutic agent can be administered in any order, within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other.

[0161] Examples of other therapeutic agents that may be combined with a compound of Formula I, IA, IB, IIA, IIB, Tables I-IV, or any of the first through thirty-five embodiments of the first aspect, or a pharmaceutically acceptable salt thereof, either administered separately or in the same pharmaceutical composition, include, but are not limited to, the following: (1) Endothelium-derived releasing factor (EDRF) or NO gas.

[0162] (2) NO donors, including, but not limited to, nitrosothiols, nitrites, sydnonimines, NONOates, N-nitrosamines, N-hydroxylnitrosamines, nitrosimines, nitrotyrosines, diazetine dioxide, oxatriazole 5-imines, oximes, hydroxylamines, N-hydroxyguanidines, hydroxyureas, or furoxans. Some examples of these types of compounds include glyceryl trinitrate (GTN, also known as nitroglycerin, nitroglycerine, and trinitroglycerin), the nitrate ester of glycerol; sodium nitroprusside (SNP), in which a molecule of nitric oxide is coordinated to metallic iron forming a tetragonal bipyramidal complex; 3-morpholinosydnonimine (SIN-1), a zwitterionic compound formed by the combination of morpholine and sydnonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid derivative with a nitrosothiol functionality; diethylenetriamine / NO (DETA / NO), a compound of nitric oxide covalently bound to diethylenetriamine; and m-nitroxymethylphenyl ester of acetylsalicylic acid. Some more specific examples of these classes of NO donors include classical nitrovasodilators, such as organic nitrate and nitrite esters including nitroglycerin, amyl nitrite, isosorbide dinitrate, 5-isosorbide mononitrate, and nicorandil; isosorbide; 3-morpholinosydnonimine; linsidomine chlorohydrate ("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione mono-ethyl-ester (GSNO-ester), 6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine, or diethylamine NONOate.

[0163] (3) Other substances that increase cGMP concentrations, including, but not limited to, protoporphyrin IX, arachidonic acid, and phenylhydrazine derivatives. (4) L-arginine, n-hydroxyguanidine-based analogs, such as N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine, and PR5 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine); L-arginine derivatives (e.g., homo-Arg, homo-NOHA, N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon caproic acid, aguanine, Nitric oxide synthase substrates, including, but not limited to, agmatine, hydroxyl-agmatine, and L-tyrosyl-L-arginine; N-alkyl-N'-hydroxyguanidines (e.g., N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidines (e.g., N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives having -F, -Cl, -methyl, -OH substituents, respectively); guanidine derivatives, such as 3-(trifluoromethyl)propylguanidine.

[0164] (5) Compounds that enhance eNOS transcription. (6) NO-independent, heme-independent sGC activators, including, but not limited to, BAY 58-2667 (described in patent publication DE19943635); HMR-1766 (ataciguat, described in patent publication WO2000002851); S 3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (described in patent publications DE19830430 and WO2000002851); and HMR-1069 (manufactured by Sanofi-Aventis).

[0165] (7) YC-1 (see Patent Publications EP667345 and DE19744026); riociguat (BAY 63-2521, Adempas®, described in DE19834044); nerociguat (BAY 60-4552, described in WO2003095451); veruiciguat (BAY 1021189, described in US8420656); BAY 41-2272 (described in DE19834047 and DE19942809); BAY 41-8543 (described in DE19834044); etriciguat (described in WO2003086407); CFM-1571 (described in patent publication WO2000027394); A-344905, its acrylamide analog A-350619 and aminopyrimidine analog A-778935; Publications US20090209556, US8455638, US20110118282(WO2009032249), US20100292192, U S20110201621, US7947664, US8053455(WO2009094242), US20100216764, US8507512 (WO2010099054) US20110218202 (WO2010065275), US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798 (WO2012058132) and other sGC stimulators described in one of Tetrahedron Letters (2003), 44(48):8661-8663; and IW1973 (praliciguat), IW1701 (olinciguat) and CY6463 (formerly IW-6463). Heme-dependent NO-independent sGC stimulators, including but not limited to:

[0166] (8) Compounds that inhibit the degradation of cGMP and / or cAMP, including but not limited to: PDE1 inhibitors, PDE2 inhibitors, PDE-3 inhibitors such as amrinone, milrinone, enoximone, vesnarinone, pimobendan and olprinone, PDE4 inhibitors such as roflumilast, PDE5 inhibitors such as sildenafil and related drugs such as avanafil, lodenafil, mirodenafil, sildenafil citrate, tadalafil, vardenafil and udenafil; alprostadil; dipyridamole and PF-00489791; PDE6 inhibitors, PDE9 inhibitors such as PF-04447943, PDE10 inhibitors such as PF-02545920 (PF-10) and PDE11 inhibitors.

[0167] (9) Anticoagulants, including but not limited to: Coumarins (vitamin K antagonists), such as warfarin, acenocoumarol, phenprocoumon and phenindione, Heparin and derivatives, such as low molecular weight heparin, fondaparinux and idraparinux, Direct thrombin inhibitors, such as argatroban, lepirudin, bivalirudin, dabigatran and ximelagatran, and Tissue plasminogen activators, such as alteplase, which are used to dissolve clots and unclog arteries.

[0168] (10) Antiplatelet agents, including but not limited to clopidogrel, ticlopidine, dipyridamole, and aspirin. (11) Supplemental oxygen therapy.

[0169] (12) Alpha-1-adrenergic receptor antagonists, including, but not limited to, prazosin, indoramin, urapidil, bunazosin, terazosin, and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine inducers, tetrahydrocannabinol (THC), and papaverine.

[0170] (13) Bronchodilators, including but not limited to: short-acting beta-2 agonists, such as salbutamol or albuterol and terbutaline; long-acting beta-2 agonists (LABAs), such as salmeterol and formoterol; Anticholinergics, such as ipratropium and tiotropium; and theophylline, bronchodilators and phosphodiesterase inhibitors.

[0171] (14) Corticosteroids, including, but not limited to, beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogs such as budesonide.

[0172] (15) Omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo biloba, pine bark, Tribulus terrestris, arginine, oat (Avena sativa), horny goat weed, maca root, muira puama, saw palmetto, and Swedish flower pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, testosterone transdermal patches; dietary supplements, including, but not limited to, zoraxel, naltrexone, bremelanotide, and melanotan II.

[0173] (16) PGD2 receptor antagonist. (17) Immunosuppressants, including but not limited to cyclosporine, tacrolimus, rapamycin and other FK-506 type immunosuppressants, mycophenolate, mycophenolate mofetil.

[0174] (18) Nonsteroidal antiasthmatics, including but not limited to: beta-2 agonists, such as terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, salmeterol, bitolterol, and pirbuterol; Beta-2 agonist-corticosteroid combinations, such as salmeterol-fluticasone, formoterol-budesonide, theophylline, cromolyn, cromolyn sodium, nedocromil, atropine, ipratropium, ipratropium bromide, and Leukotriene biosynthesis inhibitors, such as zileuton or veriflavone.

[0175] (19) Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to: Propionic acid derivatives such as alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen; Acetic acid derivatives, such as indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxypinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac; Fenamic acid derivatives, such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid, Biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal, Oxicams, such as isoxicam, piroxicam, sudoxicam and tenoxicam, Salicylates, such as acetylsalicylic acid and sulfasalazine, and Pyrazolones such as apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone.

[0176] (20) Celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib, and lumiracoxib; opioid analgesics, such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine, including, but not limited to, cyclooxygenase-2 (COX-2) inhibitors.

[0177] (21) Adrenergic neuron blocking agents, including but not limited to guanethidine and guanadrel. (22) Imidazoline I-1 receptor agonists, including but not limited to rilmenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.

[0178] (23) Potassium channel activators, including but not limited to pinacidil. (24) Fenoldopam mesylate; other dopamine agonists, such as dopamine D1 agonists, including but not limited to ibopamine, dopexamine, and docarpamine.

[0179] (25) 5-HT2 antagonists, including but not limited to ketanserin. (26) Vasopressin antagonists, including but not limited to tolvaptan. (27) Calcium channel sensitizers, including but not limited to levosimendan or activators such as nicorandil.

[0180] (28) Adenylate cyclase activators, including but not limited to colforsin dalopate hydrochloride. (29) Positive inotropes, including but not limited to digoxin and methyldigoxin; metabolic inotropes, such as ubidecarenone; brain natriuretic peptides, such as nesiritide.

[0181] (30) Drugs used to treat erectile dysfunction, including but not limited to alprostadil, aviptadil, and phentolamine mesylate. (31) Drugs used to treat Alzheimer's disease and dementia, including but not limited to: Acetylcholinesterase inhibitors, such as galantamine, rivastigmine, donepezil and tacrine, and NMDA receptor antagonists, such as memantine, and 10. Oxidoreductase inhibitors, such as idebenone.

[0182] (32) Psychiatric medications, including but not limited to: Ziprasidone, risperidone, olanzapine, valproate, dopamine D4 receptor antagonists, such as clozapine; dopamine D2 receptor antagonists, such as nemonapride, mixed dopamine D1 / D2 receptor antagonists, such as zuclopenthixol; GABA A receptor modulators, such as carbamazepine, sodium channel inhibitors, e.g. lamotrigine, Monoamine oxidase inhibitors, such as moclobemide and indeloxazine, and Pimavanserin and perospirone.

[0183] (33) Drugs used to treat movement disorders or symptoms, including but not limited to: Catechol-O-methyltransferase inhibitors, such as entacapone, Monoamine oxidase B inhibitors, e.g. selegiline, dopamine receptor modulators, such as levodopa; dopamine D3 receptor agonists, such as pramipexole; decarboxylase inhibitors, e.g., carbidopa; Other dopamine receptor agonists, such as pergolide, ropinirole, cabergoline, ritigonide, istradefylline, talipexole, zonisamide and safinamide, and 10. Synaptic vesicular amine transporter inhibitors, such as tetrabenazine.

[0184] (34) Medications used to treat mood or affective disorders or OCD, such as the following types: tricyclic antidepressants, such as amitriptyline, desipramine, imipramine, amoxapine, nortriptyline, doxepin and clomipramine, selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, fluoxetine, sertraline, trazodone, and citalopram; atypical antidepressants, such as agomelatine, Selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, reboxetine, and atomoxetine; dopaminergic antidepressants, such as bupropion and amineptine.

[0185] (35) Drugs used to enhance synaptic plasticity, including but not limited to: Nicotinic receptor antagonists, such as mecamylamine, and 10. Mixed 5-HT, dopamine and norepinephrine receptor agonists, such as lurasidone.

[0186] (36) Drugs used in the treatment of ADHD, such as amphetamines; 5-HT receptor modulators, such as vortioxetine, and alpha-2 adrenoceptor agonists, such as clonidine.

[0187] (37) Nitric oxide synthase cofactors, including but not limited to tetrahydrobiopterin, dihydrobiopterin, and sapropterin. (38) Blood glucose lowering drugs (also called blood glucose control drugs or antidiabetic drugs), including but not limited to: biguanides, e.g. metformin, sulfonylureas, such as glyburide, glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, atorvastatin calcium in combination with glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide and tolazamide; alpha-glucosidase inhibitors, such as acarbose, epalrestat, voglibose and miglitol, insulin secretagogues, such as repaglinide, mitiglinide and nateglinide; Thiazolidinediones, such as rosiglitazone, troglitazone, ciglitazone, pioglitazone, englitazone, lobeglitazone sulfate and balaglitazone, DPP-4 inhibitors (or DPP-IV inhibitors), such as sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alogliptin benzoate in combination with metformin or metformin hydrochloride, anagliptin, teneligliptin, atorvastatin calcium and glimepiride, empagliflozin in combination with linagliptin, gemigliptin, sitagliptin phosphate monohydrate in combination with pioglitazone hydrochloride, sitagliptin in combination with pioglitazone, sitagliptin in combination with atorvastatin calcium, and (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile (DBPR-108), GLP-1 receptor agonists or incretin mimetics, such as exenatide, dulaglutide, liraglutide, semaglutide, lixisenatide, lixisenatide in combination with insulin glargine, albiglutide and pegapamozutide (TT-401), LY3298176 (a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist), SGLT2 inhibitors (SGLT2i), such as empagliflozin, empagliflozin in combination with linagliptin, empagliflozin in combination with metformin, ipragliflozin, ipragliflozin L-proline, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, ertugliflozin in combination with sitagliptin, ertugliflozin in combination with metformin, sotagliflozin, canagliflozin, canagliflozin in combination with metformin or metformin hydrochloride, dapagliflozin, dapagliflozin in combination with metformin or metformin hydrochloride and luseogliflozin, dapagliflozin in combination with saxagliptin, SGLT1 inhibitors or a combination of SGLT1 and SGLT2 inhibitors, such as sotagliflozin, Insulin therapy, such as one of many types of insulin, such as insulin glulisine, insulin degludec, insulin lispro, insulin aspart, insulin glargine, insulin detemir, isophane insulin, insulin Mixtard (human insulin containing both rapid-acting (soluble) and long-acting (isophane) insulin), insulin degludec in combination with insulin aspart, insulin human (rDNA origin) inhalation powder, recombinant human insulin, liver-directed endoplasmic reticulum insulin, insulin Tregopil (IN-105), insulin degludec in combination with liraglutide, insulin peglispro (LY-2605541) and nodulin, and Trimidone (lyn kinase activator).

[0188] (39) Blood pressure lowering drugs (also known as antihypertensives), including but not limited to: Diuretics, such as thiazide diuretics, chlorothiazide, chlorthalidone, hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xipamide, metolazone, indapamide, cicletanine, furosemide, toresamide, amiloride, spironolactone, canrenoate potassium, eplerenone, triamterene, acetazolamide and carperitide; beta-blockers, such as acebutolol, atenolol, metoprolol and nebivolol; Angiotensin-converting enzyme (ACE) inhibitors, such as sulfhydryl-containing drugs (e.g., captopril, zofenopril), dicarboxylate-containing drugs (e.g., enalapril, quinapril, ramipril, perindopril, lisinopril, and benazepril), phosphonate-containing drugs (e.g., fosinopril), naturally occurring ACE inhibitors (e.g., casokinins, lactokineins, lactotripeptides Val-Pro-Pro and Ile-Pro-Pro), alacepril, delapril, cilazapril, imidapril, temocapril, moexipril, lisinopril, combinations of lisinopril with hydrochlorothiazide, trandolapril, and spirapril, Angiotensin II receptor blockers (ARBs), such as candesartan, losartan, losartan potassium-hydrochlorothiazide, valsartan, candesartan cilexetil, eprosartan, irbesartan, telmisartan, olmesartan medoxomil (or olmesartan), azilsartan medoxomil, azilsartan, amlodipine besilate in combination with irbesartan, azilsartan in combination with amlodipine besilate, cilnidipine in combination with valsartan, fimasartan rbesartan in combination with atorvastatin, irbesartan in combination with trichlormethiazide, losartan potassium in combination with hydrochlorothiazide and / or amlodipine besilate, atorvastatin calcium in combination with pratosartan, losartan potassium, nifedipine and candesartan cilexetil, sacubitril in combination with valsartan or LCZ-696, angiotensin AT2 antagonist and TAK-591 and olmesartan medoxomil, Endothelin receptor antagonists (ERAs), such as atrasentan, bosentan, sitaxsentan, ambrisentan, actelion-1 (macitentan), cyclo(D-trp-D-asp-L-pro-D-val-L-leu) (BQ-123), sparsentan, and tezosentan disodium; Electrocorticoid receptor antagonists (MRAs), such as spironolactone, amiloride hydrochloride in combination with spironolactone, aparalenone or MT-3995, eplerenone, and finerenone (BAY-94-8862); calcium channel blockers, such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, diltiazem, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, isradipine, verapamil, gallopamil, diltiazem, mibefradil, bepridil, fluspirilene and fendiline; Renin inhibitors, e.g. aliskiren, alpha-blockers, such as doxazosin and prazosin, alpha-beta blockers, such as carvedilol and labetalol; centrally acting agents, such as clonidine, guanfacine and methyldopa, vasodilators, such as nitroglycerin, hydralazine, and minoxidil, and Aldosterone antagonists such as finerenone, spironolactone and eplerenone.

[0189] (40) Antihyperlipidemic drugs, including but not limited to: statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; Combinations of statins with other drugs, such as amlodipine / atorvastatin, aspirin / pravastatin, ezetimibe / simvastatin, niacin / simvastatin, lovastatin / niacin, simvastatin / sitagliptin, and atorvastatin / ezetimibe; Fibrate or fibric acid derivatives. Examples include, but are not limited to, fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate, and clofibrate.

[0190] Niacin (or nicotinic acid), bile acid ciquestrants, such as cholestyramine, colesevelam, colestilan, and colestipol; ezetimibe, lomitapide, phytosterols or orlistat, and PCSK9 inhibitors, such as alirocumab and evolocumab, (41) Sacubitril, or a combination of Sacubitril with Valsartan; a neprilysin inhibitor (also known as an endopeptidase inhibitor or NEP inhibitor or enkephalinase inhibitor), including but not limited to the investigational neprilysin inhibitors TD-1439 or TD-0714.

[0191] (42) Nephroprotective drugs, including but not limited to: bardoxolone, ACE inhibitors, e.g. captopril, ARBs, such as losartan or irbesartan, SGLT2 inhibitors, e.g. canagliflozin, GLP1 receptor agonists, MRAs, such as finerenone, ERAs, such as atrasentan, and apoptosis signal-regulating kinase 1 (ASK1) inhibitors, such as selonsertib.

[0192] (43) Hydroxyurea (HU, hydroxycarbamide). (44) Anti-sickling agents, including but not limited to hydroxyurea, voxerotol, or GBT-440.

[0193] (45) Anti-adhesion therapies, including but not limited to blocking antibodies against P-selectin, E-selectin, VLA-4, and VCAM-1. (46) Glutamine.

[0194] (47) Erythropoietin (EPO) (also known as hematopoietin or hemopoietin), including all its forms, such as exogenous erythropoietin, recombinant human erythropoietin (rhEPO), or other erythropoiesis-stimulating agents (ESAs). Two examples are epoetin alfa and epoetin beta.

[0195] (48) Antibiotics, including but not limited to: Penicillin and its derivatives, including but not limited to penicillin, amoxicillin, ampicillin, azlocillin, cloxacillin, penicillin G, penicillin V, procaine penicillin or benzathine penicillin, among others.

[0196] cephalosporins, such as cephalexin, cefadroxil, cefaclor, cefuroxime and cefixime, macrolides, such as erythromycin, clarithromycin, azithromycin, and roxithromycin; Tetracycline and its derivatives, such as demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline, Sulfonamides, including but not limited to mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfasalazine, trimethoprim-sulfamethoxazole (cotrimoxazole), and sulfisoxazole; Quinolones, including but not limited to ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, and nalidixic acid.

[0197] (49) FXR agonists, including but not limited to obeticholic acid, cenicriviroc, emricasan, GR-MD-02, selonsertib, and elafibranor. (50) Thyroid receptor-beta agonists, including but not limited to MGL-3196.

[0198] (51) Acetyl-CoA carboxylase inhibitors, including but not limited to GS-0976. (52) Treatments for mitochondrial disorders, including, but not limited to, vitamins and supplements including coenzyme Q10; B complex vitamins, especially thiamine (B1) and riboflavin (B2); alpha lipoic acid; L-carnitine; creatine; citrulline, and L-arginine.

[0199] (53) Treatment for epilepsy or seizures, including, but not limited to, phenytoin, valproic acid, phenobarbital, lamotrigine, carbamazepine, topiramate, oxcarbazepine, zonisamide, gabapentin, levetiracetam, pregabalin, clonazepam, lacosamide, rufinamide, and vigabatrin.

[0200] Packaging and Kits Pharmaceutical compositions (or formulations) for use can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has affixed thereto a label that describes the contents of the container. The label also includes appropriate warnings.

[0201] The compounds and pharmaceutical preparations described herein can be contained in a kit. The kit can include two or more drugs, each individually packaged or formulated, in single or multiple doses, or two or more drugs packaged or formulated in combination, in single or multiple doses. Thus, one or more drugs can be present in a first container, and the kit can optionally include one or more drugs in a second container. One or more containers can be placed in a package, and the package can optionally include administration or administration instructions. The kit can include additional components, such as a syringe or other means for administering the drug, as well as a diluent or other means for formulation. Thus, the kit can include: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle, or diluent; and b) a container or package. The kit can optionally include instructions describing how to use the pharmaceutical composition in one or more methods described herein (e.g., preventing or treating one or more of the diseases and disorders described herein). The kit may optionally include a second pharmaceutical composition containing one or more additional agents described herein for combination therapy, a pharmaceutically acceptable carrier, vehicle, or diluent. The pharmaceutical composition containing the compound described herein and the second pharmaceutical composition contained in the kit may optionally be combined in the same pharmaceutical formulation. [Example]

[0202] All references provided in examples are incorporated herein by reference.When used herein, all abbreviations, symbols and conventions are consistent with those used in modern scientific literature.See, for example, Janet S.Dodd (ed.), The ACS Style Guide: A Manual for Authors and Editors, 2nd edition, Washington, DC:American Chemical Society, 1997, which is incorporated herein by reference in its entirety.

[0203] Various embodiments of the present invention may be described below. Definitions of abbreviations used in the Examples section are provided in the table below.

[0204] [Table 5-1]

[0205] [Table 5-2]

[0206] Synthesis Section Example 1 Synthesis of Compounds of Tables I-IV The present invention also provides methods for synthesizing the compounds in Tables I-IV, which represent another aspect of the present invention. The compounds of the present invention can be prepared by the general and specific syntheses described herein, synthetic procedures reported in the chemical literature, or methods known to those of skill in the art. As will be understood by those of skill in the art, optimal reaction conditions can be determined empirically and may vary based on the type of reaction and the specific reagents used in the reaction. Thus, unless specifically stated, reaction conditions, such as pressure, temperature, relative ratios of reagents, solvents, and reaction times, can be readily selected and modified by those of skill in the art without undue experimentation. The compounds and intermediates of the present invention can be purified by purification methods known to those of skill in the art. These methods include, but are not limited to, silica gel chromatography, recrystallization, reverse-phase HPLC (RP-HPLC), and supercritical fluid chromatography (SFC). Purification by RP-HPLC can be achieved on a suitable reverse-phase column (e.g., Waters XBridge OBD C18, 5 μm, 19 × 150 mm) using a suitable gradient selected from a range of 0% to 100% acetonitrile in water containing an additive such as 0.1% TFA or formic acid. Diastereomers can be separated by silica gel chromatography, RP-HPLC, or chiral HPLC. Discrete enantiomers can be obtained from a mixture of enantiomers by resolution using chiral HPLC. Reaction progress can be monitored by methods known to those skilled in the art, such as thin-layer chromatography, reversed-phase HPLC, or tandem reversed-phase HPLC-mass spectrometry (LC-MS).

[0207] Starting materials used in the syntheses described herein are available from commercial sources or can be prepared by one of ordinary skill in the art using methods reported in the chemical literature or referenced herein.

[0208] The general methods described herein can be used to prepare the compounds of Tables I-IV. The general and specific methods described herein are provided as illustrations of the operability of the present invention. As such, they are not intended to impose any limitations on the subject matter and scope of the compounds claimed in the present invention.

[0209] All references provided in examples are incorporated herein by reference.When used herein, all abbreviations, symbols and conventions are consistent with those used in modern scientific literature.See, for example, GM Banik, G.Baysinger, PV Kamat, NJPienta (eds.), The ACS Guide to Scholarly Communication, Washington, DC: American Chemical Society, 2020 (https; / / pub.acs.org / doi / book / 10.1021 / acsguide), which is incorporated herein by reference in its entirety.

[0210] General Scheme 1:

[0211] [ka]

[0212] The compounds in Tables I-IV can be prepared using the general synthetic method described in Scheme 1. C , J C1 , J B , J D1 , and J. D2 Each of the following, or precursors, intermediates, or protected forms thereof, is defined above. Specific variations of each compound will be apparent to those skilled in the art and, in some cases, are shown below.

[0213] Synthesis of 2-(8-(2,4-difluorobenzyl)-3-mercaptoimidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-2):

[0214] [ka]

[0215] Compound I-2-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can be subjected to Negishi coupling in the presence of compound I-2-2 to give compound I-2-3. Compound I-2-3 can be further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-2-4. PMBSH can be added to compound I-2-4 in the presence of a strong base to give compound I-2-5. The nitrile of compound I-2-5 can be reacted with ammonium chloride to give compound I-2-6. The amidine of compound I-2-6 can be condensed with compound I-2-7 to give the cyclized compound I-2-8. Finally, the protected thiol of compound I-2-8 can be deprotected to give compound I-2.

[0216] Synthesis of 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-(2,4,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-2-carbonitrile (I-3):

[0217] [ka]

[0218] Compound I-3-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-3-2 to give compound I-3-3. Compound I-3-3 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-3-4. Compound I-3-4 was condensed with compound I-3-5 under heat to give cyclized compound I-3-6. The nitrile of compound I-3-6 was reacted with ammonium chloride to give compound I-3-7. The amidine of compound I-3-7 was condensed with compound I-3-8 to give cyclized compound I-3-9. The carboxylic acid of compound I-3-9 was converted to the corresponding amide, which was then dehydrated to give nitrile compound I-3.

[0219] Synthesis of I-3-3 A solution of Zn (6.54 g, 100.031 mmol, 1.50 equiv) in THF (300 mL) was treated with 1,2-dibromoethane (0.63 g, 3.333 mmol, 0.05 equiv) under a nitrogen atmosphere at 50 °C for 10 min, followed by the dropwise addition of TMSCl (0.43 mL, 3.364 mmol, 0.05 equiv) at 50 °C. 1-(Bromomethyl)-2,4,5-trifluorobenzene (I-3-1, 15 g, 66.664 mmol, 1.00 equiv) was then added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. To the above mixture was added 3,5-dibromopyrazin-2-amine (I-3-2, 13.49 g, 53.331 mmol, 0.8 equiv.) and Pd(PPh3)2Cl2 (0.94 g, 1.333 mmol, 0.02 equiv.) at room temperature. The resulting mixture was stirred at 45 °C for an additional 2 h, and the reaction was monitored by LCMS. The reaction was quenched with saturated aqueous NH4Cl (300 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 5-bromo-3-[(2,4,5-trifluorophenyl)methyl]pyrazin-2-amine (I-3-3, 13.9 g, 65.5% yield) as a yellow solid. LC-MS: (ESI) m / z 318.00 [M+H].

[0220] Synthesis of I-3-4 A solution of 5-bromo-3-[(2,4,5-trifluorophenyl)methyl]pyrazin-2-amine (I-3-3, 13.9 g, 43.697 mmol, 1 equiv.), Zn(CN) (5.13 g, 43.697 mmol, 1.00 equiv.), Zn (0.57 g, 8.739 mmol, 0.20 equiv.), and Pd(dppf)Cl (0.80 g, 1.093 mmol, 0.03 equiv.) in DMF (250 mL) was stirred at 120 °C for 2 h under a nitrogen atmosphere. The mixture was then cooled to room temperature. The reaction was quenched at room temperature by the addition of water (200 mL), and the resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 5-amino-6-[(2,4,5-trifluorophenyl)methyl]pyrazine-2-carbonitrile (I-3-4, 10 g, 86.6% yield) as a brown solid. LC-MS: (ESI) m / z 262.9 [M−H].

[0221] Synthesis of I-3-6 A solution of 5-amino-6-[(2,4,5-trifluorophenyl)methyl]pyrazine-2-carbonitrile (I-3-4, 10 g, 37.849 mmol, 1 equiv.) and ethyl 3-bromo-2-oxopropanoate (I-3-5, 8.86 g, 45.419 mmol, 1.20 equiv.) in EtOH (150 mL) was stirred at 80 °C overnight under a nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL), and the combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 100% gradient over 8 min; and UV detection at 254 nm to give ethyl 6-cyano-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxylate (I-3-6, 5.7 g, 42% yield) as a yellow solid. LC-MS: (ESI) m / z 361.1 [M+H].

[0222] Synthesis of I-3-7 A solution of 2-[ethoxy(hydroxy)methyl]-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-3-6, 5.7 g, 15.732 mmol, 1 equiv.) and NaOMe (0.28 g, 1.573 mmol, 0.1 equiv., 30 wt % in MeOH) in MeOH (120 mL) was stirred at 45 °C for 2 h under a nitrogen atmosphere. To the above mixture was added NHCl (1.68 g, 31.464 mmol, 2 equiv.) at 45 °C, and the resulting mixture was stirred at 45 °C for an additional 2 h. The reaction was quenched with water (50 mL) at room temperature. The aqueous layer was extracted with CHCl / IPA in a 3 / 1 ratio (3 × 150 mL). The combined organic extracts were then washed with brine (150 mL), dried over anhydrous NaSO, and concentrated in vacuo to give methyl 6-carbamimidoyl-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxylate (I-3-7, 5 g, crude) as a yellow solid. LC-MS: (ESI) m / z 364.1 [M+H].

[0223] Synthesis of I-3-9 To a stirred solution of methyl 6-carbamimidoyl-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxylate (I-3-7, 3.4 g, 9.359 mmol, 1 equiv.) and ethyl 2-fluoro-3-oxopropanoate (I-3-8, 2.51 g, 18.718 mmol, 2.00 equiv.) in MeOH (70 mL, 1728.918 mmol, 184.74 equiv.) under a nitrogen atmosphere, NaOMe (5.90 g, 32.757 mmol, 3.50 equiv., 30 wt. % in MeOH) was added dropwise at room temperature. The resulting mixture was stirred at 70 °C for an additional 4 h. The mixture was then cooled to room temperature and acidified to pH 4 with 2 M HCl (10 mL). The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 × 120 mL). The combined organic layers were washed with brine (2 × 120 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to afford 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxylic acid (I-3-9, 600 mg, 15.3% yield) as a yellow solid. LC-MS: MS(ESI) m / z 420.1 [M+H].

[0224] Synthesis of I-3 To a stirred solution of 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxylic acid (I-3-9, 600 mg, 1.431 mmol, 1 equiv.) and HATU (816 mg, 2.146 mmol, 1.50 equiv.) in DMF (14 mL) was added dropwise TEA (434 mg, 4.289 mmol, 3.00 equiv.) and NH(g) (0.95 mL, 1.240 mmol, 4 equiv., 1.3 M in THF) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for an additional 4 h at room temperature. The resulting mixture was then extracted with EtOAc (3 × 60 mL), and the combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol per 1 L of NH4HCO3), 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxamide (amide intermediate, 200 mg, 33.5% yield) as a yellow solid. LC-MS: (ESI) m / z 419.15 [M+H].

[0225] A solution of 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxamide (amide intermediate, 100 mg, 0.239 mmol, 1 equiv.) produced above in phosphorus oxychloride (2 mL) was stirred at 90° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with 1,4-dioxane (5 mL) and then concentrated under reduced pressure. To the above mixture was added NaOH (2.5 mL, 2 mmol) and dioxane (2 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was then extracted with EtOAc (3×20 mL), and the combined organic layers were washed with brine (2×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 100% gradient in 10 min; and detector UV at 254 nm to give 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carbonitrile (I-3, 4.8 mg, 4% yield, purity 80.4%) as an off-white solid.

[0226] LC-MS: (ESI) m / z 410.10 [M+H]. 1 H NMR: (400 MHz, methanol-d4) δ 9.39 (s, 1H), 8.78 (s, 1H), 8.09 (d, J = 3.5 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.18 (td, J = 10.0, 6.7 Hz, 1H), 4.65 (s, 2H). 19 F NMR:(400 MHz, methanol-d4) δ -119.26 (dd, J = 15.3, 3.7 Hz), -137.90 (d, J = 18.6 Hz), -145.38 (dd, J = 21.2, 15.3 Hz), -153.03. Synthesis of 2-fluoro-4-((3-fluoro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl)methyl)-5-methylbenzonitrile (I-4) and 2-fluoro-4-((6-(5-fluoro-4-hydroxypyrimidin-2-yl)-3-methoxyimidazo[1,2-a]pyrazin-8-yl)methyl)-5-methylbenzonitrile (I-32):

[0227] [ka]

[0228] Compound I-4-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-4-2 to give compound I-4-3. Compound I-4-3 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-4-4. The nitrile of compound I-4-4 was reacted with ammonium chloride to give amidine compound I-4-5. The amidine of compound I-4-5 was condensed with compound I-4-6 in NaOMe / MeOH to give cyclized compound I-4-7 and compound I-32-1. Both cyclized products were carried forward. The aryl bromides of compounds I-4-7 and I-32-1 were reacted in the presence of zinc, zinc cyanide, and Pd2(dba)3, and diphenylphosphinoferrocene to give the cyano compounds I-4 and I-32, respectively.

[0229] Synthesis of I-4-1 To a stirred solution of 4-bromo-5-fluoro-2-methylbenzoic acid (4.7 g, 20.169 mmol, 1 equiv.) in THF (50 mL) at 0 °C, BH3-THF (30.25 mL, 30.254 mmol, 1.5 equiv., 1 M in THF) was added dropwise. The mixture was stirred at 50 °C for 3 h. The reaction was quenched at room temperature by the addition of water (100 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give (4-bromo-5-fluoro-2-methylphenyl)methanol (4.5 g, crude) as an off-white solid. 1 H NMR: (400 MHz, CDCl3) δ 7.32 (d, J = 6.8 Hz, 1H), 7.19 (d, J = 9.4 Hz, 1H), 4.62 (s, 2H), 2.24 (s, 3H). To a stirred solution of the above-produced (4-bromo-5-fluoro-2-methylphenyl)methanol (1.5 g, 6.848 mmol, 1 equiv.) in diethyl ether (20 mL) was added phosphorus tribromide (0.93 g, 3.424 mmol, 0.5 equiv.) at 0 °C. The mixture was stirred at 25 °C for 4 h. The reaction was quenched at room temperature by the addition of water (50 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford 1-bromo-4-(bromomethyl)-2-fluoro-5-methylbenzene (I-4-1, 2.1 g, crude) as an off-white solid, which was used directly in the next step without further purification.

[0230] Synthesis of I-4-2 To a stirred solution of 6,8-dibromoimidazo[1,2-a]pyrazine (5 g, 18.056 mmol, 1 equiv.) in acetonitrile (50 mL) was added Selectfluor® (9.59 g, 27.084 mmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 60 °C for 10 h. The reaction was quenched at room temperature by the addition of water (200 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 6,8-dibromo-3-fluoroimidazo[1,2-a]pyrazine (I-4-2, 1.5 g, 28% yield) as a pale yellow solid. LC-MS: (ESI) m / z 295.9 [M+H]. 1 H NMR: (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.58 (d, J = 6.8 Hz, 1H). Synthesis of I-4-3 To a stirred solution of Zn (221.7 mg, 3.390 mmol, 2 equiv.) in anhydrous THF (5 mL) was added dibromoethane (31.8 mg, 0.170 mmol, 0.1 equiv.) dropwise at 25° C. under a nitrogen atmosphere. The mixture was stirred at 50° C. for 10 minutes under a nitrogen atmosphere. TMSCl (18.42 mg, 0.170 mmol, 0.1 equiv.) was then added, and the mixture was cooled to ambient temperature. 1-Bromo-4-(bromomethyl)-2-fluoro-5-methylbenzene (I-4-1, 717.0 mg, 2.542 mmol, 1.5 equiv.) was then added dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. Then, 6,8-dibromo-3-fluoroimidazo[1,2-a]pyrazine (I-4-2, 500 mg, 1.695 mmol, 1 equiv.) and Pd(PPh3)2Cl2 (23.8 mg, 0.034 mmol, 0.02 equiv.) were added at 25 °C while still under a nitrogen atmosphere. The mixture was stirred at 50 °C for 4 h under a nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 6-bromo-8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine (I-4-3, 600 mg, 85% yield) as a pale yellow solid. LC-MS: (ESI) m / z 417.9 [M+H]. 1 H NMR: (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.33 (d, J = 7.1 Hz, 1H), 7.14 (d, J = 9.5 Hz, 1H), 4.44 (s, 2H), 2.45 (s, 3H). Synthesis of I-4-4 To a stirred solution of 6-bromo-8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine (I-4-3, 600 mg, 1.439 mmol, 1 equiv.) in anhydrous DMF (5 mL) was added zinc cyanide (101.3 mg, 0.863 mmol, 0.6 equiv.), Zn (18.8 mg, 0.288 mmol, 0.2 equiv.), and Pd(dppf)Cl (26.3 mg, 0.036 mmol, 0.025 equiv.) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. The reaction was then quenched at room temperature by the addition of water (100 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4, 365 mg, 70% yield) as an off-white solid. LC-MS: (ESI) m / z 363.0 [M+H]. 1 H NMR: (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.35 (d, J = 7.0 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 4.47 (s, 2H), 2.44 (s, 3H). Synthesis of I-4-5 To a stirred solution of 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4, 365 mg, 1.005 mmol, 1 equiv.) in MeOH (5 mL) at 25 °C was added NaOMe (18.1 mg, 0.100 mmol, 0.1 equiv., 30 wt % in MeOH). The mixture was stirred at 70 °C for 4 h, at which point NHCl (107.5 mg, 2.010 mmol, 2 equiv.) was added and the mixture was stirred at 70 °C for an additional 4 h. The reaction was quenched by the addition of water (10 mL) at room temperature, and the resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carboximidamide (I-4-5, 392 mg, crude) as a brown solid. LC-MS: (ESI) m / z 380.0 [M+H].

[0231] Synthesis of I-4-6 To a stirred solution of NaH (0.23 g, 9.425 mmol, 1 equiv) in EtO (50 mL) was added EtOH (0.05 mL, 0.943 mmol, 0.1 equiv) at 0 °C. The mixture was stirred at 0 °C for 10 min. Ethyl 2-fluoroacetate (1 g, 9.425 mmol, 1 equiv) and ethyl formate (0.70 g, 9.425 mmol, 1 equiv) were added at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight, after which the filtrate was concentrated under reduced pressure to give ethyl 2-fluoro-3-oxo-2-sodiopropanoate (I-4-6, 1.5 g, crude) as a pale yellow solid, which was used directly in the next step.

[0232] Synthesis of I-4-7 To a stirred solution of 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carboximidamide (I-4-5, 390 mg, 1.026 mmol, 1 equiv.) in MeOH (5 mL) at 25 °C, ethyl 2-fluoro-3-oxo-2-sodiopropanoate (I-4-6, 275.1 mg, 2.052 mmol, 2 equiv.) and NaOMe (369.4 mg, 2.052 mmol, 2 equiv., 30% in MeOH) were added. The mixture was stirred at 70 °C for 8 h. The reaction was quenched at room temperature by the addition of water (50 mL) and then acidified to pH 3–4 with concentrated HCl (10 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to give 2-{8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-4-7, 280 mg, 60.5% yield) as a brown solid.

[0233] LC-MS: (ESI) m / z 449.95 [M+H]. Synthesis of I-4 To a stirred solution of 2-{8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-4-7, 265 mg, 0.589 mmol, 1 equiv.) in anhydrous DMF (5 mL) was added Zn(CN) (138.2 mg, 1.178 mmol, 2 equiv.), Zn (7.7 mg, 0.118 mmol, 0.2 equiv.), and Pd(dppf)Cl (43.0 mg, 0.059 mmol, 0.1 equiv.) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The reaction was quenched with water (3 mL) at room temperature, and the resulting mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol per L of NH4HCO3), 5% to 80% gradient over 15 min; and detector, UV 254 / 220 nm, to give 2-fluoro-4-{[3-fluoro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}-5-methylbenzonitrile (I-4, 45.4 mg, 91% purity, 18% yield) as an off-white solid.

[0234] LC-MS: (ESI) m / z 397.05 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.99 (s, 1H), 8.20 (d, J = 3.6 Hz, 1H), 7.75 (d, J = 6.9 Hz, 2H), 7.63 (d, J = 10.6 Hz, 1H), 4.57 (s, 2H), 2.50 (s, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ-113.32, -150.46, -152.09. Compound I-32 can also be isolated by the above scheme as an impurity derived from I-32-1, formed in steps towards the synthesis of I-4-7, or made by a different route described below.

[0235] Synthesis of 2-fluoro-4-((6-(5-fluoro-4-hydroxypyrimidin-2-yl)-3-methoxyimidazo[1,2-a]pyrazin-8-yl)methyl)-5-methylbenzonitrile (I-32):

[0236] [ka]

[0237] Compound I-32 can be prepared by the following method summarized in the scheme above. Compound I-4-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-4-2-1 to give compound I-4-3-1. Compound I-4-3-1 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-4-4-1. Compound I-4-4-1 was fluorinated using Selectfluor™ to give compound I-4-4. The nitrile of compound I-4-4 was reacted with ammonium chloride in the presence of sodium methoxide in methanol to give amidine compound I-4-5-1. The amidine of compound I-4-5-1 was condensed with compound I-4-6 in NaOMe / MeOH to give the cyclized compound I-32-1. The aryl bromide of compound I-32-1 was reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give the cyano compound I-32.

[0238] Synthesis of I-4-3-1 To a stirred solution of Zn (1.19 g, 18.128 mmol, 2 equiv.) in anhydrous THF (40 mL) was added dibromoethane (DBE, 0.17 g, 0.906 mmol, 0.1 equiv.) at 25° C. under a nitrogen atmosphere. The mixture was stirred at 50° C. for 10 minutes under a nitrogen atmosphere. TMSCl (0.10 g, 0.906 mmol, 0.1 equiv.) was added, and the mixture was cooled to ambient temperature. 1-Bromo-4-(bromomethyl)-2-fluoro-5-methylbenzene (I-4-1, 3.83 g, 13.596 mmol, 1.5 equiv.) was then added dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. Then, 6,8-dibromoimidazo[1,2-a]pyrazine (I-4-2-1, 2.51 g, 9.064 mmol, 1 equiv.) and Pd(PPh3)2Cl2 (0.13 g, 0.181 mmol, 0.02 equiv.) were added at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 4 h under a nitrogen atmosphere. The reaction was then quenched by the addition of water (100 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 6-bromo-8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]imidazo[1,2-a]pyrazine (I-4-3-1, 3.46 g, 96% yield) as an off-white solid. LC-MS: (ESI) m / z 399.9 [M+H].

[0239] Synthesis of I-4-4-1 To a stirred solution of 6-bromo-8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]imidazo[1,2-a]pyrazine (I-4-3-1, 3.46 g, 8.670 mmol, 1 equiv.) in anhydrous DMF (30 mL) was added zinc cyanide (0.51 g, 4.335 mmol, 0.5 equiv.), Zn (0.11 g, 1.734 mmol, 0.2 equiv.), and Pd(dppf)Cl (0.13 g, 0.173 mmol, 0.02 equiv.). The mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. The reaction was quenched at room temperature by the addition of water (200 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4-1, 2.2 g, 73.5% yield) as a pale yellow solid. LC-MS: (ESI) m / z 345.0 [M+H].

[0240] Synthesis of I-4-4 To a stirred solution of 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4-1, 2.2 g, 6.374 mmol, 1 equiv.) in THF (10 mL) and MeCN (20 mL) was added Selectfluor® (4.52 g, 12.748 mmol, 2 equiv.) and NaHCO (1.34 g, 15.935 mmol, 2.5 equiv.) at 25° C. under a nitrogen atmosphere. The mixture was stirred at 80° C. for 12 hours under a nitrogen atmosphere. The reaction was quenched at room temperature by the addition of water (100 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4, 1.3 g, 56% yield) as an off-white solid. LC-MS: MS(ESI) m / z 363.0 [M+H].

[0241] Synthesis of I-4-5-1 To a stirred solution of 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4, 980 mg, 2.698 mmol, 1 equiv.) in MeOH (5 mL) was added NaOMe (48.5 mg, 0.270 mmol, 0.1 equiv., 30 wt % in MeOH) at 25 °C. The mixture was stirred at 70 °C for 3 h. MeONa (437.3 mg, 8.094 mmol, 3 equiv.) was then added, and the mixture was stirred at 70 °C for an additional 4 h. NHCl (288.6 mg, 5.396 mmol, 2 equiv.) was then added, and the mixture was stirred at 70 °C for an additional 5 h. The reaction was quenched at room temperature by the addition of saturated NaHCO3 (aq) (20 mL), and the resulting mixture was extracted with IPA / DCM = 1:3 (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazine-6-carboximidamide (I-4-5-1, 1.1 g, crude) as a brown solid. LC-MS (ESI) m / z 392.0 [M+H].

[0242] Synthesis of I-32-1 To a stirred solution of 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazine-6-carboximidamide (I-4-5-1, 1.1 g, 2.804 mmol, 1 equiv.) in MeOH (6 mL) was added ethyl 2-fluoro-3-oxopropanoate (I-4-6, 940.2 mg, 7.010 mmol, 2.5 equiv.) and NaOMe (1.51 g, 8.412 mmol, 3 equiv., 30 wt % in MeOH) at 25 °C. The mixture was stirred at 70 °C for 8 h. The reaction was then quenched at room temperature by the addition of 1 M HCl (aq.) (10 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to give 2-{8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-32-1, 402 mg, 31% yield) as an off-white solid. LC-MS (ESI) m / z 462.0 [M+H].

[0243] Synthesis of I-32 To a stirred solution of 2-{8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-32-1, 200 mg, 0.433 mmol, 1 equiv.) in anhydrous DMF (3 mL) was added Zn(CN) (101.6 mg, 0.866 mmol, 2 equiv.), Pd(dppf)Cl (6.3 mg, 0.009 mmol, 0.02 equiv.), and Zn (5.6 mg, 0.087 mmol, 0.2 equiv.) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The mixture was then cooled to room temperature. The resulting mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 5% to 80% gradient over 10 min; and detector, UV 254 / 220 nm, to afford 2-fluoro-4-{[6-(5-fluoro-4-hydroxypyrimidin-2-yl)-3-methoxyimidazo[1,2-a]pyrazin-8-yl]methyl}-5-methylbenzonitrile (I-32, 40.1 mg, 22% yield) as an off-white solid. LC-MS (ESI) m / z 409.10 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.08 (d, J = 3.8 Hz, 1H), 7.58 (d, J = 10.6 Hz, 1H), 7.46 (s, 1H), 4.52 (s, 2H), 4.12 (s, 3H), 2.50 (s, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ-113.38, -153.49. Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoro-6-(fluoromethyl)pyrimidin-4-ol (I-5) and 2-(8-(2,5-difluoro-4-methylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6-(ethoxymethyl)-5-fluoropyrimidin-4-ol (I-44):

[0244] [ka]

[0245] Compound I-5-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-5-2 to give compound I-5-3. Compound I-5-3 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-5-4. The nitrile of compound I-5-4 was reacted with ammonium chloride to give amidine compound I-5-5. The amidine of compound I-5-5 was condensed with compound I-5-6 to give cyclized compound I-5 and compound I-44.

[0246] Synthesis of I-5-6 To a stirred solution of ethyl 2-fluoroacetate (500 mg, 4.713 mmol, 1 equiv.) in EtO (10 mL) was added NaH (282.7 mg, 11.783 mmol, 2.5 equiv., 60% mineral oil) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40 °C for 4 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The reaction was then quenched at 0 °C by the addition of water / ice (40 mL) and concentrated HSO (1 mL). The resulting mixture was extracted with EtO (3 × 20 mL), and the combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the crude product ethyl 2,4-difluoro-3-oxobutanoate (I-5-6, 600 mg, crude) as a pale yellow oil. Synthesis of I-5-1 To a stirred solution of 2,5-difluoro-4-methylbenzoic acid (500 mg, 2.905 mmol, 1 equiv.) in THF (2.5 mL) under a nitrogen atmosphere at 0 °C, BH3-THF (499.2 mg, 5.810 mmol, 2 equiv., 1 M in THF) was added dropwise. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The reaction was quenched by the addition of brine (10 mL) at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give (2,5-difluoro-4-methylphenyl)methanol (380 mg, 83% yield) as an off-white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 7.20 - 7.07 (m, 2H), 5.32 (t, J = 5.7 Hz, 1H), 4.49 (d, J = 5.7 Hz, 2H), 2.21 (s, J = 2.0 Hz, 3H). To a stirred solution of (2,5-difluoro-4-methylphenyl)methanol (380 mg, 2.403 mmol, 1 equiv.) produced above in EtO (5 mL) was added phosphorus tribromide (260.2 mg, 0.961 mmol, 0.4 equiv.) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched at room temperature by the addition of water / ice (20 mL). The organic layer was washed with saturated NaHCO (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 1-(bromomethyl)-2,5-difluoro-4-methylbenzene (I-5-1, 350 mg, crude) as a pale yellow oil. 1 H NMR: (400 MHz, DMSO-d6) δ 7.45 - 7.34 (m, 1H), 7.22 (dd, J = 10.2, 6.3 Hz, 1H), 4.65 (s, J = 1.1 Hz, 2H), 2.23 (s, J = 2.1 Hz, 3H). Synthesis of I-5-3 To a stirred mixture of Zn (155.3 mg, 2.374 mmol, 1.5 equiv) in THF (5 mL) was added dropwise dibromoethane (14.9 mg, 0.079 mmol, 0.05 equiv) under a nitrogen atmosphere at 50° C. The resulting mixture was stirred at 50° C. for 10 minutes under a nitrogen atmosphere. To the above mixture was then added TMSCl (8.6 mg, 0.079 mmol, 0.05 equiv), and the resulting mixture was stirred at room temperature for an additional 10 minutes. To this mixture was added 1-(bromomethyl)-2,5-difluoro-4-methylbenzene (I-5-1, 350 mg, 1.583 mmol, 1 equiv) at 0° C. The resulting mixture was then stirred at 0° C. for an additional 15 minutes, then at room temperature for 2 hours. To this mixture was then added 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (I-5-2, 352.0 mg, 1.266 mmol, 0.8 equiv.) and Pd(PPh3)2Cl2 (33.3 mg, 0.047 mmol, 0.03 equiv.) at room temperature. The resulting mixture was stirred at 40 °C for an additional 1 h and then filtered. The filter cake was washed with THF (1 × 4 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 6-bromo-8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazine (I-5-3, 240 mg, 45% yield) as a pale yellow solid. LC-MS: (ESI) m / z 338.85 [M+H].

[0247] Synthesis of I-5-4 To a stirred mixture of 6-bromo-8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazine (I-5-3, 240 mg, 0.708 mmol, 1 equiv.) and Zn(CN) (49.9 mg, 0.425 mmol, 0.6 equiv.) in DMF (4 mL) was added Pd(dppf)Cl (13.0 mg, 0.018 mmol, 0.025 equiv.) and Zn (9.3 mg, 0.142 mmol, 0.2 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The resulting mixture was filtered, and the filtrate was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and detector, UV 254 nm, to give 8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile (136 mg, 67% yield) as a pale yellow solid. LC-MS (ESI) m / z 286.10 [M+H].

[0248] Synthesis of I-5-5 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile (I-5-4, 136 mg, 0.477 mmol, 1 equiv.) in methanol (2 mL) was added NaOMe (2.6 mg, 0.048 mmol, 0.1 equiv., 30 wt % in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40° C. for 3 hours under a nitrogen atmosphere. Then, to the above mixture was added NHCl (51.0 mg, 0.954 mmol, 2 equiv.) at room temperature, and the resulting mixture was stirred at 40° C. overnight. The mixture was cooled to room temperature. The reaction was quenched at room temperature by the addition of saturated NaHCO (aq) (5 mL). The resulting mixture was diluted with water (20 mL) and extracted with CHCl / IPA (3 / 1) (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide (I-5-5, 130 mg, crude) as a pale yellow solid. LC-MS: (ESI) m / z 303.20 [M+H].

[0249] Synthesis of compounds I-5 and I-44 To a stirred mixture of 8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide (I-5-5, 130 mg, 0.430 mmol, 1 equiv.) and ethyl 2,4-difluoro-3-oxobutanoate (I-5-6, 107.2 mg, 0.645 mmol, 1.5 equiv.) in MeOH (2 mL) was added NaOMe (232.3 mg, 1.290 mmol, 3 equiv., 30 wt% in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 1.5 hours under a nitrogen atmosphere. The reaction was then quenched at room temperature by the addition of water (1 mL), and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and detector, UV 254 nm to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazin-6-yl}-5-fluoropropanediol. Fluoro-6-(fluoromethyl)pyrimidin-4-ol (I-5, 44.0 mg, 25% yield) as an off-white solid and 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrazin-6-yl}-6-(ethoxymethyl)-5-fluoropyrimidin-4-ol (I-44, 30.0 mg, 16% yield) as an off-white solid.

[0250] I-5=LC-MS:(ESI)m / z405.15[M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.82 (s, 1H), 7.34 (dd, J = 9.9, 6.4 Hz, 1H), 7.16 (dd, J = 9.9, 6.5 Hz, 1H), 5.44 (dd, J = 46.9, 2.7 Hz, 2H), 4.57 (s, 2H), 2.18 (s, J = 1.8 Hz, 3H). 19F NMR:(376 MHz, DMSO-d6) δ -123.09 (d, J = 18.1 Hz), -123.21 (d, J = 18.3 Hz), -150.51, -220.47 (d, J = 6.6 Hz). I-44=LC-MS:(ESI)m / z431.20[M+H]. 1 H NMR:(400 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.54 (s, 1H), 8.84 (s, 1H), 7.36 (dd, J = 9.9, 6.4 Hz, 1H), 7.17 (dd, J = 9.8, 6.6 Hz, 1H), 4.57 (s, 4H), 4.48 (d, J = 3.0 Hz, 2H), 2.18 (s, J = 1.9 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ -123.10 (d, J = 18.1 Hz), -123.21 (d, J = 18.3 Hz), -151.04. Synthesis of 2-(8-(4-chloro-2,5-difluorobenzyl)-3-methylimidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidine-4,6-diol (I-6) and 2,5-difluoro-4-((6-(5-fluoro-4,6-dihydroxypyrimidin-2-yl)-3-methylimidazo[1,2-a]pyrazin-8-yl)methyl)benzonitrile (I-42):

[0251] [ka]

[0252] Compound I-6-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. Compound I-6-2 can be synthesized by cyclizing compound I-6-2-1 with 2-bromo-1,1-diethoxypropane. The organozinc compound can undergo Negishi coupling in the presence of compound I-6-2 to give compound I-6-3. Compound I-6-3 can be further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-6-4. The nitrile of compound I-6-4 can be reacted with ammonium chloride to give amidine compound I-6-5. The amidine of compound I-6-5 can be condensed with compound I-6-6 to give cyclized compound I-6. The aryl chloride of I-6 can be reacted in the presence of zinc, zinc cyanide, and Pd2(dba)3, and diphenylphosphinoferrocene to give the cyano compound I-42, respectively.

[0253] Synthesis of I-6-1 To a stirred solution of 4-chloro-2,5-difluorobenzoic acid (2 g, 10.387 mmol, 1.0 equiv.) in anhydrous THF (30 mL) at 0 °C, LiAlH (867.2 mg, 22.851 mmol, 2.2 equiv.) was added portionwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched by the addition of water (20 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1), to afford (4-chloro-2,5-difluorophenyl)methanol (1.7 g, 92% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.34-7.22 (m, 1H), 7.12 (dd, J = 9.0, 5.9 Hz, 1H), 4.71 (s, 2H). To a stirred solution of (4-chloro-2,5-difluorophenyl)methanol (1.7 g, 9.55 mmol, 1.0 equiv.) produced as shown above in anhydrous EtO (25 mL) was added PBr (1.28 g, 4.77 mmol, 0.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of water (20 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to afford 1-(bromomethyl)-4-chloro-2,5-difluorobenzene (I-6-1, 2.28 g, crude) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.23-7.13 (m, 2H), 4.43 (s, 2H). Synthesis of I-6-2 To a stirred solution of 3,5-dibromopyrazin-2-amine (I-6-2-1, 1 g, 3.954 mmol, 1 equiv.) in anhydrous i-PrOH (15 mL) at room temperature was added 2-bromo-1,1-diethoxypropane (1.25 g, 5.931 mmol, 1.5 equiv.). The resulting mixture was stirred at 85 °C overnight. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with water (3 × 10 mL) to give 6,8-dibromo-3-methylimidazo[1,2-a]pyrazine (I-6-2, 700 mg, crude) as a white solid. This crude material was used in the next step without further purification. LC-MS: MS (ESI) m / z 291.9 [M+H].

[0254] Synthesis of I-6-3 To a stirred solution of Zn (211.2 mg, 3.23 mmol, 2.0 equiv) in anhydrous THF (4 mL) was added 1,2-dibromoethane (12.1 mg, 0.065 mmol, 0.04 equiv) at 50° C. The resulting mixture was stirred at 50° C. for 10 minutes. Then, to the above mixture was added TMSCl (8.7 mg, 0.081 mmol, 0.05 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional 10 minutes and then cooled to 0° C., at which point 1-(bromomethyl)-4-chloro-2,5-difluorobenzene (I-6-1, 585.1 mg, 2.422 mmol, 1.5 equiv) was added, and the resulting mixture was stirred at room temperature for 2 hours. A solution of 6,8-dibromo-3-methylimidazo[1,2-a]pyrazine (I-6-2, 470 mg, 1.615 mmol, 1 equiv.) and Pd(PPh3)2Cl2 (45.4 mg, 0.065 mmol, 0.04 equiv.) in THF (2 mL) was added to the above mixture, and the resulting mixture was stirred at 45 °C for 2 h. The mixture was cooled to room temperature and then diluted with water (5 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give 6-bromo-8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine (I-6-3, 380 mg, 63% yield) as a yellow solid. LC-MS (ESI) m / z 374.0 [M+H].

[0255] Synthesis of I-6-4 To a stirred solution of 6-bromo-8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine (I-6-3, 370 mg, 0.993 mmol, 1.0 equiv.) in anhydrous DMF (5 mL) was added Zn(CN) (58.3 mg, 0.496 mmol, 0.5 equiv.) and Pd(dppf)Cl (20.1 mg, 0.025 mmol, 0.025 equiv.) at room temperature. The resulting mixture was stirred at 120 °C for 2 h. The mixture was then cooled to room temperature and quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give 8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carbonitrile (I-6-4, 260 mg, 82% yield) as a white solid. LC-MS: (ESI) m / z 319.10 [M+H].

[0256] Synthesis of I-6-5 To a stirred solution of 8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carbonitrile (I-6-4, 235 mg, 0.737 mmol, 1.0 equiv) in anhydrous methanol (5 mL) was added NaOMe (2.8 mg, 0.016 mmol, 0.10 equiv, 30 wt% in MeOH) at room temperature, and the resulting mixture was stirred at 45 °C for 2 h. NHCl (78.9 mg, 1.474 mmol, 2.0 equiv) was then added, and the mixture was stirred at 45 °C for an additional 2 h. The reaction was quenched by the addition of water (5 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The combined organic layers were dried under vacuum to give (8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carboximidamide (I-6-5, 240 mg, crude) as a brown solid. LC-MS: (ESI) m / z 335.9 [M+H].

[0257] Synthesis of compound I-6 To a stirred solution of 8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carboximidamide (I-6-5, 230 mg, 0.685 mmol, 1 equiv) in anhydrous MeOH (5 mL) was added 1,3-dimethyl 2-fluoropropanedioate (I-6-6, 154.3 mg, 1.028 mmol, 1.5 equiv) and NaOMe (431.8 mg, 2.397 mmol, 3.5 equiv, 30 wt % in MeOH) at room temperature, and the resulting mixture was stirred at 70 °C for 2 h and then cooled to room temperature. The crude product was precipitated by adding 1M HCl (5 mL) and purified by trituration with DMSO (5 mL) to obtain 2-{8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidine-4,6-diol (compound I-6, 64.4 mg, 21% yield) as a white solid. LC-MS: (ESI) m / z 422.05 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 12.25 (s, 2H), 8.90 (s, 1H), 7.72 (s, 1H), 7.72-7.68 (dd, J= 9.0, 5.8 Hz, 1 H), 7.62 (dd, J= 9.1, 6.2 Hz, 1H), 4.54 (s, 2H), 2.56 (s, 3H). 19 F NMR-PH-CYCN-CYC-006-0: (376 MHz, DMSO-d6) δ -119.20 (d, J= 15.9 Hz), -122.01 (d, J= 15.8 Hz), -177.59. Compound I-6 can be reacted in the presence of zinc, zinc cyanide, and Pd2(dba)3 and diphenylphosphinoferrocene to give the cyano compound I-42.

[0258] Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-methoxyimidazo[1,2-a]pyrazin-6-yl)-5-methylpyrimidin-4-ol (I-7) and compound I-46:

[0259] [ka]

[0260] Compound I-7-4 was prepared via a method similar to that for compound I-4-4. The nitrile of compound I-7-4 was reacted with ammonium chloride in NaOMe / MeOH to give compounds I-7-5 and I-46-5. The amidines of compounds I-7-5 and I-46-5 were condensed with compound I-7-6 to give cyclized compounds I-29 and I-46-7. Compound I-29 and compound I-46-7 were reacted with 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane in the presence of palladium to give compounds I-7 and I-46.

[0261] Synthesis of compound I-7 To a stirred mixture of 5-chloro-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazin-6-yl}pyrimidin-4-ol (I-29, 200 mg, 0.479 mmol, 1 equiv.) and trimethyl-1,3,5,2,4,6-trioxatriborinane (120.2 mg, 0.958 mmol, 2 equiv.) in dioxane (4 mL) was added SPhos (19.7 mg, 0.048 mmol, 0.1 equiv.), SPhos palladacycle 3rd generation (37.35 mg, 0.048 mmol, 0.1 equiv.), and KCO (132.3 mg, 0.958 mmol, 2 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere overnight and then cooled to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and detector: UV 254 nm to afford 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazin-6-yl}-5-methylpyrimidin-4-ol (I-7, 17.4 mg, 9% yield) as an off-white solid. LC-MS (ESI): m / z 398.15 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ11.85 (s, 1H), 8.71 (s, 1H), 7.94 (s, 2H), 7.48 (s, 1H), 7.34 (s, 1H), 7.14 (t, J = 8.4 Hz, 2H), 4.47 (s, 2H), 4.13 (s, 4H), 2.18 (s, 5H), 1.98 (s, 4H). 19 FNMR:(376 MHz, DMSO-d6) δ -123.12 (dd, J = 26.2, 18.8 Hz), -129.25. Synthesis of 1-(8-(2,5-difluorobenzyl)-6-(5-fluoro-4-hydroxy-6-methylpyrimidin-2-yl)imidazo[1,2-a]pyrazin-3-yl)ethan-1-one (I-8) and 2-(8-(2,5-difluorobenzyl)-3-(1-hydroxyethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoro-6-methylpyrimidin-4-ol (I-31):

[0262] [ka]

[0263] Compound I-8-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-8-2 to give compound I-8-3. Compound I-8-3 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-8-4. The nitrile of compound I-8-4 was reacted with ammonium chloride to give amidine compound I-8-5. The amidine of compound I-8-5 was condensed with compound I-8-6 to give cyclized compound I-8-7. Compound I-8-7 was reacted with N-bromosuccinimide to give the brominated product, compound I-8-8. Compound I-8-8 was subjected to a Stille reaction with stannous ethoxyvinyl to give compound I-8-9. Compound I-8-9 was hydrolyzed to compound I-8 using hydrochloric acid, and compound I-8 was reduced to compound I-31 in the presence of sodium borohydride.

[0264] Synthesis of I-8-3 To a stirred solution of Zn (0.95 g, 14.491 mmol, 1.5 equiv) in anhydrous THF (20 mL) was added dibromoethane (90.7 mg, 0.483 mmol, 0.05 equiv) at 25° C. under a nitrogen atmosphere. The mixture was stirred at 50° C. for 10 minutes under a nitrogen atmosphere. TMSCl (52.4 mg, 0.483 mmol, 0.05 equiv) was added, and the mixture was cooled to ambient temperature. Then, 2-(bromomethyl)-1,4-difluorobenzene (I-8-1, 2 g, 9.661 mmol, 1 equiv) was added dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. Then, 6,8-dibromoimidazo[1,2-a]pyrazine (I-8-2, 1.87 g, 6.763 mmol, 0.7 equiv) and Pd(PPh)Cl (135.6 mg, 0.193 mmol, 0.02 equiv) were added at 25 °C under a nitrogen atmosphere. The mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The reaction was then quenched by the addition of water (50 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 6-bromo-8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine (I-8-3, 1.82 g, 58% yield) as an off-white solid. LC-MS: (ESI) m / z 323.9 [M+H]. 1 H NMR: (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.79 (d, J = 0.9 Hz, 1H), 7.67 (d, J = 0.9 Hz, 1H), 7.10 - 7.04 (m, 1H), 7.00 (h, J = 8.9, 4.5 Hz, 1H), 6.92 - 6.81 (m, 1H), 4.58 (s, 2H). Synthesis of I-8-4 To a stirred solution of 6-bromo-8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine (I-8-3, 2 g, 6.170 mmol, 1 equiv.) in anhydrous DMF (40 mL) was added Zn (80.6 mg, 1.234 mmol, 0.2 equiv.), Zn(CN) (434.7 mg, 3.702 mmol, 0.6 equiv.), and Pd(dppf)Cl (112.8 mg, 0.154 mmol, 0.025 equiv.) under a nitrogen atmosphere at 25 °C, and the resulting mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. The reaction was quenched by the addition of water (200 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give 8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-8-4, 1.72 g, crude) as a pale yellow solid. This crude was used in the next step without further purification. LC-MS: (ESI) m / z 271.0 [M+H].

[0265] Synthesis of I-8-5 To a stirred solution of 8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-8-4, 1.7 g, 6.291 mmol, 1 equiv.) in MeOH (20 mL) was added NaOMe (0.11 g, 0.629 mmol, 0.1 equiv., 30 wt % in MeOH) at 25 °C. The mixture was stirred at 50 °C for 4 h, after which NHCl (0.67 g, 12.582 mmol, 2 equiv.) was added. The resulting mixture was stirred at 50 °C for 4 h. The reaction was then quenched by the addition of saturated NaHCO (aq.) (100 mL) at room temperature, and the resulting mixture was extracted with IPA / DCM = 1:3 (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-8-5, 1.34 g, 74% yield) as a brown oil, which was used in the next step without further purification. LC-MS: (ESI) m / z 288.1 [M+H].

[0266] Synthesis of I-8-7 To a stirred solution of 8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-8-5, 1.3 g, 4.525 mmol, 1 equiv.) in MeOH (20 mL) at 25 °C, ethyl 2-fluoro-3-oxobutanoate (I-8-6, 1.01 g, 6.788 mmol, 1.5 equiv.) and NaOMe (0.18 g, 0.996 mmol, 0.22 equiv., 30 wt% in MeOH) were added. The mixture was stirred at 70 °C for 8 h. The reaction was quenched at room temperature by the addition of water (50 mL), and the mixture was acidified to pH 3-4 with 1 M HCl (10 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH₃·HO) in water, 10% to 80% gradient over 10 min; and UV detection at 254 / 220 nm to give 2-{8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-7, 720 mg, 42% yield) as a pale yellow solid. LC-MS: (ESI) m / z 372.1 [M+H].

[0267] Synthesis of I-8-8 To a stirred solution of 2-{8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-7, 600 mg, 1.616 mmol, 1 equiv.) in CHCl3 (10 mL) at 25 °C was added NBS (316.3 mg, 1.778 mmol, 1.1 equiv.). The mixture was stirred at 25 °C for 3 h. The reaction was quenched at room temperature by the addition of water (50 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-{3-bromo-8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-8, 756 mg, crude) as a yellow solid. LC-MS: (ESI) m / z 450.0 [M+H].

[0268] Synthesis of I-8-9 To a stirred solution of 2-{3-bromo-8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-8, 700 mg, 1.555 mmol, 1 equiv.) in toluene (10 mL) under a nitrogen atmosphere at 25 °C, tributyl(1-ethoxyethenyl)stannane (673.8 mg, 1.866 mmol, 1.2 equiv.) and Pd(PPh3)4 (179.6 mg, 0.155 mmol, 0.1 equiv.) were added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 h. The reaction was quenched at room temperature by the addition of water (50 mL), and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-{8-[(2,5-difluorophenyl)methyl]-3-(1-ethoxyethenyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-9, 600 mg, 87% yield) as a brown solid.

[0269] LC-MS: (ESI) m / z 442.1 [M+H]. Synthesis of compound I-8 To a stirred solution of 2-{8-[(2,5-difluorophenyl)methyl]-3-(1-ethoxyethenyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-9, 600 mg, 1.359 mmol, 1 equiv.) in tetrahydrofuran (10 mL) under a nitrogen atmosphere at 25° C., 2 M HCl (10 mL) was added. The mixture was stirred at 25° C. for 4 hours. The reaction was quenched at room temperature by the addition of water (50 mL). The resulting mixture was extracted with DCM (3×100 mL), and the combined organic layers were washed with brine (1×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3·H2O) in water, 10% to 80% gradient over 20 min; and detector, UV 254 / 220 nm, to give 1-{8-[(2,5-difluorophenyl)methyl]-6-(5-fluoro-4-hydroxy-6-methylpyrimidin-2-yl)imidazo[1,2-a]pyrazin-3-yl}ethanone (I-8, 50.8 mg, 18% yield) as an off-white solid. LC-MS: (ESI) m / z 414.15 [M+H]. 1 H NMR: (400 MHz, CDCl3) δ 10.75 (s, 1H), 10.33 (s, 1H), 8.47 (s, 1H), 7.15 - 7.01 (m, J = 13.6, 9.0, 5.0 Hz, 2H), 7.01 - 6.84 (m, 1H), 4.70 (s, 2H), 2.71 (s, 3H), 2.42 (d, J = 3.7 Hz, 3H). 19 F NMR:(376 MHz, CDCl3) δ -118.49 (d, J = 17.6 Hz), -122.25 (d, J = 17.5 Hz), -149.61. Synthesis of I-31 To a stirred solution of 1-{8-[(2,5-difluorophenyl)methyl]-6-(5-fluoro-4-hydroxy-6-methylpyrimidin-2-yl)imidazo[1,2-a]pyrazin-3-yl}ethanone (I-8, 55 mg, 0.133 mmol, 1 equiv.) in THF (1 mL) and MeOH (0.2 mL) was added NaBH (15.1 mg, 0.399 mmol, 3 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction was quenched at room temperature by the addition of water (2 mL). The resulting mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (0.1% TFA) in water, 10% to 80% gradient over 10 min; and detector, UV 254 / 220 nm, to give 2-{8-[(2,5-difluorophenyl)methyl]-3-(1-hydroxyethyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-31, 35.1 mg, 63% yield) as a white solid. LC-MS: (ESI) m / z 416.20 [M+H]. 1 H NMR: (400 MHz, CDCl3) δ 10.78 (s, 1H), 9.29 (s, 1H), 7.78 (s, 1H), 7.06 (td, J = 8.9, 4.9 Hz, 2H), 6.98 - 6.88 (m, 1H), 5.36 (q, J = 6.6 Hz, 1H), 4.62 (s, 2H), 2.39 (d, J = 3.7 Hz, 3H), 1.86 (d, J = 6.6 Hz, 3H). 19 F NMR: (376 MHz, CDCl 3 ) δ -118.77 (d, J = 17.9 Hz), -122.41 (d, J = 17.9 Hz), -150.57. Synthesis of 1-(4-((3-chloro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl)methyl)-3-fluorophenyl)ethan-1-one (I-9) and 2-(3-chloro-8-(2-fluoro-4-(1-hydroxyethyl)benzyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-33):

[0270] [ka]

[0271] Compound I-9-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-9-2 to give compound I-9-3. Compound I-9-3 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-9-4. The nitrile of compound I-9-4 was reacted with ammonium chloride to give compound I-9-5. The amidine of compound I-9-5 was condensed with compound I-9-6 to give the cyclized compound I-9-7. Compound I-9-7 was converted to intermediate I-9-8 in the presence of Weinreb amide. Compound I-9-8 was chlorinated using N-chlorosuccinimide to give compound I-9-9. The amide moiety of compound I-9-9 was reacted with a methyl Grignard reagent to give compound I-9. The resulting ketone of compound I-9 was reduced to a secondary alcohol to give compound I-33.

[0272] Synthesis of I-9-3 To a stirred solution of Zn (1.59 g, 24.285 mmol, 1.5 equiv) in THF (25 mL) was added dropwise 1,2-dibromoethane (0.15 g, 0.810 mmol, 0.05 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 10 minutes under a nitrogen atmosphere. To the above mixture was then added TMSCl (0.09 g, 0.810 mmol, 0.05 equiv) dropwise. The mixture was cooled to 0° C. To the above mixture was then added methyl 4-(bromomethyl)-3-fluorobenzoate (I-9-1, 4 g, 16.190 mmol, 1 equiv) dropwise at 0° C., and the resulting mixture was stirred at 0° C. for 10 minutes under a nitrogen atmosphere, followed by an additional 2 hours at room temperature under a nitrogen atmosphere. To the above mixture was added 6,8-dibromoimidazo[1,2-a]pyrazine (I-9-2, 3.14 g, 11.333 mmol, 0.7 equiv.) and Pd(PPh3)2Cl2 (0.23 g, 0.324 mmol, 0.02 equiv.) at room temperature, and the resulting mixture was stirred at 40 °C for an additional 1 h. The mixture was cooled to room temperature. The reaction was quenched with saturated NH4Cl(aq) (30 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give methyl 4-({6-bromoimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-3, 2.18 g, 37% yield) as a yellow solid. LC-MS (ESI) m / z 364.00 [M+H].

[0273] Synthesis of I-9-4 To a stirred solution of methyl 4-({6-bromoimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-3, 2 g, 5.492 mmol, 1 equiv.), Zn(CN) (0.39 g, 3.295 mmol, 0.6 equiv.), and Zn (0.07 g, 1.098 mmol, 0.2 equiv.) in DMF (40 mL) was added Pd(dppf)Cl (0.10 g, 0.137 mmol, 0.025 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature, and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 100 mL) and brine (3 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (2:1) to give methyl 4-({6-cyanoimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-4, 1.26 g, 74% yield) as an off-white solid. LC-MS: (ESI) m / z 311.09 [M+H].

[0274] Synthesis of I-9-5 To a stirred solution of methyl 4-({6-cyanoimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-4, 1.09 g, 3.513 mmol, 1 equiv.) in MeOH (22 mL) was added dropwise NaOMe (0.06 g, 0.351 mmol, 0.1 equiv., 30 wt % in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40° C. for 3 hours under a nitrogen atmosphere. To the above mixture was added NHCl (0.38 g, 7.026 mmol, 2 equiv.) at 40° C., and the resulting mixture was stirred at 40° C. overnight. The reaction was quenched with saturated NaHCO (aq.) (20 mL) at room temperature. The resulting mixture was extracted with DCM:IPA (3:1) (3×40 mL), and the combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-({6-carbamimidoylimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-5, 822 mg, 71.5%) as a yellow solid. LC-MS: (ESI) m / z 328.11 [M+H].

[0275] Synthesis of I-9-7 To a stirred solution of methyl 4-({6-carbamimidoylimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-5, 372 mg, 1.137 mmol, 1 equiv.) and ethyl 2-fluoro-3-oxopropanoate (I-9-6, 457.2 mg, 3.411 mmol, 3 equiv.) in MeOH (7 mL) was added dropwise NaOMe (716.3 mg, 3.979 mmol, 3.5 equiv., 30 wt % in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was then acidified to pH 4 with 1 M HCl (aq.) (2 mL), and the resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (1 × 60 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 3-fluoro-4-{[6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}benzoic acid (I-9-7, 120 mg, 27.5% yield) as a pale yellow solid. LC-MS: (ESI) m / z 384.08 [M+H].

[0276] Synthesis of I-9-8 To a stirred solution of 3-fluoro-4-{[6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}benzoic acid (I-9-7, 100 mg, 0.261 mmol, 1 equiv.), HATU (119.1 mg, 0.313 mmol, 1.2 equiv.), and DIEA (101.2 mg, 0.783 mmol, 3 equiv.) in DMF (1 mL) was added Weinreb amine (19.1 mg, 0.313 mmol, 1.2 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 3-fluoro-4-{[6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}-N-methoxy-N-methylbenzamide (I-9-8, 33 mg, 30% yield) as a yellow solid. LC-MS: (ESI) m / z 427.13 [M+H].

[0277] Synthesis of I-9-9 To a stirred solution of 3-fluoro-4-{[6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}-N-methoxy-N-methylbenzamide (I-9-8, 171 mg, 0.401 mmol, 1 equiv.) in DMF (3 mL) was added NCS (32.1 mg, 0.241 mmol, 0.6 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 4-{[3-chloro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}-3-fluoro-N-methoxy-N-methylbenzamide (I-9-9, 94 mg, 51% yield) as an off-white solid. LC-MS: (ESI) m / z 461.09 [M+H].

[0278] Synthesis of I-9 To a stirred solution of bromo(methyl)magnesium (0.25 mL, 0.760 mmol, 5 equiv., 2 M in THF) under a nitrogen atmosphere at 0 °C, a solution of 4-{[3-chloro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}-3-fluoro-N-methoxy-N-methylbenzamide (I-9-9, 70 mg, 0.152 mmol, 1 equiv.) in THF (2 mL) was added dropwise. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was then quenched at room temperature by the addition of saturated NH4Cl(aq) (5 mL), and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 1-(4-{[3-chloro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl]methyl}-3-fluorophenyl)ethanone (I-9, 20 mg, 32% yield) as a yellow solid. The reaction was repeated three more times, yielding a total of 53 mg of product. LC-MS: (ESI) m / z 416.05 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.77 - 7.67 (m, 2H), 7.66-7.60 (m, 1H), 4.67 (s, 2H), 2.56 (s, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ -115.84, -151.89. Synthesis of 2-(8-(4-ethyl-2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoro-6-methoxypyrimidin-4-ol (I-10) and 2-(8-(4-ethyl-2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoro-6-(methylthio)pyrimidin-4-ol (I-34):

[0279] [ka]

[0280] Compound I-10-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can be subjected to Negishi coupling in the presence of compound I-10-2 to give compound I-10-3. Compound I-10-3 can be further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-10-4. The nitrile of compound I-10-4 can be reacted with ammonium chloride to give amidine compound I-10-5. The amidine of compound I-10-5 can be condensed with compound I-10-6 to give cyclized compound I-10-7. The aryl alcohol of compound I-10-7 can be converted to an aryl chloride in the presence of POCl3 to give compound I-10-8. Compound I-10-8 can be partially hydroxylated in the presence of sodium hydroxide to give compound I-10-9. The remaining aryl chloride of compound I-10-9 can be converted to either compound I-10 using sodium methoxide or compound I-34 using SHMe.

[0281] 2-(8-(2,5-difluoro-4-(methylthio)benzyl)-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-39), 2-(8-(2,5-difluoro-4-(methylthio)benzyl)-3-(fluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-11), 2- Synthesis of (8-(4,5-difluoro-2-(methylthio)benzyl)-3-(fluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-40) and 2-(8-(4,5-difluoro-2-(methylthio)benzyl)-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-41)

[0282] [ka]

[0283] Compound I-11-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can be subjected to Negishi coupling with compound I-11-2 to give compound I-11-3. Compound I-11-3 can be further reacted in the presence of lead, zinc cyanide, and tris(dibenzylideneacetone)dipalladium(0) to give compound I-11-4. The nitrile of compound I-11-4 can be reacted with ammonium chloride to give amidine compound I-11-5. The amidine of compound I-11-5 can be condensed with compound I-11-6 to give cyclized compound I-11-7. Compound I-11-7 can be converted to an aryl aldehyde in the presence of POCl3 to give compound I-11-8. Compound I-11-8 can be reduced with sodium borohydride to give compound I-39. The primary alcohol of compound I-39 can be halogenated with DAST to give compound I-11. Compounds I-40 and I-41 can be made in a similar manner.

[0284] Synthesis of 6-bromo-2-(8-(2,5-difluoro-4-methylbenzyl)-3-(methylthio)imidazo[1,2-a]pyrazin-6-yl)-5-methylpyrimidin-4-ol (I-12) and 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(methylthio)imidazo[1,2-a]pyrazin-6-yl)-5-methylpyrimidine-4,6-diol (I-38):

[0285] [ka]

[0286] The nitrile of compound I-7-4 was reacted with NaSMe to produce the advanced intermediate I-7-4-1, which was reacted in situ with ammonium chloride to give the amidine compound I-12-5. The amidine of compound I-12-5 was condensed with compound I-12-6 to give the cyclized compound I-38. The aryl alcohol of the pyrimidine of I-38 was converted to bromine using POBr3 to give the dibromo compound I-12-7. The single aryl bromide of the pyrimidine ring of compound I-12-7 was converted to -OMe in the presence of sodium methoxide to give compound I-12-8. Compound I-12-8 was dealkylated to give the hydroxy compound I-12.

[0287] Synthesis of I-12-5 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-7-4, 400 mg, 1.324 mmol, 1.0 equiv) in anhydrous MeOH (6 mL) at room temperature was added sodium methanethiolate (185.3 mg, 2.648 mmol, 2.0 equiv) and the resulting mixture was stirred at 45 °C for 2 h. NHCl (141.6 mg, 2.648 mmol, 2.0 equiv) was added to the reaction and the mixture was stirred at 45 °C for 2 h. The reaction was then quenched with water (20 mL) at room temperature and the aqueous layer was extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to afford (8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylsulfanyl)imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 360 mg, crude) as a brown solid, which was used in the next step without further purification. LC-MS: (ESI) m / z 348.05 [M+H].

[0288] Synthesis of I-38 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylsulfanyl)imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 360 mg, 1.036 mmol, 1.0 equiv) in anhydrous MeOH (6 mL) was added 1,3-diethyl 2-methylpropanedioate (I-12-6, 270.8 mg, 1.556 mmol, 1.5 equiv) and NaOMe (653.1 mg, 3.628 mmol, 3.5 equiv, 30 wt% in MeOH) at room temperature, and the resulting mixture was stirred at 70 °C overnight. The mixture was cooled to room temperature, and the crude product was precipitated by the addition of 1 M HCl (10 mL) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}-5-methylpyrimidine-4,6-diol (I-38, 400 mg, crude) as a white solid. LC-MS: (ESI) m / z 430.05 [M+H].

[0289] Synthesis of I-12-7 To a stirred solution of 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}-5-methylpyrimidine-4,6-diol (I-38, 400 mg, 0.94 mmol, 1.0 equiv.) in anhydrous acetonitrile (10 mL) was added POBr (1.08 g, 3.76 mmol, 4.0 equiv.) at room temperature, and the resulting mixture was refluxed for 6 h. The mixture was cooled to room temperature and quenched with water (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give 6-(4,6-dibromo-5-methylpyrimidin-2-yl)-8-(2,5-difluoro-4-methylbenzyl)-3-(methylthio)imidazo[1,2-a]pyrazine (I-12-7, 440 mg, 85% yield) as a yellow solid. LC-MS: (ESI) m / z 556.00 [M+H].

[0290] Direct synthesis of I-12 from I-12-7 To a stirred solution of 4,6-dibromo-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}-5-methylpyrimidine (I-12-7, 280 mg, 0.504 mmol, 1.0 equiv.) in dioxane (5 mL) and THF (5 mL) was added 2 M aqueous NaOH (5.60 mL, 11.194 mmol, 22.21 equiv.) at room temperature, and the resulting mixture was stirred at room temperature for 48 h. The mixture was acidified with 1 M HCl (10 mL), and the aqueous layer was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / ethyl acetate (10:1) to give 6-bromo-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}-5-methylpyrimidin-4-ol (I-12, 100 mg, 40% yield) as a white solid. LC-MS: (ESI) m / z 493.95 [M+H]. 1 H NMR: (300 MHz, chloroform-d) δ 10.67 (s, 1H), 9.26 (s, 1H), 7.99 (s, 1H), 7.01 (dd, J = 9.1, 6.5 Hz, 1H), 6.96 - 6.86 (m, 1H), 4.60 (s, 2H), 2.43 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H). 19 F NMR: (282 MHz, chloroform-d) δ -123.03 (d, J= 16.8 Hz), -123.09 (d, J= 17.8 Hz). Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(methoxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-13) and 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-35):

[0291] [ka]

[0292] Compound I-13-5 can be synthesized via a method similar to that for compound I-8-5. The amidine of compound I-13-5 can be condensed with compound I-12-6 to give cyclized compound I-13-7, which can then be converted to the bromide using N-bromosuccinimide. Brominated compound I-13-8 can be esterified using carbon monoxide and methanol in the presence of a palladium catalyst to give compound I-13-9. The aryl alcohol of the pyrimidine of I-13-9 can be protected using MOMBr to give compound I-13-10. The ester of compound I-13-10 can be reduced with sodium borohydride to give alcohol compound I-13-11, which can then be alkylated with oxygen to give compound I-13-12. Deprotection of the MOM group of compound I-13-12 can give compound I-13. Alternatively, compound I-13-11 can be deprotected to give compound I-35.

[0293] Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(methoxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-13):

[0294] [ka]

[0295] Alternatively, compound I-13 can be prepared as follows: The aryl alcohol of the pyrimidine of I-13-9 was converted to a chlorine using POCl to give the chloro compound I-13-9-1. The aryl chloride of compound I-13-9-1 was converted to the corresponding methoxide using sodium methoxide in methanol to give compound I-13-9-2. The ester of compound I-13-9-2 was reduced with sodium borohydride to give compound I-35. Finally, the alcohol of compound I-13-9-3 was methylated with MeI and NaH, followed by dealkylation of the aryl methoxy group of the pyrimidine with HCl to give compound I-13.

[0296] Synthesis of Compound I-47 from Compound I-35

[0297] [ka]

[0298] Compound I-35 was prepared as shown below in the following protocol. This compound could be converted to I-13 by the final step of the above protocol. Alternatively, it was converted to I-47 by using the method described below.

[0299] To a stirred solution of 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-35, 52 mg, 0.130 mmol, 1 equiv.) in DMF (2 mL) was added NaH (4.6 mg, 0.195 mmol, 1.5 equiv., 60% in mineral oil) and MeI (36.7 mg, 0.260 mmol, 2 equiv.) at 0° C. The mixture was stirred at 25° C. for 4 h. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 5% to 80% gradient over 10 min; and detector, UV 254 / 220 nm, to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methoxymethyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-47, 2 mg, 4% yield) as an off-white solid. LC-MS: (ESI) m / z 416.05 [M+H]. 1 H NMR:(400 MHz, CDCl3) δ 10.97 (s, 1H), 9.19 (s, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.74 (s, 1H), 6.92 (dd, J = 9.8, 6.1 Hz, 1H), 6.79 (dd, J = 10.1, 6.3 Hz, 1H), 5.31 (q, J = 7.1 Hz, 1H), 5.02 (s, 2H), 2.14 (d, J = 1.8 Hz, 3H), 1.74 (d, J = 7.1 Hz, 3H). 19 F NMR:(376 MHz, CDCl3) δ -122.51 (d, J = 17.4 Hz), -123.36 (d, J = 17.6 Hz), -149.44. Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-35):

[0300] [ka]

[0301] Alternatively, compound I-35 was made from compound I-13-8 using either alternative route 1 or alternative route 2. Alternative Route 1: I-13-8 was esterified using carbon monoxide and methanol in the presence of the palladium catalyst (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-13-9. The ester of compound I-13-9 was reduced with sodium borohydride to give the alcohol compound I-35 directly.

[0302] Alternative Route 2: I-13-8 was carbonylated using carbon monoxide and triethylsilane in the presence of the palladium catalyst (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-13-9-0. The aldehyde of compound I-13-9-0 was reduced with sodium borohydride to give the alcohol compound I-35 directly.

[0303] Synthesis of I-13-7 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-13-5, 2 g, 6.638 mmol, 1 equiv.) in MeOH (20 mL) was added ethyl 2-fluoro-3-oxo-2-sodiopropanoate (I-13-6, 2.23 g, 16.595 mmol, 2.5 equiv.) and NaOMe (3.59 g, 19.914 mmol, 3 equiv., 30 wt % in MeOH) at 25 °C. The mixture was stirred at 70 °C for 8 h. The reaction was quenched at room temperature by the addition of 1 M HCl (aq.) (50 mL), and the resulting mixture was extracted with IPA / DCM = 1:3 (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-13-7, 2.4 g, 97.5% yield) as a yellow solid. LC-MS: (ESI) m / z 372.1 [M+H].

[0304] Synthesis of I-13-8 To a stirred solution of 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-13-7, 2.4 g, 6.463 mmol, 1 equiv.) in CHCl3 (50 mL) was added NBS (1.27 g, 7.109 mmol, 1.1 equiv.) at 25 °C. The mixture was stirred at 25 °C for 8 h. The reaction was then quenched by the addition of water (100 mL) at room temperature, and the resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by trituration with ACN (10 mL). The precipitated solid was collected by filtration, washed with ACN (3 mL), and dried under vacuum to give 2-{3-bromo-8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-13-8, 1.4 g, 48% yield) as a pale yellow solid. LC-MS: (ESI) m / z 450.0 [M+H].

[0305] Synthesis of I-13-9-0 (Alternative Route 2) To a solution of 2-{3-bromo-8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-13-8, 1.1 g, 2.443 mmol, 1 equiv.) in anhydrous DMF (10 mL) was added EtSiH (0.85 g, 7.329 mmol, 3 equiv.), Pd(dppf)Cl (0.18 g, 0.244 mmol, 0.1 equiv.), and TEA (0.74 g, 7.329 mmol, 3 equiv.) in a pressure tank. The mixture was purged with nitrogen for 1 minute and then pressurized to 10 atm with carbon monoxide at 80 °C for 12 h. The reaction mixture was cooled to room temperature, filtered to remove insoluble solids, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to give 8-[(2,5-difluoro-4-methylphenyl)methyl]-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazine-3-carbaldehyde (I-13-9-0, 700 mg, 25% yield, 35% purity) as a pale yellow solid. LC-MS: (ESI) m / z 400.05 [M+H].

[0306] Synthesis of compound I-35 To a stirred solution of crude 8-[(2,5-difluoro-4-methylphenyl)methyl]-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazine-3-carbaldehyde (I-13-9-0, 700 mg, 1.753 mmol, 1 equiv.) obtained above in THF (20 mL) was added NaBH (198.9 mg, 5.259 mmol, 3 equiv.) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction was quenched by the addition of water (10 mL) at room temperature, and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 5% to 80% gradient over 10 min; and UV detection at 254 / 220 nm to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-35, 47.2 mg, 6.4% yield) as an off-white solid. LC-MS: (ESI) m / z 402.10 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 9.19 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 7.14 (dd, J = 9.9, 6.6 Hz, 1H), 5.55 (s, 1H), 4.91 (d, J = 5.2 Hz, 2H), 4.53 (s, 2H), 2.18 (s, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ -123.08 (d, J = 17.7 Hz), -123.35, -152.58. Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoro-6-(methylthio)pyrimidin-4-ol (I-15):

[0307] [ka]

[0308] Compound I-15-4 can be synthesized similarly to compound I-8-4. Compound I-15-4 can be brominated in the presence of N-bromosuccinimide to give compound I-15-5. Compound I-15-5 can be esterified in the presence of carbon monoxide, palladium, and methanol to give compound I-15-6. The nitrile of compound I-15-6 can be reacted with ammonium chloride to give amidine compound I-15-7. The amidine of compound I-15-7 can be condensed with compound I-15-8 to give cyclized compound I-15-9. The aryl alcohol of compound I-15-9 can be converted to an aryl chloride in the presence of POCl3 to give compound I-15-10. One of the pyrimidine chlorines of compound I-15-10 can be converted to a methyl thioether in the presence of NaSMe to give compound I-15-11, which can be reduced in the presence of sodium borohydride to give compound I-15-12. Compound I-15-12 can be hydroxylated in the presence of sodium hydroxide to give compound I-15.

[0309] Synthesis of 2-(8-(2,5-difluoro-4-hydroxybenzyl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-5-fluoro-6-hydroxypyrimidine-4-carbonitrile (I-16):

[0310] [ka]

[0311] Compound I-16-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can be subjected to Negishi coupling in the presence of compound I-16-2 to give compound I-16-3. Compound I-16-3 can be further reacted in the presence of zinc, zinc cyanide, and tris(dibenzylideneacetone)dipalladium(0) to give compound I-16-4. The nitrile of compound I-16-4 can be reacted with ammonium chloride to give amidine compound I-16-5. The amidine of compound I-16-5 can be condensed with compound I-16-6 to give cyclized compound I-16-7. The aryl alcohol of compound I-16-7 can be converted to an aryl chloride in the presence of POCl3 to give compound I-16-8. The single aryl chloride on the pyrimidine ring of compound I-16-8 can be converted to -OMe in the presence of sodium methoxide to give compound I-16-9. The remaining aryl chloride of compound I-16-9 can be converted to compound I-16 using zinc cyanide and hydrochloric acid.

[0312] Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-hydroxypyrimidine-5-carbonitrile (I-17):

[0313] [ka]

[0314] The nitrile of compound I-7-4 was reacted with ammonium chloride to give amidine compound I-17-5. The amidine of compound I-17-5 was reacted with compound I-17-6 to give cyclized compound I-17-7. The ester of compound I-17-7 was converted to an amide in the presence of ammonia to give compound I-17-8, which was then converted to a cyano in the presence of TFAA to give compound I-17.

[0315] Synthesis of I-17-7 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carboximidamide (I-17-5, 370 mg, 1.159 mmol, 1 equiv.), obtained as described elsewhere in this disclosure, in MeOH (5 mL) was added 1,3-diethyl 2-(ethoxymethylidene)propanedioate (I-17-6, 375.8 mg, 1.739 mmol, 1.5 equiv.) and NaOMe (417.3 mg, 2.318 mmol, 2 equiv., 30% in MeOH) at 25 °C. The mixture was stirred at 70 °C for 8 h. The mixture was then cooled to room temperature and acidified to pH 3 with 1 M HCl (10 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to afford methyl 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carboxylate (I-17-7, 422 mg, 85% yield) as a yellow solid. LC-MS: (ESI) m / z 430.1 [M+H].

[0316] Synthesis of I-17-8 To a stirred solution of methyl 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carboxylate (I-17-7, 365 mg, 0.850 mmol, 1 equiv.) in MeOH (10 mL) was added NH(g) (60 mL, 420.000 mmol, 494.06 equiv., 7 M in MeOH) at 25° C. The mixture was stirred at 90° C. for 24 h. The mixture was then cooled to room temperature, and the resulting mixture was concentrated under reduced pressure to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carboxamide (I-17-8, 420 mg, crude) as a yellow solid, which was used directly in the next step. LC-MS: (ESI) m / z 415.1 [M+H].

[0317] Synthesis of compound I-17 POCl3 (5 mL) was added to 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carboxamide (I-17-8, 420 mg, 1.014 mmol, 1 equiv.). The mixture was stirred at 90 °C for 2 h, and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in dioxane (5 mL) and HO (2 mL). 2 M NaOH (1.1 mL, 2.028 mmol, 2 equiv.) was then added, and the mixture was stirred at 25 °C for 4 h. The resulting mixture was then diluted with water (10 mL) and acidified to pH 3 with 1 M HCl (10 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carbonitrile (I-17, 55.1 mg, 97% purity, 13% yield) as a pale yellow solid. LC-MS: (ESI) m / z 397.15 [M+H]. 1 H NMR:(400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.60 (s, 1H), 8.75 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.16 (t, J = 8.2 Hz, 1H), 4.45 (s, 2H), 2.18 (s, 3H). 19 F NMR:(376 MHz, DMSO-d6) δ -122.44, -123.15. Synthesis of 2-(8-(2,5-difluoro-4-(methoxymethyl)benzyl)imidazo[1,2-a]pyrazin-6-yl)-5-(methylthio)pyrimidin-4-ol (I-18) and 2-(8-(4-bromo-2,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-(methylthio)pyrimidin-4-ol (I-36):

[0318] [ka]

[0319] Compound I-18-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can be subjected to Negishi coupling in the presence of compound I-18-2 to give compound I-18-3. Compound I-18-3 can be further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-18-4. The nitrile of compound I-18-4 can be reacted with ammonium chloride to give amidine compound I-18-5. The amidine of compound I-18-5 can be condensed with compound I-18-6 to give cyclized compound I-36. Compound I-36 can be alkylated in a cross-coupling reaction in the presence of palladium to give compound I-18.

[0320] Synthesis of 6-chloro-5-(difluoromethyl)-2-(3-fluoro-8-(3-fluoro-4-(hydroxymethyl)benzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (I-20):

[0321] [ka]

[0322] Compound I-20-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can be subjected to Negishi coupling in the presence of compound I-20-2 to give compound I-20-3. Compound I-20-3 can be further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-20-4. Compound I-20-4 can be fluorinated in the presence of selctfluor™ to give compound I-20-5. The nitrile of compound I-20-5 can be reacted with ammonium chloride to give amidine compound I-20-6. The amidine of compound I-20-6 can be condensed with compound I-20-7 to give cyclized compound I-20-8. The aryl hydroxyl group of I-20-8 can be converted to a chlorine in the presence of POCl3 to give compound I-20-9. The acyl substitution of compound I-20-9 can be fluorinated in the presence of DAST to give compound I-20-10, which can then be deprotected in the presence of a strong base to give compound I-20.

[0323] Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-6-(fluoromethyl)-5-methoxypyrimidin-4-ol (I-21) and 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-methoxy-6-(methoxymethyl)pyrimidin-4-ol (I-27):

[0324] [ka]

[0325] Compound I-12-5 was synthesized via a method similar to that of compound I-8-5. The amidine of compound I-12-5 was condensed with compound I-21-6 or I-27-6 to give compound I-21 or I-27, respectively.

[0326] Synthesis of I-21-6 To a stirred solution of methyl methoxyacetate (2 g, 19.211 mmol, 1 equiv.) in THF (40 mL) under a nitrogen atmosphere at −78 °C, LDA (19.2 mL, 38.422 mmol, 2 equiv., 2 M in THF) and ethyl 2-fluoroacetate (1.85 g, 17.482 mmol, 0.91 equiv.) were added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was quenched with 1 M HCl (aq.) (10 mL) at room temperature, and the resulting mixture was extracted with EtO (3 × 40 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4-fluoro-2-methoxy-3-oxobutanoate (I-21-6, 1.17 g, 37% yield) as a yellow oil. The crude product was used directly in the next step without further purification.

[0327] Synthesis of compound I-21 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 20 mg, 0.066 mmol, 1.00 equiv.) and methyl 4-fluoro-2-methoxy-3-oxobutanoate (I-21-6, 43.6 mg, 0.264 mmol, 4 equiv.) in MeOH (1 mL) was added dropwise NaOMe (41.8 mg, 0.231 mmol, 3.5 equiv., 30 wt. % in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-6-(fluoromethyl)-5-methoxypyrimidin-4-ol (compound I-21, 15 mg, 54% yield) as an off-white solid. The reaction was repeated twice, yielding a total of 27.5 mg of product. LC-MS: (ESI) m / z 416.20 [M+H]. 1 H NMR: (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.46 (s, 1H), 8.35 (d, J = 1.1 Hz, 1H), 7.88 (d, J = 1.1 Hz, 1H), 7.38 (dd, J = 10.0, 6.3 Hz, 1H), 7.16 (dd, J = 9.9, 6.5 Hz, 1H), 5.44 (s, 1H), 5.28 (s, 1H), 4.54 (s, 2H), 3.92 (s, 3H), 2.19 (d, J = 1.9 Hz, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ -73.40, -123.13 (d, J = 18.1 Hz), -123.39 (d, J = 18.1 Hz). Synthesis of I-27-6 To a stirred solution of methyl methoxyacetate (500 mg, 4.803 mmol, 1 equiv.) in THF (10 mL) under a nitrogen atmosphere at −78 °C, LDA (4.8 mL, 9.606 mmol, 2 equiv., 2 M in THF) was added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was quenched with 1 M HCl (aq.) (10 mL) at room temperature, and the resulting mixture was extracted with EtO (3 × 15 mL). The combined organic layers were washed with brine (2 × 40 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2,4-dimethoxy-3-oxobutanoate (I-27-6, 190 mg, 22% yield, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0328] Synthesis of compound I-27 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 56 mg, 0.186 mmol, 1 equiv.) and methyl 2,4-dimethoxy-3-oxobutanoate (I-27-6, 131 mg, 0.744 mmol, 4 equiv.) in MeOH (1 mL) was added dropwise NaOMe (117.1 mg, 0.651 mmol, 3.5 equiv., 30 wt. % in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was then acidified to pH 4 with 1 M HCl (aq.) (1 mL), extracted with EtOAc (3 × 10 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by trituration with MeOH (2 mL) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-methoxy-6-(methoxymethyl)pyrimidin-4-ol (I-27, 53.5 mg, 75.5% yield) as an off-white solid. LC-MS: (ESI) m / z 428.05 [M+H. 1H NMR: (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 9.43 (s, 1H), 8.35 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.36 (dd, J = 10.1, 6.3 Hz, 1H), 7.16 (dd, J = 9.9, 6.4 Hz, 1H), 4.53 (s, 2H), 4.37 (s, 2H), 3.86 (s, 3H), 3.35 (s, 3H), 2.19 (d, J = 2.0 Hz, 3H). 19 F NMR:(377 MHz, DMSO-d6) δ -74.24, -123.27 (dd, J = 98.5, 18.1 Hz). Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoro-6-(methoxymethyl)pyrimidin-4-ol (I-22):

[0329] [ka]

[0330] Compound I-12-5 was synthesized via a method similar to that for compound I-8-5. The amidine of compound I-12-5 was condensed with compound I-22-6 to give cyclized compound I-22-7. The aryl hydroxyl group of compound I-22-7 was converted to a chlorine in the presence of POCl to give compound I-22-8. The single aryl chlorine of I-22-8 was converted to a methoxy ether in the presence of sodium methoxide to give compound I-22-9. Compound I-22-9 was alkylated in a cross-coupling reaction in the presence of palladium to give compound I-22-10, which was dealkylated to give compound I-22.

[0331] Synthesis of I-22-7 To a stirred mixture of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 2 g, 6.638 mmol, 1 equiv.) and 1,3-dimethyl 2-fluoropropanedioate (I-22-6, 1.49 g, 9.957 mmol, 1.5 equiv.) prepared as described elsewhere in this disclosure in MeOH (20 mL), NaOMe (3.59 g, 19.914 mmol, 3 equiv., 30% in MeOH) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70°C for 1.5 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and diluted with water (50 mL). The residue was acidified to pH 5 with HCl (aq), and the precipitated solid was collected by filtration and washed with water (2 × 50 mL) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidine-4,6-diol (I-22-7, 1.6 g, 62%) as a pale yellow solid. LC-MS: (ESI) m / z 388.10 [M+H].

[0332] Synthesis of I-22-8 To a stirred solution of 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidine-4,6-diol (I-22-7, 500 mg, 1.291 mmol, 1 equiv.) in ACN (10.00 mL) was added phosphorus oxychloride (989.6 mg, 6.455 mmol, 5 equiv.) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was then quenched at 0° C. by the addition of water (20 mL), and the resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 4,6-dichloro-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidine (I-22-8, 500 mg, crude) as a pale yellow solid. LC-MS: (ESI) m / z 424.0 [M+H].

[0333] Synthesis of I-22-9 To a stirred solution of 4,6-dichloro-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidine (I-22-8, 600 mg, 1.414 mmol, 1 equiv.) in MeOH (12 mL) was added sodium methoxide (382.0 mg, 2.121 mmol, 1.5 equiv., 30 wt % in MeOH) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure and then diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 4-chloro-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methoxypyrimidine (I-22-9, 460 mg, crude) as a pale yellow solid. LC-MS: (ESI) m / z 420.10 [M+H].

[0334] Synthesis of I-22-10 To a stirred mixture of 4-chloro-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methoxypyrimidine (I-22-9, 200 mg, 0.476 mmol, 1 equiv.) and potassium trifluoro(methoxymethyl)-lambda 4-borane (144.8 mg, 0.952 mmol, 2 equiv.) in dioxane (5 mL) and HO (1 mL) was added KPO (202.2 mg, 0.952 mmol, 2 equiv.) and Pd(Amphos)Cl (67.4 mg, 0.095 mmol, 0.2 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere overnight. The mixture was then cooled to room temperature and filtered. The filter cake was washed with THF (3 × 5 mL), and the filtrate was concentrated under reduced pressure and purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and detector, UV 254 nm, to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-4-methoxy-6-(methoxymethyl)pyrimidine (I-22-10, 80 mg, 39%) as a pale yellow solid. LC-MS: (ESI) m / z 430.20 [M+H].

[0335] Synthesis of compound I-22 A solution of 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-4-methoxy-6-(methoxymethyl)pyrimidine (I-22-10, 80 mg, 0.186 mmol, 1 equiv.) in HCl (gas) in 1,4-dioxane (2 mL) was stirred under a nitrogen atmosphere at 60° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-(methoxymethyl)pyrimidin-4-ol (I-22, 42.1 mg, 54.5% yield) as an off-white solid. LC-MS: (ESI) m / z 416.15 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.45 (s, 1H), 8.34 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 1.1 Hz, 1H), 7.36 (dd, J = 10.1, 6.2 Hz, 1H), 7.15 (dd, J = 10.0, 6.4 Hz, 1H), 4.52 (s, 2H), 4.42 (d, J = 3.0 Hz, 2H), 3.37 (s, 3H), 2.18 (d, J = 2.0 Hz, 3H). Synthesis of 5-chloro-2-(8-(2,5-difluorobenzyl)-3-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (I-29):

[0336] [ka]

[0337] The amidine of compound I-7-5 was condensed with compound I-29-6 to give the cyclized compound I-29. Synthesis of I-7-5 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-7-4, 560 mg, 1.853 mmol, 1 equiv., prepared as described above) in MeOH (10 mL) was added NaOMe (1.0 g, 5.559 mmol, 3 equiv., 30% in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 50° C. under a nitrogen atmosphere. To the above mixture was added NHCl (198.2 mg, 3.706 mmol, 2 equiv.) at 50° C. The resulting mixture was stirred at 70° C. for an additional 2 hours. The mixture was then cooled to room temperature. The reaction was quenched at room temperature by the addition of saturated NaHCO (aq.) (40 mL), and the resulting mixture was extracted with CHCl / IPA (3 / 1) (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazine-6-carboximidamide (I-7-5, 500 mg, crude) as a brown solid, which was used directly in the next step without further purification. LC-MS: (ESI) m / z 332.05 [M+H].

[0338] Synthesis of compound I-29 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazine-6-carboximidamide (I-7-5, 160 mg, 0.483 mmol, 1 equiv.) and ethyl 2-chloro-3-oxopropanoate (I-29-6, 109.06 mg, 0.724 mmol, 1.5 equiv.) in MeOH (3 mL) was added NaOMe (173.9 mg, 0.966 mmol, 2 equiv., 30 wt % in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction was quenched by the addition of 1 M HCl (5 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3 × 5 mL) to give 5-chloro-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazin-6-yl}pyrimidin-4-ol (I-29, 51.0 mg, 25%) as a pale yellow solid. LC-MS: (ESI) m / z 418.15 [M+H]. 1 H NMR: (400 MHz, chloroform-d) δ 10.88 (s, 1H), 8.92 (s, 1H), 8.13 (s, 1H), 7.28 (s, 1H), 7.04 - 6.97 (m, 1H), 6.92 (t, J = 8.0 Hz, 1H), 4.55 (s, 2H), 4.17 (s, 3H), 2.23 (s, 3H). 19 FNMR: (376 MHz, chloroform-d) δ -123.12 (d, J = 2.8 Hz), -150.71. Synthesis of 1-(2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-4-hydroxypyrimidin-5-yl)ethan-1-one (I-24) and 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-(1-hydroxyethyl)pyrimidin-4-ol (I-28):

[0339] [ka]

[0340] Compound I-12-5 was synthesized via a method similar to that for compound I-8-5. The amidine of compound I-12-5 was cyclized with compound I-28-6 to give compound I-24. The aryl hydroxyl of compound I-24 was alkylated in the presence of bromodimethyl ether to give compound I-28-7. The aryl ketone of compound I-28-7 was reduced in the presence of lithium aluminum hydride to give compound I-28-8, which was then deprotected in the presence of TFA to give compound I-28.

[0341] Synthesis of compound I-24 A solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 200 mg, 0.664 mmol, 1 equiv.), synthesized as described elsewhere in this disclosure, in MeOH (4 mL) was treated with ethyl (2E)-2-(ethoxymethylidene)-3-oxobutanoate (I-28-6, 124 mg, 0.666 mmol, 1.00 equiv.) at room temperature for 5 min under a nitrogen atmosphere, followed by the dropwise addition of NaOMe (418 mg, 2.321 mmol, 3.50 equiv., 30 wt. % in MeOH) at 70° C. The resulting mixture was stirred at 70° C. for an additional 4 h before being concentrated under reduced pressure. The residue was acidified to pH 4 with 1 M aqueous HCl (3 mL) and then purified by trituration with THF (50 mL) to give 1-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidin-5-yl)ethanone (I-24, 85.6 mg, 30% yield) as a yellow solid. LC-MS: (ESI) m / z 396.15 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 9.64 (s, 1H), 9.19 (s, 1H), 8.34 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.17 (ddd, J = 20.9, 10.1, 6.4 Hz, 2H), 4.55 (s, 2H), 2.83 (s, 3H), 2.18 (d, J = 2.0 Hz, 3H). 19 F NMR: (377 MHz, DMSO-d6) δ -123.03 (d, J = 18.1 Hz), -123.46 (d, J = 18.0 Hz). Synthesis of compound I-28-7 To a stirred solution of 1-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidin-5-yl)ethanone (I-24, 1.4 g, 3.541 mmol, 1 equiv) and bromomethoxy-methane (0.88 g, 7.082 mmol, 2 equiv) in DCM (25 mL) under a nitrogen atmosphere at 0 °C, DIEA (1.14 g, 8.852 mmol, 2.5 equiv) was added dropwise. The resulting mixture was stirred at room temperature for an additional 4 h. The reaction was then quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with DCM (3 × 50 mL), and the combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 100% gradient over 10 min; and detector, UV 254 nm, to give 1-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-(methoxymethoxy)pyrimidin-5-yl)ethanone (I-28-7, 680 mg, 44% yield) as a white solid. LC-MS: (ESI) m / z 440.2 [M+H].

[0342] Synthesis of compound I-28-8 To a stirred solution of 1-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-(methoxymethoxy)pyrimidin-5-yl)ethanone (I-28-7, 680 mg, 1.547 mmol, 1 equiv) in THF (14 mL) under a nitrogen atmosphere at 0 °C, NaBH (176 mg, 4.652 mmol, 3.01 equiv) was added portionwise. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched at 0 °C by the addition of water (40 mL), and the resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 40 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol per L of NH4HCO3), 0% to 100% gradient over 10 min; and detector, UV 254 nm, to give 1-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-(methoxymethoxy)pyrimidin-5-yl)ethanol (I-28-8, 110 mg, 16%) as a yellow solid.

[0343] LC-MS: (ESI) m / z 442.0 [M+H]. Synthesis of compound I-28 To a 50 mL round-bottom flask was added 1-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-(methoxymethoxy)pyrimidin-5-yl)ethanol (I-28-8, 110 mg, 0.249 mmol, 1 equiv.), TFA (1 mL), and DCM (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was then diluted with DCM (2 × 10 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol per L of NH4HCO3), 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-(1-hydroxyethyl)pyrimidin-4-ol (I-28, 50 mg, 47.5%) as a yellow solid. LC-MS (ESI) m / z 398.05 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.24 (s, 1H), 8.27 (s, 1H), 7.86 (d, J = 1.1 Hz, 1H), 7.23 (dd, J = 9.9, 6.3 Hz, 1H), 7.17 (dd, J = 9.8, 6.5 Hz, 1H), 4.52 (s, 2H), 4.24 (s, 2H), 2.24 (s, 3H), 2.19 (d, J = 1.9 Hz, 3H). 19 F NMR: (376 MHz, DMSO-d6) δ -73.40, -123.12 (d, J = 17.7 Hz). Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-(hydroxymethyl)pyrimidin-4-ol (I-25):

[0344] [ka]

[0345] Compound I-12-5 was synthesized via a method similar to that for compound I-8-5. The amidine of compound I-12-5 was condensed with compound I-25-6 to give cyclized compound I-25-7. The aryl ester of compound I-25-7 was reduced in the presence of lithium aluminum hydride to give compound I-25.

[0346] Synthesis of I-25-7 A solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (2 g, 6.638 mmol, 1 equiv.) in MeOH (40 mL) was treated with 1,3-diethyl 2-(ethoxymethylidene)propanedioate (I-25-6, 1.44 g, 6.638 mmol, 1 equiv.) at room temperature for 5 minutes under a nitrogen atmosphere, followed by the dropwise addition of NaOMe (4.18 g, 23.233 mmol, 3.5 equiv., 30 wt % in MeOH) at 70 °C. The resulting mixture was stirred at 70 °C for an additional 4 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 2 M aqueous HCl (6 mL), and then the mixture was filtered, and the filter cake was washed with water (3 × 50 mL). The filtrate was concentrated under reduced pressure to give methyl 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carboxylate (I-25-7, 2.09 g, 76.5% yield) as a yellow solid. LC-MS: (ESI) m / z 412.2 [M+H].

[0347] Synthesis of I-25 To a stirred solution of methyl 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-4-hydroxypyrimidine-5-carboxylate (I-25-7, 500 mg, 1.215 mmol, 1 equiv.) in THF (10 mL) under a nitrogen atmosphere at 0 °C, LiAlH (184.5 mg, 4.860 mmol, 4 equiv.) was added portionwise. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was then quenched with NaSO·10H O (50 mg) at room temperature, and the resulting mixture was filtered. The filter cake was washed with THF (3 × 10 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 0% to 100% gradient over 10 min; and UV detection at 254 nm to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-5-(hydroxymethyl)pyrimidin-4-ol (I-25, 80.6 mg, 17%) as a white solid. LC-MS: (ESI) m / z 384.15 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.52 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 7.16 (dd, J = 9.9, 6.5 Hz, 1H), 5.18 (s, 1H), 4.54 (s, 2H), 4.37 (s, 2H), 2.18 (d, J = 1.9 Hz, 3H). 19 F NMR-PH-CYCN-CYC-025-0: (376 MHz, DMSO-d6) δ -123.12 (d, J = 18.2 Hz), -123.22 - -123.54 (m). Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-6-(2-hydroxyethyl)pyrimidin-4-ol (I-26):

[0348] [ka]

[0349] Compound I-12-5 was synthesized via a method similar to that for compound I-8-5. The amidine of compound I-12-5 was condensed with compound I-26-6 to give cyclized compound I-26-7. The aryl ester of compound I-26-7 was reduced in the presence of lithium aluminum hydride to give compound I-26.

[0350] Synthesis of I-26-7 To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 500 mg, 1.66 mmol, 1.0 equiv) in anhydrous MeOH (10 mL) at room temperature was added 1,5-dimethyl 3-oxopentanedioate (I-26-6, 578.0 mg, 3.32 mmol, 2.0 equiv) and NaOMe (224.1 mg, 4.15 mmol, 2.5 equiv) and the resulting mixture was stirred at 70 °C overnight. The mixture was cooled to room temperature, and the crude product was precipitated by the addition of 1 M HCl (10 mL) to give methyl 2-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-6-hydroxypyrimidin-4-yl)acetate (I-26-7, 470 mg, crude) as a white solid. MS (ESI) m / z 426.15 [M+H].

[0351] Synthesis of I-26 To a solution of methyl 2-(2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-6-hydroxypyrimidin-4-yl)acetate (I-26-7, 470 mg, 1.105 mmol, 1 equiv) in THF (10 mL) at 0 °C was added LiAlH (98.1 mg, 2.60 mmol, 2.2 equiv) in portions. The mixture was stirred at room temperature for 2 h. The reaction was then quenched at 0 °C by the addition of water (10 mL). The aqueous layer was extracted with CHCl (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:2) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-6-(2-hydroxyethyl)pyrimidin-4-ol (I-26, 130 mg, 29.5%) as a white solid. LC-MS-PH-CYCN-CYC-026-0: MS(ESI) m / z 398.14 [M+H]. 1 H NMR-PH-CYCN-CYC-026-0: (400 MHz, chloroform-d) δ= 9.20 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.01 (dd, J= 9.3, 6.3 Hz, 1H), 6.93 (dd, J= 9.4, 6.5 Hz, 1H), 6.31 (s, 1H), 4.62 (s, 2H), 4.03 (t, J= 5.7 Hz, 2H), 2.86 (t, J= 5.6 Hz, 2H), 2.24 (d, J= 1.8 Hz, 3H). 19 F NMR-PH-CYCN-CYC-026-0: (376 MHz, chloroform-d) δ -123.11, -123.14. Synthesis of compounds 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-6-(ethoxymethyl)-5-fluoropyrimidin-4-ol (I-43) and 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoro-6-(fluoromethyl)pyrimidin-4-ol (I-45):

[0352] [ka]

[0353] Compound I-45-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound underwent Negishi coupling in the presence of compound I-45-2 to give compound I-45-3. Compound I-45-3 was further reacted in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-45-4. The nitrile of compound I-45-4 was reacted with ammonium chloride to give amidine compound I-45-5. The amidine of compound I-45-5 was condensed with compound I-45-6 to give cyclized compound I-45 and by-product compound I-43.

[0354] These compounds were made by procedures similar to those utilized in the synthesis of compounds I-5 and I-44, but starting with I-4-2-1 instead of the aza version of core I-5-2. These procedures are also similar to those used to make compounds I-21 and I-27, in each case using different condensation reagents.

[0355] Compound I-30

[0356] [ka]

[0357] To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (I-45-5, 500 mg, 1.659 mmol, 1.0 equiv.) in anhydrous MeOH (5 mL) was added NaOMe (1045.9 mg, 5.806 mmol, 3.5 equiv., 30 wt% in MeOH). To the above mixture was added methyl 3-oxopentanoate (I-30-1, 324.0 mg, 2.489 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The reaction was quenched by the addition of 1 M HCl (5 mL) at room temperature, and the precipitated solid was collected by filtration and washed with water (3 × 5 mL). The solid was purified by trituration with acetonitrile (10 mL) to give 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazin-6-yl}-6-ethylpyrimidin-4-ol (I-30, 100 mg, 23% yield) as a pale yellow solid. The reaction was repeated three more times to give a total of 381.5 mg of product. LC-MS: (ESI) m / z 382.15 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.50 (s, 1H), 8.35 (d, J= 1.1 Hz, 1H), 7.89 (d, J= 1.1 Hz, 1H), 7.36 (dd, J= 10.1, 6.3 Hz, 1H), 7.16 (dd, J= 10.0, 6.4 Hz, 1H), 6.21 (s, 1H), 4.54 (s, 2H), 2.57 (q, J= 7.5 Hz, 2H), 2.19 (d, J= 1.9 Hz, 3H), 1.23 (t, J= 7.5 Hz, 3H). 19 F NMR: (377 MHz, DMSO-d6) δ -123.13 (d, J= 18.1 Hz), -123.40 (d, J= 18.1 Hz). Example 2 cGMP measurements in rat primary neurons Primary rat neurons were isolated from term-pregnant female Sprague-Dawley (SD) rats, washed once with HBSS containing calcium and magnesium, and incubated with 0.5 mM 3-isobutyl-1-methylxanthine (IBMX) in HBSS (80 μL / well) for 15 minutes at 37°C. Next, 20 μL of a 5× stock of test compound containing a fixed concentration of DETA (diethylenetriamine NONOate) was added to the wells to a concentration of x nM for the test compound solution and 30 μM for the DETA solution, where x is one of the following final concentrations: 0.029, 0.114, 0.460, 1.83, 7.32, 29.29, 117.2, 468.8, 1875, 7500, and 30,000 nM. The cells were then incubated at 37°C for 20 minutes. At the end of the incubation, 100 μL of lysis buffer (Molecular Devices) was added to the cells. The CatchPoint™ Cyclic-GMP Fluorescent Assay Kit was used with a Molecular Devices ID3 multimode plate reader. Sample cGMP concentrations were extrapolated from a standard curve using Softmax Pro7 software. A well-characterized, potent sGC stimulator was included in all assay results and used as a positive control.

[0358] Test compound ("agonist") concentration versus extrapolated cGMP concentration ("response") was plotted and analyzed using GraphPad Prism version 9.4.1. Curve fitting was used for each data set; nonlinear log(agonist) versus response-variable slope (4 parameters). EC 50 is interpolated from the curve fit and is defined as the concentration at which the compound elicits 50% of the maximal response. If experiments are performed more than three times, the geometric mean is reported; otherwise, the arithmetic mean is shown. EC 50To increase the accuracy of the calculations, upper and lower parameters were constrained when consistent with the data observed for a given assay. For example, in assays where the cGMP response values ​​in the absence of test substance were consistent across plates, the average of all of these wells was used as the smaller constraint in the calculation. In assays where the maximum cGMP response was consistent with the positive control, an upper constraint equal to the maximum cGMP response of the positive control was applied. If there was significant variability in the cGMP response in the absence of compound wells or variation in the maximum response across plates, no constraint was applied. The EC of the test substance was calculated for compounds that did not achieve a response greater than 50% of the positive control (when an upper constraint was applied) or did not show a plateau in response at higher concentrations (in the absence of an upper constraint). 50 was defined as >30 μM (highest concentration tested). EC for compounds that did not show a dose response 50 Values ​​were characterized as ND (not determined).

[0359] [Table 6]

Claims

1. Formula I: 【Chemistry 1】 [In the formula, X is N or C(J Ｃ１ ) and J Ｃ is hydrogen, halogen, C １～６ Alkyl, —OH, —OR, —SH, —SR, —CN, —C(O)R, and C ３～５ cycloalkyl; ３～５ Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; １～６ the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J Ｃ１ is hydrogen, halogen, C １～６ Alkyl, —OH, —OR, —SH, —SR, —CN, —C(O)R, and C ３～５ cycloalkyl; ３～５ Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; １～６ the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; n is an integer selected from 0, 1, 2, or 3; Each J Ｂ is a halogen, C １～６ Alkyl, —OH, —OR, —SH, —SR, —CN, —C(O)R, and C ３～５ cycloalkyl; ３～５ Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; １～６ the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J Ｄ１ is hydrogen, halogen, C １～６ Alkyl, —OH, —OR, —SH, —SR, —CN, —C(O)R, and C ３～５ cycloalkyl; ３～５ Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; １～６ the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; J Ｄ２ is hydrogen, halogen, C １～６ Alkyl, —OH, —OR, —SH, —SR, —CN, —C(O)R, and C ３～５ cycloalkyl; ３～５ Cycloalkyl is optionally substituted independently with 1 to 3 halogen atoms; １～６ the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR, —SR, and —C(O)R; R is each independently a C optionally substituted with 1 to 3 independently selected halogen atoms. １～４ is alkyl, J Ｄ２ is hydrogen and n is 1, 2 or 3, J Ｃ , J Ｃ１ , J Ｄ１ , and J. Ｂ At least one of is —OH, —OR, —SH, —SR, —CN, —C(O)R, C optionally and independently substituted with 1 to 3 halogen atoms. ３～５ cycloalkyl, or C substituted with 1 to 3 substituents independently selected from the group consisting of —OH, —OR, —SR, and —C(O)R １～６ is alkyl, J Ｄ２ is hydrogen and n is 0, then J Ｃ , J Ｃ１ , and J. Ｄ１ At least one of is —OH, —OR, —SH, —SR, —CN, —C(O)R, C optionally and independently substituted with 1 to 3 halogen atoms. ３～５ cycloalkyl, or C substituted with 1 to 3 substituents independently selected from the group consisting of —OH, —OR, —SR, and —C(O)R １～６ alkyl] or a pharmaceutically acceptable salt thereof, provided that the compound is 【Chemistry 2】 It is not one of The compound or a pharmaceutically acceptable salt thereof.

2. The compound has formula IA: 【Transformation 3】 2. The compound of claim 1, wherein:

3. J Ｃ１ But hydrogen, halogen, C １～３ is selected from the group consisting of alkyl, —CN, —SH, —SR, —OR, and —C(O)R; １～３ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -OH and -OR.

4. J Ｃ１ is hydrogen, -F, -Cl, -CN, -CH ３ , -CH ２ F, -SH, -CH ２ OH, -CH ２ OCH ３ , -SCH ３ , -CH(OH)CH ３ , —C(O)CH ３ , and -OCH ３ 4. The compound of claim 3, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

5. J Ｃ１ is hydrogen, halogen, and C １～３ alkyl, C １～３ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with 1 to 3 independently selected halogen substituents.

6. J Ｃ１ is hydrogen, -F, -Cl, -CH ３ , and -CH ２ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

7. J Ｃ１ The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or -F.

8. The compound has formula IB: 【Chemistry 4】 2. The compound of claim 1, wherein:

9. The compound according to any one of claims 1 to 8, wherein n is 2 or 3, or a pharmaceutically acceptable salt thereof.

10. 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein n is 2.

11. 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein n is 3.

12. The compound according to any one of claims 1 to 8, wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

13. 9. The compound according to any one of claims 1 to 8, wherein n is 1, or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 8, wherein n is 0, or a pharmaceutically acceptable salt thereof.

15. Each J Ｂ is halogen, —CN, —OH, —OR, —SR, —C(O)R and C １～３ alkyl; １～３ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH and -OR.

16. Each J Ｂ is -F, -Cl, -Br, -CN, -CH ３ , -CF ３ , -CH ２ F, -CHFCH ３ , -CH ２ CH ２ F, —C(O)CH ３ , -CH(OH)CH ３ , -CH ２ CH ３ , -SCH ３ , -OCH ３ , —OH, —CH ２ OCH ３ , and -CH ２ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of: OH.

17. n is 2 or 3, and each J Ｂ is halogen, —OR, —CN, —OH, and C １～３ alkyl; １～３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with 1 to 3 independently selected halogen substituents.

18. n is 2 or 3, and each J Ｂ is -F, -Cl, -CH ３ , -CF ３ , —CN, —OH and —OCH ３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of:

19. n is 2; each J Ｂ But -F, -CH ３ and -CF ３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of:

20. n is 2; J Ｂ One of them is -CH ３ or -CF ３ and the other is -F, or a pharmaceutically acceptable salt thereof.

21. n is 2; and both J Ｂ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein is -F.

22. n is 3; each J Ｂ -F, -OH, -CH ３ , -CH ２ F and -CF ３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of:

23. n is 3; J Ｂ One of the is -F and the second J Ｂ Ga-CH ３ or -CH ２ F, and the other is —F, —OH, or —CH ３ and -CH ２ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

24. n is 1; J Ｂ is optionally substituted with halogen, —OR, and 1 to 3 independently selected halogen substituents; １～３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

25. n is 1; J Ｂ is optionally substituted with —F, —OR, and 1 to 3 independently selected halogen substituents; １～３ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

26. n is 1; J Ｂ But -F, -CH ３ , -CF ３ and -OCH ３ 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. J Ｄ２ is optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —OH, —OR, —SR, —C(O)R, and halogen, —OH, —OR, and —C(O)R; １～３ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

28. J Ｄ２ is hydrogen, —F, —Cl, —Br, —CH ３ , -SCH ３ , —OH, —CH ２ F, -CH ２ OCH ２ CH ３ , -OCH ３ , -CH ２ OCH ３ , and -CH ２ CH ２ 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: OH.

29. J Ｄ２ is optionally substituted with 1 to 3 substituents independently selected from hydrogen, halogen, —OR, and halogen and —C(O)R; １～３ 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

30. J Ｄ２ 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, -F and -Cl.

31. J Ｄ２ 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or -F.

32. J Ｄ２ 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

33. J Ｃ is hydrogen, -F, -Cl, -CH ３ , -CH ２ F, -OCH ３ , -SCH ３ , —C(O)CH ３ , -CH ２ OCH ３ , -CH ２ 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, selected from the group consisting of -OH and -CN.

34. J Ｃ is hydrogen, -F, -Cl, -CH ３ and -CH ２ 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

35. The compound has the formula IIA: 【Transformation 5】 The compound according to any one of claims 1 to 7, 9 to 26, 33 and 34, or a pharmaceutically acceptable salt thereof, wherein

36. The compound has the formula IIB: 【Transformation 6】 The compound according to any one of claims 1, 8 to 26, 33 and 34, or a pharmaceutically acceptable salt thereof, wherein

37. J Ｄ１ is optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CN, —OH, —OR, —SR, —C(O)R, and halogen, —OH, and —OR; １～３ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

38. J Ｄ１ is hydrogen, -F, -CH ３ , -CN, -SCH ３ , -CHF ２ , -OCH ３ , —C(O)CH ３ , -CH(OH)CH ３ , or -CH ２ CH ２ 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: OH.

39. J Ｄ１ is optionally substituted with 1 to 3 substituents independently selected from hydrogen, halogen, —OR, and halogen and —C(O)R; １～３ 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl.

40. J Ｄ１ 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, -F and -Cl.

41. J Ｄ１ 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein is halogen.

42. J Ｄ１ 38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein is -F.

43. R is each individually and independently C １～４ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, which is alkyl.

44. The compound is Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

45. The compound is Table 2-1 Table 2-2 Table 2-3 Table 2-4 45. The compound of claim 44, selected from: or a pharmaceutically acceptable salt thereof.

46. The compound is Table 3 45. The compound of claim 44, selected from: or a pharmaceutically acceptable salt thereof.

47. The compound is Table 4 45. The compound of claim 44, selected from: or a pharmaceutically acceptable salt thereof.

48. 48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

49. 49. A method of treating a disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, alone or in combination therapy, wherein the disease or disorder would benefit from sGC stimulation or from increased concentrations of NO and / or cGMP.

50. 50. The method of claim 49, for treating a CNS disease, condition, or disorder.

51. 51. The method of claim 50, wherein the CNS disease is Alzheimer's disease.

52. 52. The method of claim 51, wherein the Alzheimer's disease is mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease.

53. 51. The method of claim 50, wherein the CNS disease is a cognitive disorder.

54. 51. The method of claim 50, wherein the CNS disease is dementia.

55. 51. The method of claim 50, wherein the CNS disease is subjective cognitive impairment (SCI).

56. 51. The method of claim 50, wherein the CNS disorder is cognitive aging.

57. 51. The method of claim 50, wherein the CNS disease is vascular dementia.

58. 51. The method of claim 50, wherein the CNS disease is mixed dementia.

59. 51. The method of claim 50, wherein the CNS disease is Parkinson's disease.

60. 51. The method of claim 50, wherein the CNS disease is mild cognitive impairment.

61. 51. The method of claim 50, wherein the CNS disease is a traumatic (closed or open) penetrating brain injury, traumatic brain injury (TBI), non-traumatic stroke, aneurysm, hypoxia, or other injury to the brain.

62. 51. The method of claim 50, wherein the CNS disease is stroke.

63. 63. The method of claim 62, wherein the CNS disease is ischemic stroke.

64. 51. The method of claim 50, wherein the CNS disease is cognitive impairment associated with schizophrenia (CIAS).

65. 50. The method of claim 49, for treating a mitochondrial disease.

66. 66. The method of claim 65, wherein the mitochondrial disease is a mitochondrial disease of genetic origin.

67. 67. The method of claim 66, wherein the genetically inherited mitochondrial disease is selected from the group consisting of Alpers, carnitine-acyl-carnitine deficiency, carnitine deficiency, complex I, II, III, IV deficiency, CPEO, CPT II deficiency, creatine deficiency syndrome, KSS, LCHAD, Leigh syndrome, leukodystrophy, LHON, MELAS, MEPAN, MERRF, MIRAS, mitochondrial DNA depletion, MNGIE, NARP, Pearson syndrome, and POLG mutations.

68. 68. The method of any one of claims 49 to 67, further comprising administering to the subject an additional therapeutic agent.

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