Pyrimidine sGC stimulators

Abstract

The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts thereof and pharmaceutical formulations comprising them and their use, alone or in combination with one or more additional agents, for the treatment of various diseases wherein the concentration of nitric oxide (NO) and / or the concentration of cyclic guanosine monophosphate (cGMP), or both, is increased, such as, for example, the concentration of nitric oxide (NO) and / or the concentration of cyclic guanosine monophosphate (cGMP). Or regulation of the NO pathway is desirable. In some embodiments, the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 417,180, filed on October 18, 2022. The entire content of the foregoing application is hereby incorporated by reference in its entirety. Field of the Invention

[0003] The present disclosure relates to stimulators of soluble guanylate cyclase (sGC) and pharmaceutically acceptable salts thereof. It also relates to pharmaceutical formulations and dosage forms containing them and their use, alone or in combination with one or more additional agents, for the treatment of various diseases. The diseases are those that would benefit from sGC stimulation or from an increase in the concentration of nitric oxide (NO) and / or cyclic guanosine monophosphate (cGMP). Background of the Invention

[0004] sGC is the major receptor for NO in vivo. After binding to sGC, NO activates its catalytic domain and causes the conversion of guanosine-5'-triphosphate (GTP) to the second messenger cGMP. The increase in cGMP levels in turn regulates the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels. In vivo, NO is synthesized from arginine and oxygen by various nitric oxide synthases (NOS) as well as by the sequential reduction of inorganic nitrate. Experimental and clinical evidence indicates that reduced NO concentration, reduced NO bioavailability, and / or reduced responsiveness to endogenously produced NO contribute to the development of multiple diseases. sGC stimulators are heme-dependent agonists of the sGC enzyme that act in concert with variable amounts of NO to increase its enzymatic conversion of GTP to cGMP. sGC stimulators are distinct from another class of NO-independent, heme-independent sGC agonists, known as sGC activators, and are not structurally related.

[0005] Therapies that improve or restore sGC function offer significant advantages over current alternative therapies that target upregulation of the NO-sGC-cGMP pathway or otherwise benefit from upregulation of the NO-sGC-cGMP pathway. There is an urgent need to develop new and safe therapies for patients suffering from NO-sGC-cGMP pathway dysfunction. Summary of the Invention

[0006] In a first aspect, the compounds of the invention are represented by Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] X is N or C(J C1 );

[0010] JC Selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted by 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R;

[0011] J C1 Selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted by 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R;

[0012] n is an integer selected from 0, 1, 2 or 3;

[0013] Each J B is independently selected from halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted by 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R;

[0014] J D1 Selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted by 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R;

[0015] J D2 Selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5The cycloalkyl group is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl group is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R;

[0016] Each occurrence of R is independently C 1-4 alkyl, which is optionally substituted with 1 to 3 independently selected halogen atoms;

[0017] Wherein, when J D2 is hydrogen and n is 1, 2, or 3, then at least one of J C , J C1 , J D1 , and J B is -OH, -OR, -SH, -SR, -CN, -C(O)R, C 3-5 cycloalkyl optionally and independently substituted with 1 to 3 halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R;

[0018] When J D2 is hydrogen and n is 0, then at least one of J C , J C1 , and J D1 is -OH, -OR, -SH, -SR, -CN, -C(O)R, C 3-5 cycloalkyl optionally and independently substituted with 1 to 3 halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R; and

[0019] provided that the compound is not one of the following:

[0020]

[0021] 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.

[0022] In a third aspect, the present invention relates to a method of treating a disease in a subject in need thereof, which comprises 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 is a disease that would benefit from sGC stimulation or from an increase in the concentration of NO and / or cGMP. DETAILED DESCRIPTION OF THE INVENTION

[0024] Reference will now be made in detail to certain embodiments of the present 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 should be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. The invention is not limited to the methods and materials described herein, but includes any methods and materials similar or equivalent to those described herein that can be used to practice the invention. If one or more of the incorporated references, patents, or similar materials are different from or conflict with the present application, including but not limited to defined terms, term usage, described techniques, etc., the present application shall prevail.

[0025] Definitions and General Terms Related to Compounds

[0026] For the 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). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5 th th Ed., Smith, M.B. and March, J., eds. John Wiley & Sons, New York: 2001, which are hereby incorporated by reference in their entirety.

[0027] Generally, the term "substituted" means that one or more hydrogen groups of a given structure are replaced by another specific group substituent different from hydrogen (some non-limiting examples would be hydroxy, phenyl, or alkyl). If a structure is "optionally substituted", it may be substituted or unsubstituted. When a structure is substituted, the substituents are allowed on any substitutable atom. A "substitutable atom" is any atom bonded to at least one hydrogen atom (e.g., carbon, nitrogen, oxygen, or sulfur). When a certain ring is optionally substituted, it should be understood that it may be substituted at one or some or all of its substitutable ring atoms, depending on the number of allowed substituents. A "substitutable ring atom" is any ring atom bonded to at least one hydrogen atom (e.g., carbon or nitrogen), excluding ring atoms where the structure shows that they are already connected to one or more moieties or substituents other than hydrogen and there are no more hydrogens available for substitution.

[0028] When one or more positions of a structure are to be substituted with one or more substituents selected from a particular group or list, unless otherwise specified, the one or more substituents at each position may be "independently selected" to be equal or the same at each position and for each instance. For example, if a phenyl group is substituted with two instances of R 100 and each R 100 is independently selected from halogen and methyl, this means that each instance of R 100 is separately selected from halogen or methyl; for example, one R 100 may be fluorine and one may be methyl, or both may be chlorine, or one may be fluorine and the other chlorine, or both may be methyl, and so on. Similarly, if the atom that can be substituted is hydrogen-bonded to more than one (e.g., CH3 or NH2), unless otherwise stated, the substituents may be "independently selected" to be equal or the same for each instance of hydrogen. For example, if a methyl group (e.g., CH3) is substituted with two instances of R 100 and each R 100 is independently selected from halogen and methyl, this means that each instance of R 100 is individually selected from halogen or methyl; for example, one R 100 (i.e., one of the hydrogens attached to C in the CH3 group) can be substituted with fluorine and one R 100 can be substituted with methyl (e.g., CHF(CH3)), or both can be substituted with chlorine (e.g., CHCl2), and so on.

[0029] The selections of substituents and combinations contemplated by the present disclosure are only those that result in the formation of stable or chemically viable compounds. Such selections and combinations will be apparent to those skilled in the art and can be determined without undue experimentation. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that permit its production, detection, and in some embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein. A chemically viable compound is one that can be prepared by those skilled in the art based on the present disclosure and, if needed, supplemented with relevant knowledge in the art.

[0030] As used herein, the phrase "at most" means zero or any integer equal to or less than the number following the phrase. For example, "at most 3" means any one of 0, 1, 2, or 3.

[0031] As described herein, a specified range of numbers of atoms or substituents includes any integer therein. For example, a group having 1 - 4 atoms can 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 all other occurrences. When a moiety is replaced by 0 instances of a variable, this means that the moiety is unsubstituted (i.e., it may only have hydrogen radicals attached to any replaceable atoms).

[0032] Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are also within the scope of the present invention, regardless of how the specific compounds are drawn.

[0033] In one embodiment, the present disclosure can include replacing hydrogen with deuterium (i.e., 2 H), which can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in - vivo half - life or reduced dosage requirements), and may thus be preferred in certain cases. Deuterium - labeled compounds of the present invention can generally be prepared by procedures similar to those disclosed in the schemes and / or examples below herein by replacing non - deuterated reagents with deuterated reagents.

[0034] As used herein, the term "alkyl" as in, for example, "alkyl chain" or "alkyl group" refers to a saturated, unbranched (e.g., straight - chain) or branched monovalent hydrocarbon group. C x alkyl is an alkyl chain containing x carbon atoms, where x is an integer other than 0. "C x-y alkyl", where x and y are two different integers (both different from 0), is an alkyl chain containing between x and y carbon atoms (inclusive of the end values). For example, C 1-6 alkyl is an alkyl containing any number of carbon atoms between 1 and 6 as defined above. Examples of alkyl groups include, but are not limited to, methyl (i.e., C1 alkyl), ethyl (i.e., C2 alkyl), n - propyl (C3 alkyl), isopropyl (a different C3 alkyl), n - butyl, isobutyl, sec - butyl, tert - butyl, pentyl, hexyl, heptyl, octyl, etc.

[0035] As used herein, the term "cycloalkyl" as in "cycloalkyl ring" or "cycloalkyl group" refers to a fully saturated ring system formed only of carbon and hydrogen atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. A cycloalkyl ring will be represented by the term "C x-y cycloalkyl"; where x and y are the minimum and maximum number of carbon atoms forming the cycloalkyl ring.

[0036] As used herein, the term "halogen" or "halo" refers to F, Cl, Br, or I.

[0037] The compounds of the present invention are defined herein by their chemical structure and / or chemical name. When a compound is mentioned by both its chemical structure and chemical name and there is a conflict between the chemical structure and the chemical name, the chemical structure determines the identity of the compound.

[0038] Substituents, such as J C 、J C1 、J B and J D are generally defined upon introduction and this definition is retained throughout the specification and all independent claims, unless otherwise specified.

[0039] The compounds of the present invention are defined herein by their chemical structure and / or chemical name. When a compound is mentioned by both its chemical structure and chemical name and there is a conflict between the chemical structure and the chemical name, the chemical structure determines the identity of the compound.

[0040] Compound / composition embodiments

[0041] The present invention is based on the discovery that the compounds disclosed herein are sGC stimulators. Compounds having similar structural features, particularly compounds having a 4-OH substituent on the pyrimidine ring, were previously only known as synthetic intermediates that can be used to prepare sGC stimulators having a 4-amino substituent on the pyrimidine ring. Unexpectedly, it has been found that the compounds of the present disclosure have potent sGC stimulating activity and thus have the potential for treating diseases that can benefit from the stimulation of the NO-sGC-cGMP pathway.

[0042] In a first embodiment of the first aspect, the compounds of the present invention are represented by Formula I:

[0043]

[0044] or a pharmaceutically acceptable salt thereof, wherein:

[0045] X is N or C(J C1 );

[0046] J C is selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R;

[0047] J C1 is selected from hydrogen, halogen, C 1-6alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, where the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R;

[0048] n is an integer selected from 0, 1, 2, or 3;

[0049] Each J B is independently selected from halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, where the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R;

[0050] J D1 is selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, where the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R;

[0051] J D2 is selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, where the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R;

[0052] Each occurrence of R is independently C 1-4 alkyl, which is optionally substituted with 1 to 3 independently selected halogen atoms;

[0053] where, when J D2 is hydrogen and n is 1, 2, or 3, then J C , J C1 , J D1 and JB at least one of which is —OH, —OR, —SH, —SR, —CN, —C(O)R, C 3-5 cycloalkyl optionally and independently substituted with up to 3 halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from —OH, —OR, —SR and —C(O)R;

[0054] When J D2 is hydrogen and n is 0, then at least one of J C , J C1 and J D1 is —OH, —OR, —SH, —SR, —CN, —C(O)R, C 3-5 cycloalkyl optionally and independently substituted with up to 3 halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from —OH, —OR, —SR and —C(O)R; and

[0055] provided that the compound is not one of the following:

[0056]

[0057] In a second embodiment, the compound of formula I is a compound of formula IA:

[0058]

[0059]

[0060] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for formula I;

[0061] wherein, when J D2 is hydrogen and n is 1, 2 or 3, then at least one of J C , J C1 , J D1 and J B is —OH, —OR, —SH, —SR, —CN, —C(O)R, C 3-5 cycloalkyl optionally and independently substituted with 1 to 3 halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from —OH, —OR, —SR and —C(O)R; and

[0062] when J D2 is hydrogen and n is 0, then at least one of J C , J C1 and J D1 is —OH, —OR, —SH, —SR, —CN, —C(O)R, C3-5 cycloalkyl, or C alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R 1-6 alkyl.

[0063] In a third embodiment, for a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof, J C1 is selected from hydrogen, halogen, C 1-3 alkyl, -CN, -SH, -SR, -OR, and -C(O)R, wherein C 1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, and -OR; and the remaining variables are as defined in the first or second embodiment.

[0064] In a fourth embodiment, for a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof, J C1 is selected from hydrogen, -F, -Cl, -CN, -CH3, -CH2F, -SH, -CH2OH, -CH2OCH3, -SCH3, -CH(OH)CH3, -C(O)CH3, and -OCH3; and the remaining variables are defined in the first, second, or third embodiment.

[0065] In a fifth embodiment, for a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof, J C1 is selected from hydrogen, halogen, and C 1-3 alkyl, wherein C 1-3 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.

[0066] In a sixth embodiment, for a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof, J C1 is selected from hydrogen, -F, -Cl, -CH3, and -CH2F; and the remaining variables are defined in the first, second, third, fourth, or fifth embodiment.

[0067] 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.

[0068] In an eighth embodiment, the compound of formula I is a compound of formula IB:

[0069]

[0070] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for formula I,

[0071] wherein, when JD2 When J is hydrogen and n is 1, 2, or 3, then J C , J D1 and J B at least one of which is -OH, -OR, -SH, -SR, -CN, -C(O)R, a C 3-5 cycloalkyl ring optionally and independently substituted with 1 to 3 halogen atoms, or a C 1-6 alkyl group substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R;

[0072] When J D2 is hydrogen and n is 0, then J C and J D1 at least one of which is -OH, -OR, -SH, -SR, -CN, -C(O)R, a C 3-5 cycloalkyl ring optionally and independently substituted with 1 to 3 halogen atoms, or a C 1-6 alkyl group substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R; and

[0073] provided that the compound is not one of the following:

[0074]

[0075] 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.

[0076] In a tenth embodiment, for a compound 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.

[0077] In an eleventh embodiment, for a compound of formula I, IA, or IB or a pharmaceutically acceptable salt thereof, each J B is independently selected from halogen, -CN, -OH, -OR, -SR, -C(O)R, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, –OH, and -OR; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0078] In a twelfth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, J B is independently selected from -F, -Cl, -Br, -CN, -CH3, -CF3, -CH2F, -CHFCH3, -CH2CH2F, -C(O)CH3, -CH(OH)CH3, -CH2CH3, -SCH3, -OCH3, -OH, -CH2OCH3 and -CH2OH; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment.

[0079] In a thirteenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 2 or 3, and each J B is independently selected from halogen, -OR, -CN, -OH and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1 to 3 independently selected halogen substituents; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or eleventh embodiment.

[0080] In a fourteenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 2 or 3, and each J B is independently selected from -F, -Cl, -CH3, -CF3, -CN, -OH and –OCH3; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth or thirteenth embodiment.

[0081] In a fifteenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 2; each J B is independently selected from -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 –CH3 or –CF3, and the other is -F. In other embodiments, both J B are -F.

[0082] In a sixteenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 3; each J B is independently selected from -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 JB is -F, and the second J B is -CH3 or –CH2F, and the others are -F, -OH, -CH3 or –CH2F.

[0083] In the seventeenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 1; and J B is selected from halogen, -OR and C 1-3 alkyl optionally substituted with 1 to 3 independently selected halogen substituents; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth or eleventh embodiment.

[0084] In the eighteenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 1; and J B is selected from -F, -OR and C 1-3 alkyl optionally substituted with 1 to 3 independently selected halogen substituents; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth or eleventh embodiment.

[0085] In the nineteenth embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, n is 1; and J B is selected from -F, -CH3, –CF3 and –OCH3; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth or eleventh embodiment.

[0086] In the twentieth embodiment, for a compound 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.

[0087] In the twenty-first embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, J D2 is selected from hydrogen, halogen, -OH, -OR, -SR, -C(O)R and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, –OH, -OR and –C(O)R; 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 or twentieth embodiment.

[0088] In the twenty-second embodiment, for a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, J D2selected from hydrogen, -F, -Cl, -Br, -CH3, -SCH3, -OH, -CH2F, -CH2OCH2CH3, -OCH3, -CH2OCH3, and -CH2CH2OH; 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, or twenty-first embodiment.

[0089] In the twenty-third embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J D2 is selected from hydrogen, halogen, –OR, and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and –C(O)R; 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, or twenty-first embodiment. In some embodiments, J D2 is selected from hydrogen, -F, and -Cl. In other embodiments, it is hydrogen or -F. In still other embodiments, it is hydrogen.

[0090] In the twenty-fourth embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J C is selected from hydrogen, halogen, -OR, -SR, -C(O)R, -CN, and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -OR, and –OH; and wherein R is C 1-3 alkyl optionally substituted with 1 to 3 fluorines; and the remaining variables are 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.

[0091] In the twenty-fifth embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, J C is selected from hydrogen, -F, -Cl, -CH3, -CH2F, -OCH3, -SCH3, -C(O)CH3, -CH2OCH3, -CH2OH, 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 CSelected from hydrogen, -F, -Cl, -CH3, and –CH2F.

[0092] In the twenty-sixth embodiment, for a compound of formula I or formula IA, the compound is one of formula IIA or a pharmaceutically acceptable salt thereof:

[0093]

[0094] wherein 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; and

[0095] wherein, when n is 1, 2, or 3, then at least one of J C 、J C1 、J D1 and J B is -OH, -OR, -SH, -SR, -CN, -C(O)R, C 3-5 cycloalkyl optionally and independently substituted with 1 to 3 independently selected halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R; and

[0096] when n is 0, then at least one of J C 、J C1 and J D1 is -OH, -OR, -SH, -SR, -CN, -C(O)R, C 3-5 cycloalkyl optionally and independently substituted with 1 to 3 independently selected halogen atoms, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R.

[0097] In the twenty-seventh embodiment, for a compound of formula I or formula IB, the compound is one of formula IIB, or a pharmaceutically acceptable salt thereof:

[0098]

[0099] wherein 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; and

[0100] wherein, when n is 1, 2, or 3, then at least one of J C 、J D1 and J Bat least one of which is -OH, -OR, -SH, -SR, -CN, -C(O)R, C 3-5 cycloalkyl, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R;

[0101] When n is 0, then J C and J D1 at least one of which is -OH, -OR, -SH, -SR, -CN, -C(O)R, C 3-5 cycloalkyl, or C 1-6 alkyl substituted with 1 to 3 substituents independently selected from –OH, -OR, -SR, and –C(O)R; and

[0102] provided that the compound is not one of the following:

[0103]

[0104] In the twenty-eighth embodiment, for a compound of formula I, IA, IB, IIA or IIB or a pharmaceutically acceptable salt thereof, J D1 is selected from hydrogen, halogen, -CN, -OH, -OR, -SR, -C(O)R, and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, –OH, and -OR; 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 or twenty-seventh embodiment.

[0105] In the twenty-ninth embodiment, for a compound of formula I, IA, IB, IIA or IIB or a pharmaceutically acceptable salt thereof, J D1 is selected from hydrogen, -F, -CH3, -CN, -SCH3, -CHF2, -OCH3, -C(O)CH3, -CH(OH)CH3 or -CH2CH2OH; 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.

[0106] In the thirtieth embodiment, for a compound of formula I, IA, IB, IIA or IIB or a pharmaceutically acceptable salt thereof, J D1 is selected from hydrogen, halogen, -OR and C optionally substituted with 1 to 3 substituents independently selected from halogen and –C(O)R 1-3 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 or twenty - eighth embodiment. In some embodiments, J D1 is selected from hydrogen, -F and -Cl. In some embodiments, J D1 is halogen. In other embodiments, it is -F.

[0107] In the thirty - first embodiment, for a compound of formula I, IA, IB, IIA or IIB or a pharmaceutically acceptable salt thereof, each occurrence of R is 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 thirtieth embodiment. In some embodiments, each occurrence of R is independently C 1-2 alkyl. In some embodiments, R is methyl.

[0108] In the thirty - second embodiment, the present invention relates to the sGC stimulant compounds of Table I, and their pharmaceutically acceptable salts.

[0109] Table I. Exemplary sGC stimulants of the present invention.

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116] The thirty - third embodiment of the present invention is a compound of Table II or a pharmaceutically acceptable salt thereof.

[0117] Table II. Exemplary sGC Stimulators of the Invention.

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] In a thirty-fourth embodiment, the compounds of the invention are selected from those compounds in Table III, or a pharmaceutically acceptable salt thereof:

[0124] Table III. Exemplary sGC Stimulators of the Invention.

[0125]

[0126]

[0127] In a thirty-fifth embodiment, the compounds of the invention are selected from those compounds in Table IV, or a pharmaceutically acceptable salt thereof:

[0128] Table IV. Exemplary sGC Stimulators of the Invention.

[0129]

[0130]

[0131] Pharmaceutically acceptable salts of the invention.

[0132] "Pharmaceutically acceptable salts" of the compounds described herein include those salts derived when the compound is mixed with an inorganic or organic acid or base. In some embodiments, the salt can be prepared in situ during the final isolation and purification of the compound. In other embodiments, the salt can be prepared from the free form of the compound in a separate synthetic step. The preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, which is incorporated herein by reference in its entirety. The pharmaceutically acceptable salts of the compounds in Table I are those salts that are useful for drugs. However, salts that are not pharmaceutically acceptable may be useful for the preparation of the compounds in Table I or their pharmaceutically acceptable salts.

[0133] When the compounds described herein (e.g., the compounds of Tables I-IV or the compounds represented by Formula I, or Formula IA, IIA, IB or IIB) are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include the following: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, etc. Specific embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts of pharmaceutically acceptable organic non-toxic bases derived from the following bases, said bases including: salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, arginine, betaine, caffeine, choline, N,N 1 -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0134] In some embodiments, the compounds of the present invention have an acidic OH group, which 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 salt, a calcium salt, a magnesium salt, a potassium salt or a sodium salt. In some embodiments, the salt is a sodium salt.

[0135] When the compounds described herein (e.g., the compounds of Tables I-IV or the compounds represented by Formula I, IA, IIA, IB, IIB) are basic, the 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, bisulfate, bitartrate, camphorsulfonic acid, chloride, citrate, citric acid, ethanesulfonate, ethanesulfonic acid, formic acid, fumarate, fumaric acid, gentisinate, gluconate, gluconic acid, glucuronic acid, glutamate, glutamic acid, hydrobromic acid, hydrochloric acid, iodide, hydroxyethanesulfonic acid, isonicotinate, lactate, lactic acid, maleate, maleic acid, malic acid, mandelic acid, methanesulfonic acid, methanesulfonate, mucic acid, nitrate, nitric acid, oleic acid, oxalate, pamoic acid, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), pantothenic acid, pantothenate, phosphate, phosphoric acid, sucrose, salicylate, succinic acid, succinate, sulfuric acid, sulfate, tannate, tartrate, tartaric acid, p-toluenesulfonate, p-toluenesulfonic acid, etc. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0136] In addition to the compounds described herein, their pharmaceutically acceptable salts can also be used in a composition for treating or preventing the diseases identified herein.

[0137] Pharmaceutical compositions and methods of administration.

[0138] 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.

[0139] In some embodiments of the second aspect, the pharmaceutical composition of the present invention comprises a compound or a pharmaceutically acceptable salt thereof 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, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiment, and at least one pharmaceutically acceptable excipient or carrier.

[0140] The compounds and their pharmaceutically acceptable salts disclosed herein can be formulated into pharmaceutical compositions or "formulations".

[0141] Typical formulations are prepared by mixing a compound described herein (e.g., a compound of Tables I-IV or a compound represented by Formula I, IA, IB, IIA, 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, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and other such materials. The specific carrier, diluent or excipient used will depend on the manner and purpose of formulating the compound described herein (e.g., a compound of Tables I-IV or a compound represented by Formula I, IA, IB, IIA, IIB or a pharmaceutically acceptable salt thereof). Solvents are typically selected based on solvents recognized by those skilled in the art as generally regarded as safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulations may also include other types of excipients, such as one or more buffering agents, stabilizers, anti-adhesion agents, surfactants, wetting agents, lubricants, emulsifying agents, binders, suspending agents, disintegrating agents, fillers, adsorbents, coatings (e.g., enteric or sustained release) preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, flavor enhancers and other known additives to provide an elegant appearance to 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 to assist in the manufacture of the pharmaceutical product (i.e., the drug).

[0142] Acceptable diluents, carriers, excipients, and stabilizers are those that are non-toxic to the recipient at the dosages and concentrations employed, and include buffering agents (such as phosphates, citrates, and other organic acids); antioxidants (including ascorbic acid and methionine); preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoic acid, such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; 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 (such as Zn-protein complexes); and / or nonionic surfactants (such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG)). The active pharmaceutical ingredient can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (such as hydroxymethylcellulose or gelatin microcapsules and poly(methylmethacrylate) microcapsules, respectively); in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21st Edition, University of the Sciences in Philadelphia, 2005 (hereinafter referred to as "Remington’s").

[0143] Formulations can be prepared using conventional dissolution and mixing procedures.

[0144] As used herein, the term "therapeutically effective amount" means the amount of an active compound or agent that a researcher, veterinarian, physician, or other clinician seeks to elicit a biological or medical response in a tissue, system, animal, or human. The therapeutically effective amount of a compound will be determined by such considerations and is the minimum amount necessary to effect improvement, cure, or treatment of the disease or one or more of its symptoms.

[0145] For the terms of the compounds, compositions or dosage forms of the present invention, "administer" (including "administer", "administering" or "administration") means introducing the compound, composition or dosage form into the system of a subject or patient in need of treatment. When the compound of the present invention is provided in combination with one or more other active agents, "administer" and its variants should be understood to include the simultaneous and / or sequential introduction of the compound, composition or dosage form and the other active agent(s).

[0146] The compositions described herein can be administered systemically or locally, for example, orally (including but not limited to solid dosage forms, including hard or soft capsules (e.g., gelatin capsules), tablets, pills, powders, sublingual tablets, troches, lozenges and granules; and liquid dosage forms, including but not limited to pharmaceutically acceptable emulsions, microemulsions, aqueous or oily solutions, suspensions, syrups and elixirs), by inhalation (e.g., using aerosols, gases, inhalants, nebulizers, etc.), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, inhalants, liniments, lotions, ointments, patches, pastes, powders, solutions, sprays, transdermal patches, etc.), to the eye (e.g., eye drops, ophthalmic gels, eye ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), by ear drops, via implanted reservoirs, etc., or parenterally, depending on the severity and type of the disease being treated. 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 composition is administered orally, intraperitoneally or intravenously.

[0147] Preparations of the compounds for oral use can be prepared by any method known in the art for the preparation of pharmaceutical compositions.

[0148] In solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dibasic calcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerin, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques, including microencapsulation to mask unpleasant tastes or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, delayed release materials such as glyceryl monostearate or glyceryl distearate, used alone or in combination with waxes, may be employed. Water-soluble taste masking materials such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be used.

[0149] Besides the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifying agents, such as ethanol, isopropanol, ethyl formate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0150] The oral composition (solid or liquid) may also contain excipients and adjuvants, such as dispersants or wetting agents, such as 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); emulsifiers and suspending agents, such as sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; sweeteners, flavoring agents and perfuming agents; and / or one or more preservatives, such as ethyl p-hydroxybenzoate or n-butyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

[0151] The pharmaceutical composition may also be administered by nasal spray or by inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and may be made into salt solutions using benzyl alcohol or other suitable preservatives, absorption promoters that enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents. The particle size of the formulations suitable for pulmonary or nasal administration is, for example, in the range of 0.1 to 500 microns (including particles in the range between 0.1 and 500 microns with increments such as 0.5, 1, 30, 35 microns, etc.), which are administered by rapid inhalation through the nasal cavity or by oral inhalation to reach the alveolar sacs.

[0152] The pharmaceutical compositions described herein may also be administered topically, especially when the targets of treatment include regions or organs that are readily accessible by topical administration, which include diseases of the eye, ear, skin or lower intestine. Suitable topical formulations for each of these regions or organs are readily prepared. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffering agents that may be required under sterile conditions.

[0153] For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing the active ingredient 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, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active ingredient 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0154] Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400) and mixtures thereof. The topical preparation can optionally include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0155] The oil phase of the emulsion prepared using the compounds of the present invention can be constituted by known components in a known manner. Although this phase can contain only an emulsifier (also known as an emulgent), it desirably contains at least one emulsifier in combination with a fat or an oil or with a mixture of a fat and an oil. A hydrophilic emulsifier can be included together with a lipophilic emulsifier as a stabilizer. In some embodiments, the emulsifier includes oils and fats. Also, emulsifiers with or without stabilizers constitute so-called emulsifying waxes, and such waxes together with oils and fats constitute so-called emulsifying ointment bases, which form the oily dispersed phase of the cream formulation. Emulsifiers and emulsifying stabilizers suitable for the formulations of the compounds of the present invention include Tween TM -60, Span TM -80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0156] In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or a gel.

[0157] For ophthalmic use, the pharmaceutical composition can be formulated as an isotonic, micronized suspension, a pH-adjusted sterile saline, or preferably as a solution in an isotonic, pH-adjusted sterile saline, which may or may not contain a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum. For treating the eye or other external tissues such as the mouth and skin, the preparation can be in the form of a topical ointment or cream, which contains an amount of the active ingredient, for example, from 0.075 to 20% w / w. When formulated as an ointment, the active ingredient can be used with an oil-based matrix, a petrolatum-based matrix, or a water-miscible ointment base.

[0158] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier such as cocoa butter, beeswax, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration can be provided in the form of pessaries, tampons, creams, gels, pastes, foams, or sprays.

[0159] The sterile injectable forms of the compositions described herein (e.g., for parenteral administration) can be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art, using suitable dispersing or wetting agents and suspending agents (including those mentioned in the preceding paragraphs). The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are commonly used as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including synthetic mono - or di - glycerides of fatty acids. Fatty acids, such as oleic acid and its glyceride derivatives, can be used in the preparation of injectables, which are natural pharmaceutically acceptable oils, such as vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, especially in their polyoxyethylated forms, or in mineral oils (such as liquid paraffin). These oil solutions or suspensions can also contain long - chain alcohol diluents or dispersing agents, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. For the purpose of injectable preparations, other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers (commonly used in manufacturing pharmaceutically acceptable solid, liquid, or other dosage forms), can also be used. The oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents, such as those mentioned above, can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants, such as butylated hydroxyanisole or α - tocopherol.

[0160] In other embodiments of the second aspect, the compounds of the present invention or their pharmaceutically acceptable salts can be formulated in a veterinary composition comprising a veterinary carrier. A veterinary carrier is a material for administering the composition and can be an inert solid, liquid, or gaseous material. It is compatible with the active ingredient in the veterinary field. These veterinary compositions can be administered parenterally, orally, or by any other desired route.

[0161] Therapeutic methods

[0162] In a third aspect, the present invention further provides a method for treating a disease in a subject in need thereof, which comprises 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 is a disease that benefits from sGC stimulation or from an increase in the concentration 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 further provides a method for treating a disease in a subject in need thereof, which comprises 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 is a disease that benefits from sGC stimulation or from an increase in the concentration of NO or cGMP or both, or from upregulation of the NO-sGC-cGMP pathway.

[0163] 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 compound of Embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising a compound of formula I, IA, IB, IIA, IIB, Tables I-IV, or any compound of Embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, for treating one of the diseases disclosed herein in a subject in need thereof.

[0164] 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 compound of Embodiments 1 to 35, 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 compound of Embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating one of the diseases disclosed herein in a subject in need thereof.

[0165] The present invention further provides a method for preparing or manufacturing a medicament for treating one of the diseases disclosed herein, which comprises using a compound of formula I, IA, IB, IIB, Tables I-IV, or any compound of Embodiments 1 to 35, 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 compound of Embodiments 1 to 35, or a pharmaceutically acceptable salt thereof.

[0166] Embodiments of the third to fifth aspects of the present invention are methods of treating a disease in a subject in need thereof, which comprise administering to the subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound or a pharmaceutically acceptable salt thereof 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, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiment) or a pharmaceutical composition comprising a compound described herein (e.g., a compound or a pharmaceutically acceptable salt thereof 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, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiment).

[0167] In some embodiments of the third to fifth aspects, the compounds disclosed herein are sGC stimulators, which can be used for preventing and / or treating diseases characterized by an undesired decrease in the bioavailability of NO and / or sensitivity to NO, such as diseases associated with conditions of oxidative stress or nitrosative stress.

[0168] Increased cGMP concentrations via the NO-sGC-cGMP pathway result in vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive effects, anti-remodeling effects, anti-apoptotic effects, anti-inflammatory, anti-fibrotic effects, metabolic effects, neuronal signaling effects and mitochondrial effects. Therefore, sGC stimulators can be used for treating and / or preventing a series of diseases.

[0169] Specific diseases or disorders that can be treated and / or prevented by administering an sGC stimulator of the present invention according to the third to fifth aspects (e.g., a compound of formula I, IA, IB, IIA, IIB, compounds of Tables I-IV or any compound in the first to thirty-fifth embodiments and pharmaceutically acceptable salts thereof) include but are not limited to:

[0170] Abetalipoproteinemia, achalasia (e.g., esophageal achalasia), acute respiratory distress syndrome (ARDS), adhesive capsulitis, age-related learning and memory disorders, age-related memory loss, alcoholism, alopecia or hair loss, altitude sickness, Alzheimer's disease (including pre-Alzheimer's disease, mild to moderate Alzheimer's disease, and moderate to severe Alzheimer's disease), amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), anal fissure, aneurysm, angina (e.g., stable or unstable angina, variant angina, Prinzmetal angina, microvascular angina), anxiety or anxiety disorders, argininosuccinic aciduria, arterial and venous thrombosis, arthritis, Asperger's syndrome, asthma and asthmatic diseases, ataxia, telangiectasia, atherosclerosis (e.g., atherosclerosis associated with endothelial 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 autism spectrum disorders, benign prostatic hyperplasia (BPH) or hypertrophy or enlargement, bipolar disorder, bladder outlet obstruction, bladder pain syndrome (BPS), blepharitis, bone and carbohydrate metabolism disorders, bone healing (e.g., bone healing after osteoclastic bone remodeling, osteoclastic bone resorption, new bone formation), brain aneurysm, cerebral hypoxia, cancer metastasis, cerebral amyloid angiopathy (CAA) or congophilic angiopathy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), cerebral perfusion, cerebral small vessel disease, cerebral vasospasm, chemo brain, childhood disintegrative disorder, chronic bronchitis, chronic fatigue, chronic traumatic encephalopathy (CTE), ciliary diseases, cirrhosis (e.g., cirrhosis, cirrhosis associated with chronic liver disease, primary biliary cirrhosis), sexual dysfunction related to CNS diseases, sleep disturbances related to CNS diseases, cognitive deficits associated with Huntington's disease, cognitive dysfunction, cognitive impairment (e.g., vascular cognitive impairment, mild cognitive impairment, cognitive impairment related to diabetes, cognitive impairment related to multiple sclerosis, cognitive impairment related to obstructive sleep apnea, cognitive impairment related to schizophrenia (CIAS), cognitive impairment related to sickle cell disease, concussion, congenital myasthenic syndrome, connective tissue diseases, 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 lobe degeneration, dementia with frontotemporal lobe degeneration, dementia with corticobasal degeneration, Creutzfeldt-Jakob dementia,HIV dementia, multi-infarct dementia, postoperative dementia, strategic single-infarct dementia, HIV-associated dementia (including asymptomatic neurocognitive disorder (ANI), mild neurocognitive disorder (MND), HIV-associated dementia (HAD, also known as AIDS dementia complex [ADC] or HIV encephalopathy), presenile dementia (mild cognitive impairment, MCI), mixed dementia, Binswanger dementia (subcortical arteriosclerotic encephalopathy), Parkinson's disease dementia), demyelination, depression, depressive disorder, dermatomyositis, diabetic angiopathy, diabetic macular edema, diabetic microangiopathy, diabetic ulcers or wounds (e.g., diabetic foot ulcers), diseases associated with or related to metabolic syndrome (e.g., obesity, diabetes, insulin resistance, elevated fasting glucose, elevated fasting insulin, elevated lipids), diseases involving neurotransmitter downregulation, diseases involving impaired cerebral blood flow, diseases involving impaired neurodegeneration, diseases involving impaired synaptic function, diseases involving neuroinflammation, diseases involving neurotoxicity, diseases of male and female urogenital organs (benign and malignant), attention disorders in children with learning and memory problems, Down syndrome, drug addiction, drug-induced psychosis, dry eye syndrome, Duchenne muscular dystrophy, Dupuytren's contracture, movement disorders (e.g., acute movement disorders, chronic or tardive movement disorders, non-motor movement disorders, levodopa-induced movement disorders (LID)), dysmenorrhea (e.g., primary dysmenorrhea, secondary dysmenorrhea), dyspaneuria, dysphagia, dystonia (e.g., generalized dystonia, focal dystonia, segmental dystonia, sexual dystonia, intermediate dystonia, acute dystonic reaction, hereditary or primary dystonia), edema, electrolyte disorders (e.g., herkalemia, hyponatremia), emphysema, endometriosis, endothelial dysfunction or injury and diseases associated with endothelial dysfunction, erectile dysfunction, esophageal achalasia, Fabry disease, female sexual dysfunction (e.g., female sexual arousal dysfunction), fibromyalgia, fibrosis (e.g., endomyocardial fibrosis, atrial fibrosis, cardiac interstitial fibrosis, cardiac fibrosis, pulmonary fibrosis, ocular fibrosis, skin fibrosis, intestinal fibrosis, renal or kidney fibrosis, interstitial renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis of the lung, liver fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, joint fibrosis, myelofibrosis, myelofibrosis with myeloid metaplasia, myelofibroma, radiation-induced fibrosis, pancreatic fibrosis), fragile X, functional dyspepsia, gastroparesis, Gaucher's disease, general attention disorder, general psychosis, glaucoma, glioblastoma, glomerulopathy (e.g., glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis), granuloma, head injury, hearing impairment (e.g., partial hearing loss, complete hearing loss,Partial deafness, complete deafness, noise-induced hearing loss), heart diseases (e.g., left ventricular myocardial remodeling, left ventricular systolic dysfunction, ischemic cardiomyopathy, dilated cardiomyopathy, alcoholic cardiomyopathy, storage cardiomyopathy, congenital heart defects, reduced coronary blood flow, diastolic or systolic dysfunction, coronary artery insufficiency, acute coronary syndrome, coronary artery disease, arrhythmia, reduced ventricular preload, cardiac hypertrophy, right heart hypertrophy, atrial and ventricular rhythm disorders and cardiac conduction disorders, first to third degree atrioventricular block (AVB I-III), supraventricular tachyarrhythmia, premature ventricular contractions, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsade-de-pointes tachycardia, atrial and ventricular premature contractions, AV junction premature contractions, sick sinus 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 existing chronic heart failure (worsening HF), transient heart failure, after acute heart failure, systolic heart failure, diastolic heart failure, congestive heart failure, acute decompensated heart failure, right ventricular failure, global heart failure, high-output heart failure, heart failure with valvular defects, diabetic heart failure, heart failure / heart-kidney syndrome, right heart failure), high concentration 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, hypertension (e.g., arterial hypertension, refractory hypertension, diabetic hypertension, idiopathic hypertension, primary hypertension, secondary hypertension, pregnancy-induced hypertension, portal hypertension, systemic hypertension, preeclampsia, increased acute and chronic coronary blood pressure), hypertonia, hypertrophic scar, hypoactive sexual arousal disorder, hypoperfusion, impotence, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), inflammation caused by cerebral malaria, inflammation caused by infectious diseases, inflammatory response in perioperative care, platelet aggregation, intellectual disability, intermittent claudication, interstitial cystitis (IC), hypotension during dialysis, ischemia (e.g., cerebral ischemia, myocardial ischemia, thromboembolic ischemia, severe limb ischemia), keloid, kidney diseases (e.g., chronic kidney disease, acute and chronic renal failure, acute and chronic renal insufficiency, sequelae of renal insufficiency, renal insufficiency associated with pulmonary enema, renal insufficiency associated with HF,Renal insufficiency associated with uremia or anemia, primary kidney diseases, congenital kidney diseases, progression of polycystic kidney disease, renal transplant rejection, immune complex-induced kidney diseases, abnormal reduction in creatinine and / or water excretion, abnormal elevation in blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme activity (such as glutamine synthetase), altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, damage to glomeruli and arterioles, tubule dilation, hyperphosphatemia, vascular kidney diseases, renal cysts, renal edema due to HF), Korsakoff psychosis, leukocyte activation, levodopa-induced addictive behavior, lichen sclerosus, lipid-related disorders (such as obesity, excessive subcutaneous fat, hyperlipidemia, dyslipidemia, hypercholesterolemia, reduced high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinanemias, sitosterolemia, fatty liver disease, hepatic steatosis or abnormal lipid accumulation in the liver, fatty degeneration of the heart, kidney, or muscle, sitosterolemia, xanthomatosis, Tangier disease), liver diseases (such as vascular liver diseases, activation of hepatic stellate cells, accumulation of hepatic fibrotic collagen and total collagen, necroinflammatory liver diseases and / or immune liver diseases, cholestatic liver diseases associated with granulomatous liver diseases, cholestatic liver diseases associated with liver malignancies, cholestatic liver diseases associated with intrahepatic cholestasis during pregnancy, cholestatic liver diseases associated with hepatitis, cholestatic liver diseases associated with sepsis, cholestatic liver diseases associated with drugs or toxins, cholestatic liver diseases associated with graft-versus-host disease, cholestatic liver diseases associated with post-liver transplantation, cholestatic liver diseases associated with common bile duct stones, cholestatic liver diseases associated with bile duct tumors, cholestatic liver diseases associated with pancreatic cancer, cholestatic liver diseases associated with Mirizzi syndrome, cholestatic liver diseases associated with AIDS, cholangiopathy, cholestatic liver diseases associated with parasites, cholestatic liver diseases associated with schistosomiasis, hepatitis, non-alcoholic fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), hepatic encephalopathy), local thrombosis, lower urinary tract syndrome (LUTS), lumbar spinal stenosis, lupus nephritis, lupus or systemic lupus erythematosus, microalbuminuria, microcirculation abnormalities, migraine, mild neurocognitive disorder (MND), morphea, moyamoya disease, multiple lacunar infarcts, multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), multiple sclerosis (MS, including 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, old myocardial infarction), myopic choroidal neovascularization, nevus, anesthetic dependence, kidney disease (e.g., diabetic nephropathy, non-diabetic nephropathy, nephritis, toxin-induced nephropathy, contrast-induced nephropathy, diabetic or non-diabetic renal sclerosis, nephrotic syndrome, pyelonephritis, nephrogenic fibrosis), neurodegenerative diseases, neurogenic bladder and incontinence, neuroinflammation, neurological disorders associated with reduced nitric oxide production, neuromuscular diseases (e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, distal myopathy, myotonic dystrophy types I and II, facioscapulohumeral muscular dystrophy, autosomal and X-linked Emery-Dreifuss muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy (SMA)), neuromyelitis optica, neuropathy (e.g., peripheral neuropathy, autonomic neuropathy, central nervous system neuropathy, chemotherapy-induced neuropathy, diabetic neuropathy, painful neuropathy, neuropathic pain, non-painful neuropathy, painful diabetic neuropathy, non-painful diabetic neuropathy, neuropathy 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), obstructive thromboanginitis, obstructive uropathy, eosinophilic fasciitis, osteoporosis, overactive bladder, pain (e.g., acute pain, central pain syndrome, inflammatory pain, postoperative pain, tonic pain, visceral pain, claudication pain, orphan pain indications (e.g., acetazolamide-responsive myotonia, autoerythrocyte 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, congenital insensitivity to pain associated with ion channelopathies, 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-hypohidrosis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial episodic pain syndrome, familial episodic pain syndrome mainly involving the lower limbs, familial episodic pain syndrome mainly involving the upper body, hereditary painful callosities, hereditary sensory and autonomic neuropathy type 4,Hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, interstitial cystitis, painful ophthalmoplegia and systemic neurofibromatosis - Marfanoid habitus syndrome, paroxysmal extreme pain disorder, persistent idiopathic facial pain, qualitative or quantitative deficiency of calpain, Tolosa-Hunt syndrome)), pancreatitis, panic disorder, Parkinson's disease, Parkinsonism Plus, Parkinsonian dysphagia, pathological eating disorder, pelvic pain, peripheral vascular diseases (e.g., peripheral artery disease, peripheral arterial occlusive disease, peripheral embolism, peripheral perfusion disorder), peritonitis, pervasive developmental disorder, Peyronie’s disease, Picks syndrome, polychondritis, polymyositis, postherpetic neuralgia, post-traumatic head injury, post-traumatic stress disorder (PTSD), premature ejaculation, progressive supranuclear palsy, prostatic hypertrophy, pulmonary diseases (e.g., plexogenic pulmonary arteriopathy, bronchial stenosis or bronchiolar stenosis, pulmonary vascular diseases, 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 hypertonia), pulmonary hypertension (PH, e.g., pulmonary arterial hypertension (PAH), primary PH, secondary PH, sporadic PH, precapillary PH, idiopathic PH, PH associated with left ventricular disease, PH associated with HIV, PH associated with sickle cell disease (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 diseases, 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 valve 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 abnormal pulmonary venous drainage, 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,PH associated with interstitial lung 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 disorders, PH associated with long-term 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 thromboembolism), radiculopathy, Raynaud’s disease, Raynaud’s syndrome (primary or secondary), intractable epilepsy, Renpennings syndrome, reperfusion injury (e.g., ischemia-reperfusion injury, ischemia-reperfusion associated with organ transplantation), restenosis (e.g., restenosis occurring after thrombolytic therapy, after percutaneous transluminal angioplasty (PTA), after transluminal coronary angioplasty (PTCA), after heart transplantation or after bypass surgery), retinopathy (e.g., diabetic retinopathy, non-diabetic retinopathy, non-proliferative diabetic retinopathy, proliferative vitreoretinopathy, peripheral retinal degeneration, retinal vein occlusion), Rhett disorder, rheumatoid or rheumatic diseases (e.g., arthritis, rheumatoid arthritis), sarcoidosis, sarcoma, schistosomiasis, schizoaffective disorder, schizophrenia, schizophrenia with dementia, scleroderma (e.g., localized scleroderma or morphea, systemic scleroderma), sclerosis (e.g., nephrosclerosis, progressive sclerosis, cirrhosis, primary sclerosing cholanginitis, sclerosis of the gastrointestinal tract, hippocampal sclerosis, focal sclerosis, primary lateral sclerosis, osteosclerosis, otosclerosis, atherosclerosis, tuberous sclerosis, systemic scleroderma), sepsis or septic shock or anaphylactic shock, sickle cell anemia, sickle cell disease, Sjogren's syndrome, sleep-wake disorders, Sneddon's syndrome, spasm (e.g., coronary spasm, vasospasm, peripheral arterial spasm), spinal cord injury, spinal muscular atrophy, spinal subluxation, spinocerebellar ataxia, Steel-Richardson-Olszewski disease (progressive supranuclear palsy), stroke, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, syncope, tauopathies, tension, thalamic degeneration, thromboembolism or thrombotic disorders, transient ischemic attack (TIA), traumatic brain injury, tubulointerstitial disease, ulcers, uterine fibroids, vaginal atrophy, valvular defects (e.g., mitral stenosis, mitral regurgitation, insufficiency or incompetence, aortic stenosis, aortic insufficiency, tricuspid insufficiency, pulmonary stenosis, pulmonary insufficiency,Combined valvular defects, cerebrovascular diseases, vascular disorders resulting from cardiac and renal complications, vascular leakage or permeability, vasculitis (e.g., thrombotic vasculitis, obliterative thrombotic vasculitis, Kawasaki disease, arteritis, aortitis), vascular occlusive crisis, venous graft failure, wet age-related macular degeneration, and Williams syndrome.

[0171] In a specific embodiment, the diseases treatable with the sGC stimulators of the present invention (e.g., any compound of Formula I, IA, IB, IIA, IIB or Tables I-IV or any compound of the first to thirty-fifth embodiments) are CNS (central nervous system) diseases. In another embodiment, the disease is a mitochondrial disease.

[0172] In one embodiment of the third to fifth aspects, the compounds disclosed herein are sGC stimulators useful for preventing and / or treating 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 compound of Formula I, IA, IIA, IB, IIB, Tables I-IV or any compound of the first to thirty-fifth embodiments or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising them.

[0173] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators useful for preventing and / or treating 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 compound of Formula I, IA, IIA, IB, IIB, Tables I-IV or any compound of the first to thirty-fifth embodiments, a pharmaceutically acceptable salt thereof or a pharmaceutical composition or dosage form comprising them.

[0174] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators useful for preventing and / or treating 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 compound of Formula I, IA, IIA, IB, IIB, Tables I-IV or any compound of the first to thirty-fifth embodiments or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising them.

[0175] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that can be used for preventing and / or treating diseases and disorders characterized by impaired synaptic function. 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 compound of Formula I, IA, IIA, IB, 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 them.

[0176] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that can be used for preventing and / or treating diseases and disorders characterized by neurotransmitter downregulation. One embodiment of the present invention is a method of normalizing neurotransmitters in a subject in need thereof by administering to the subject any compound of Formula I, IA, IIA, IB, 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 them.

[0177] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that can be used for preventing and / or treating 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 compound of Formula I, IA, IIA, IB, 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 them.

[0178] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that can be used for preventing and / or treating 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 compound of Formula I, IA, IIA, IB, 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 them.

[0179] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that are useful for preventing and / or treating 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 a compound of any one of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the first to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising the same. In some embodiments, the treatment improves memory. In other embodiments, the treatment improves attention. In other embodiments, the treatment improves executive function.

[0180] In another embodiment of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators that are neuroprotective. Specifically, the compounds of Formula I, IA, IIA, IB, IIB, Tables I-IV, or any of the first to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising the same are useful for protecting neurons in a subject in need thereof.

[0181] In another embodiment of the third to fifth aspects of the present invention, the CNS disease, health condition or disorder is selected from: 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 degeneration or dementia (FTD), asymptomatic neurocognitive disorder (ANI), subjective cognitive impairment or decline (SCD), cognitive aging, mild neurocognitive disorder (MND), HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy), dementia with Lewy bodies, presenile dementia or mild cognitive impairment (MCI).

[0182] In another embodiment of the third to fifth aspects of the present invention, the disease, health condition or disorder is a CNS disorder or condition selected from: sleep-wake disorders and neurological abnormalities associated with Sneddon syndrome.

[0183] In another embodiment of the third to fifth aspects of the present invention, the disease, health condition or disorder is a CNS disorder or condition selected from: Alzheimer's disease or pre-Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease.

[0184] In another embodiment of the third to fifth aspects of the present invention, the CNS disease is selected from glaucoma, Huntington's disease (or Huntington's chorea, HD), multiple sclerosis (MS), multiple system atrophy (MSA), Parkinson's disease (PD), Parkinson's plus, spinocerebellar ataxia (SCA), Steele-Richardson-Olszewski disease (progressive supranuclear palsy), amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), or Down syndrome.

[0185] In another embodiment of the third to fifth aspects of the present invention, the CNS disease is selected from attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD).

[0186] In another embodiment of the third to fifth aspects of the present invention, the CNS disorder is selected from traumatic (closed or open) penetrating head injury, traumatic brain injury (TBI), non-traumatic stroke (especially ischemic stroke), aneurysm, hypoxia, or other brain injury.

[0187] In other embodiments of the third to fifth aspects of the present invention, the CNS disorder is a psychiatric disorder, mental disorder, mood disorder, or affective disorder selected from the following: 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).

[0188] In other embodiments of the third to fifth aspects of the present invention, the CNS disease or disorder is selected from dystonia, including, for example, generalized, focal, segmental, sexual, intermediate, hereditary / primary dystonia, or acute dystonic reaction; or movement disorders, including, for example, acute, chronic / late-onset, and non-motor and levodopa-induced movement disorders (LID).

[0189] In other embodiments of the third to fifth aspects of the present invention, the CNS disease or disorder is selected from disorders characterized by a relative reduction in synaptic plasticity and synaptic processes, including, for example, fragile X, Rett disorder, Williams syndrome, Renpenning syndrome, autism spectrum disorder (ASD), autism, Asperger syndrome, pervasive developmental disorder, or childhood disintegrative disorder.

[0190] In other embodiments of the third to fifth aspects of the present invention, the CNS disorder is selected from chemo brain, levodopa-induced addictive behavior, alcoholism, anesthetic dependence (including but not limited to amphetamines, opioids, or other substances), and drug abuse.

[0191] In one embodiment of the third to fifth aspects, the CNS disease is a cognitive disorder or functional disorder caused by brain injury, mental disorder, neurodevelopmental disorder, or neurodegenerative disorder.

[0192] In some embodiments of the third to fifth aspects, the cognitive disorder (as MCI or dementia) is associated with Alzheimer's disease (AD), vascular dementia, mixed dementia, AD with vascular pathology (ADv), cerebral infarction, cerebral ischemia, stroke, head injury, traumatic head injury, learning disorder, autism, attention deficit disorder, depression, spinocerebellar ataxia, dementia with Lewy bodies, dementia with frontal lobe degeneration, Pick's syndrome, Parkinson's disease, progressive supranuclear 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, postoperative cognitive decline in the elderly, bipolar disorder, or mitochondrial diseases. In other embodiments, the cognitive disorder is associated with sickle cell disease.

[0193] In some embodiments of the third to fifth aspects, MCI, dementia, subclinical cognitive impairment, or SCD is associated with cognitive aging, postoperative cognitive decline, drug side effects, metabolic imbalance, hormonal problems, vitamin or nutrient deficiencies, delirium, psychiatric diseases, brain neuron damage due to injury (e.g., stroke or other cerebrovascular diseases or due to traumatic brain injury), the initial stage of neurodegenerative processes, exposure to toxins or viruses, or bacterial infections.

[0194] In other embodiments of the third to fifth aspects, the compounds disclosed herein are sGC stimulators useful for preventing and / or treating orphan pain indications. One embodiment of the invention is a method of treating an orphan pain indication in a subject in need thereof by administering to the subject any compound of Formula I, IA, IB, IIA, IIB, Tables I-IV, or any of the first to thirty-fifth embodiments of the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or dosage form comprising them.

[0195] Specifically, the orphan pain indication is selected from acetazolamide-responsive myotonia, autoerythrocyte 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, congenital insensitivity to pain related to ion channelopathy, 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-hypohidrosis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome mainly involving the lower limbs, familial paroxysmal pain syndrome mainly involving the upper body, hereditary painful callus, hereditary sensory and autonomic neuropathy type 4, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, interstitial cystitis, painful ophthalmoplegia and systemic neurofibromatosis-Maffucci syndrome, paroxysmal extreme pain disorder, persistent idiopathic facial pain, qualitative or quantitative deficiency of calpain, and Tolosa-Hunt syndrome.

[0196] In other embodiments, the CNS disorder is neuropathic pain. In some embodiments, the pain is neuropathic pain associated with a CNS disease.

[0197] In further embodiments, the disease or disorder is selected from acute pain, central pain syndrome, chemotherapy-induced neuropathy, diabetic neuropathy, fibromyalgia, inflammatory pain, painful diabetic peripheral neuropathy, postoperative pain, tonic pain, and visceral pain.

[0198] In other embodiments of the third to fifth aspects of the present invention, the compounds disclosed herein are sGC stimulators, which can be used for the prevention and / or treatment of altitude (mountain) sickness, cerebral small vessel disease, cerebral vasculitis, cerebral vasospasm, hepatic encephalopathy, moyamoya disease, parkinsonian dysphagia, ataxia telangiectasia, autism spectrum disorder, chronic fatigue, chronic traumatic encephalopathy (CTE), diabetes-related cognitive impairment, multiple sclerosis-related cognitive impairment, obstructive sleep apnea-related cognitive impairment, schizophrenia (CIAS)-related cognitive impairment, sickle cell disease-related cognitive impairment, concussion, retinopathy, diabetic retinopathy (including proliferative and non-proliferative), and dysphagia.

[0199] In other embodiments of the third to fifth aspects, the compounds disclosed herein are sGC stimulators, which can be used for the prevention and / or treatment of ocular fibrosis, Fabry disease, Gaucher disease, glioblastoma, cerebral inflammation caused by cerebral malaria (SoC), cerebral inflammation caused by infectious diseases, 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, parkinsonian dementia, peripheral and autonomic neuropathy, peripheral retinal degeneration, post-traumatic stress syndrome, postherpetic neuralgia, postoperative dementia, proliferative vitreoretinopathy, radiation-induced cerebral fibrosis, radiculopathy, refractory epilepsy, retinal vein occlusion, spinal cord injury, spinal muscular atrophy, spinal subluxation, tau proteinopathy, and wet age-related macular degeneration.

[0200] CNS diseases that may benefit from treatment with the sGC stimulator of the present invention are those CNS diseases for which an increase in NO concentration or an increase in cGMP concentration, or both, or upregulation of the NO-sGC-cGMP pathway is desirable.

[0201] The compounds described herein and their pharmaceutically acceptable salts (as sGC stimulators capable of crossing the blood-brain barrier (BBB)) can be used for the prevention and / or treatment of CNS diseases, conditions, and disorders that may benefit from sGC stimulation in the brain.

[0202] In some embodiments of the third to fifth aspects, the compounds of the present invention are capable of stimulating sGC in the brain without causing a large decrease in blood pressure (BP) in a patient. In some embodiments, for a dose that produces the desired CNS effect, the compound causes an average decrease in BP of less than 5 mmHg in the patient. In other embodiments, less than 10 mmHg on average. In other embodiments, the decrease in BP of the patient is not clinically significant. In still other embodiments, when a patient is treated for a CNS disease, the methods and uses of the present invention do not result in a significant incidence of adverse events (AEs) associated with symptomatic hypotension.

[0203] In some embodiments of the third to fifth aspects, the compounds of the present invention are used for the treatment of mitochondrial diseases of genetic origin.

[0204] Specific mitochondrial diseases that can be treated and / or prevented by administering the sGC stimulator of the present invention (e.g., the sGC stimulator of formula I, IA, IB, IIA, IIB, Tables I-IV, or any of the first to thirty-fifth embodiments of the first aspect, or its pharmaceutically acceptable salt) include, but are not limited to:

[0205] Alpers Disease, autosomal dominant optic atrophy (ADOA), Barth syndrome / LIC (lethal infantile cardiomyopathy), β-oxidation defects, systemic primary carnitine deficiency, long-chain fatty acid transport deficiency, carnitine palmitoyltransferase deficiency, carnitine / acylcarnitine translocase deficiency, carnitine palmitoyltransferase I (CPTI) deficiency, carnitine palmitoyltransferase II (CPTII) 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 (Glutaric acidurioa Type II)), mitochondrial trifunctional protein deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency, short / 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-related 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 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 cytopathy, 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.

[0206] In one embodiment, the mitochondrial disease is selected from Alpers disease, carnitine-acylcarnitine 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.

[0207] Definitions and General Terms Related to Methods of Use

[0208] As used herein, the term "disease" refers to any deviation or interruption of the normal structure or function of any body part, organ, or system, manifested as a characteristic set of symptoms and signs, and the cause, pathology, and prognosis of which may be known or unknown. The term disease encompasses other related terms such as disorder and condition (or medical condition) and syndrome, which are defined as a combination of symptoms caused by a single cause or that typically occur together to constitute a distinct clinical manifestation. In some embodiments, the term disease refers to an sGC-, cGMP-, and / or NO-mediated medical or pathological disease.

[0209] "Treat", "treating", or "treatment" with respect to a disorder, disease, condition, symptom, or syndrome means eliminating or ameliorating the cause and / or effects of the disorder, disease, condition, symptom, or syndrome (i.e., symptoms, physiological, physical, psychological, emotional, or any other clinical manifestation, observation, or measurement, or improving a pathological assessment).

[0210] As used herein, the terms "treat", "treatment", or "treating" also refer to delaying or ameliorating or preventing the progression (i.e., known or expected disease progression), severity, and / or duration of a disease, or delaying or ameliorating or preventing the progression of one or more symptoms, clinical manifestations, observations, or measurements, or preventing or slowing the negative progression of a pathological assessment (i.e., "managing" rather than "curing" the condition) caused by the administration of one or more therapies.

[0211] 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), specifically a "mammal", including non - primate animals (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primate animals (e.g., monkeys, chimpanzees, and humans), and more specifically to humans. In some embodiments, the subject is a non - human animal, such as a farm animal (e.g., a horse, cow, pig, or 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.

[0212] As used herein, the term "biological sample" refers to an in vitro or ex vivo sample, and includes but is not limited to cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, lymph fluid, ocular fluid, vitreous humor, cerebrospinal fluid (CSF), or other body fluids or extracts thereof.

[0213] In other embodiments, 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 an sGC stimulant in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include but are not limited to bioassays and biological sample storage.

[0214] Combination therapy

[0215] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy to treat diseases mediated, regulated, or affected by sGC, cGMP, and / or NO.

[0216] As used herein, the term "combination" (as in the sentence "combination therapy") or "co - administration" are used interchangeably to refer to the use of more than one therapy. The use of these terms does not limit the order in which the therapies are administered to a subject.

[0217] The compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combination therapy with more than one active agent, when the active agents are in separate dosage formulations, the active agents can be administered separately or in combination. In addition, the administration of one component can be before, simultaneous with, or after the administration of another agent.

[0218] When used in combination therapy with other agents, the "therapeutically effective amount" of the compounds and pharmaceutical compositions described herein and the "therapeutically effective amount" of one or more other agents will depend on the type of drugs used. Suitable doses of approved agents are known and can be adjusted by those skilled in the art based on the condition of the subject, the type of condition being treated, and the amount of the compounds described herein being used. In the absence of an explicitly stated amount, an effective amount should be assumed.

[0219] In some embodiments, co - administration or combination therapy encompasses administering a first and a second amount of a compound in a substantially simultaneous manner, such as in the form of a single pharmaceutical composition, such as a capsule or tablet having a fixed ratio of the first and second amounts, or in the form of multiple individual capsules or tablets for each drug. Additionally, such co - administration also encompasses using each compound sequentially in either order.

[0220] When co - administration involves separately administering a first amount of a compound of formula I, IA, IB, IIA, IIB, Tables I - IV or any one of the first to thirty - fifth embodiments of the first aspect and a second amount of an additional therapeutic agent, the compounds should be administered close enough in time to have the desired therapeutic effect. For example, the time interval between each administration that can result in the desired therapeutic effect can range from a few minutes to several hours and can be determined by considering the properties of each compound (such as potency, solubility, bioavailability, plasma half - life, and kinetic profile). For example, a compound of formula I, IA, IB, IIA, IIB, Tables I - IV or any one of the first to thirty - fifth embodiments of the first aspect and a 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.

[0221] Examples of other therapeutic agents that can be combined with a compound of formula I, IA, IB, IIA, IIB, Tables I - IV or any one of the first to thirty - fifth embodiments of the first aspect or a pharmaceutically acceptable salt thereof (administered separately or in the form of the same pharmaceutical composition) include, but are not limited to:

[0222] (1) Endothelium - derived relaxing factor (EDRF) or NO gas.

[0223] (2) NO donors, including but not limited to: nitrosothiols, nitrites, sydnonimines, NONOates, N-nitrosamines, N-hydroxy-nitrosamines, nitrosimines, nitrotyrosine, diaziridine dioxides, oxatriazole 5-imines, oximes, hydroxylamines, N-hydroxyguanidines, hydroxyureas or furoxans. Some examples of these types of compounds include: trinitroglycerin (also known as GTN, nitroglycerin, nitroglycerine and trinitroglycerol), nitrates of glycerol; sodium nitroprusside (SNP), in which a nitric oxide molecule coordinates with an iron metal to form a square bipyramidal complex; 3-morpholinosydnonimine (SIN-1), an amphoteric ionic compound formed by the combination of morpholine and sydnonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid derivative with a nitrosothiol functional group; diethylenetriamine / NO (DETA / NO), a nitric oxide compound covalently linked to diethylenetriamine; m-nitrooxymethylphenyl ester of acetylsalicylic acid. Some more specific examples in these NO donor categories include: classical nitrovasodilators, such as organic nitrates and nitrites, including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate and nicorandil; isosorbide; 3-morpholinosydnonimine; linsidomine chlorhydrate ("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione monoethyl ester (GSNO-ester), 6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexylamine or diethylamine NONOate.

[0224] (3) Other substances that increase cGMP concentration, including but not limited to protoporphyrin IX, arachidonic acid and phenylhydrazine derivatives.

[0225] (4) Nitric oxide synthase substrates, including but not limited to L-arginine-based, 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 (such as homo-Arg, homo-NOHA, N-tert-butoxy- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, ε-guanidino-caproic acid, agmatine, hydroxy-agmatine, and L-tyrosyl-L-arginine); N-alkyl-N'-hydroxyguanidines (such as N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidines (such as N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives with –F, -Cl, -methyl, -OH substituents); guanidine derivatives such as 3-(trifluoromethyl)propylguanidine.

[0226] (5) Compounds that enhance eNOS transcription.

[0227] (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); S3448 (2-(4-chlorophenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide (described in patent publications DE19830430 and WO2000002851); and HMR-1069 (Sanofi-Aventis).

[0228] (7) Heme-dependent, NO-independent sGC stimulants, including but not limited to YC-1 (see patent publications EP667345 and DE19744026); riociguat (BAY 63-2521, described in DE19834044); nelociguat (BAY 60-4552, described in WO 2003095451); vericiguat (BAY 1021189, described in US8420656); BAY 41-2272 (described in DE19834047 and DE19942809); BAY41-8543 (described in DE19834044); etriciguat (described in WO 2003086407); CFM-1571 (described in patent publication WO2000027394); A-344905, its acrylamide analogue A-350619 and aminopyrimidine analogue A-778935;

[0229] Other sGC stimulators are described in one of the following publications: US20090209556, US8455638, US20110118282 (WO2009032249), US20100292192, US20110201621, US7947664, US8053455 (WO2009094242), US20100216764, US8507512, (WO2010099054) US20110218202 (WO2010065275), US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798 (WO2012058132), and Tetrahedron Letters (2003), 44(48):8661-8663; and IW1973 (praliciguat), IW1701 (olinciguat) and CY6463 (previously IW-6463).

[0230] (8) Compounds that inhibit the degradation of cGMP and / or cAMP, including but not limited to:

[0231] PDE1 inhibitors, PDE2 inhibitors, PDE-3 inhibitors (such as amrinone, milrinone, enoximone, vesnarinone, pimobendan, and opirinone), PDE4 inhibitors (such as roflumilast), PDE5 inhibitors (such as sildenafil), and related agents (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.

[0232] (9) Anticoagulants, including but not limited to:

[0233] Coumarins (vitamin K antagonists), such as warfarin, cenocoumarol, phenprocoumon, and phenindione;

[0234] Heparin and derivatives, such as low molecular weight heparin, fondaparinux, and idraparinux;

[0235] Direct thrombin inhibitors, such as argatroban, lepirudin, bivalirudin, dabigatran, and ximelagatran; and

[0236] Tissue - plasminogen activator, for dissolving blood clots and unclogging arteries, such as reteplase.

[0237] (10) Antiplatelet drugs, including but not limited to topidogrel, ticlopidine, dipyridamole, and aspirin.

[0238] (11) Supplemental oxygen therapy.

[0239] (12) Alpha - 1 - adrenergic receptor antagonists, including but not limited to prazosin, indoramin, urapidil, bunazosin, terazosin, and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine inducer, tetrahydrocannabinol (THC), and papaverine.

[0240] (13) Bronchodilators, including but not limited to:

[0241] Short - acting beta2 - receptor agonists, such as albutamol (or albuterol) and terbutaline;

[0242] Long - acting beta2 - receptor agonists (LABA), such as salmeterol and formoterol;

[0243] Anticholinergic drugs, such as ipratropium and tiotropium; and

[0244] Theophylline, which is a bronchodilator and a phosphodiesterase inhibitor.

[0245] (14) Corticosteroids, including but not limited to beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogs such as budesonide.

[0246] (15) Dietary supplements, including but not limited to omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, tribulus terrestris, arginine, oats, epimedium, maca root, Brazilian ginseng, saw palmetto, and Swedish pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, testosterone transdermal patches; zoraxel, naltrexone, bumetanide, and melanotan II.

[0247] (16) PGD2 receptor antagonists.

[0248] (17) Immunosuppressants, including but not limited to cyclosporine, tacrolimus, rapamycin, and other FK-506 type immunosuppressants, mycophenolate mofetil, and mycophenolate.

[0249] (18) Non-steroidal anti-asthma drugs, including but not limited to:

[0250] β2-agonists such as terbutaline, orciprenaline, fenoterol, isoetharine, salbutamol, salmeterol, bitolterol, and pirbuterol;

[0251] β2-agonist-corticosteroid combinations such as salmeterol-fluticasone, formoterol-budesonide, theophylline, cromolyn, sodium cromoglycate, nedocromil, atropine, ipratropium, ipratropium bromide; and

[0252] Leukotriene biosynthesis inhibitors such as zileuton or veliflapon.

[0253] (19) Non-steroidal anti-inflammatory drugs (NSAIDs), including but not limited to:

[0254] Propionic acid derivatives such as aminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tiroxiphene;

[0255] Acetic acid derivatives such as indomethacin, acemetacin, alclofenac, cinmetacin, diclofenac, fenclofenac, fentiazac, furclofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac;

[0256] Fenamic acid derivatives such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid;

[0257] Biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal;

[0258] Oxicams, such as isoxicam, piroxicam, sudoxicam and tenoxicam;

[0259] Salicylic acids, such as acetylsalicylic acid and sulfasalazine; and

[0260] Pyrazolones, such as azapropazone, bezpiperylon, feprazone, moprolone, oxyphenbutazone and phenylbutazone.

[0261] (20) Cyclooxygenase-2 (COX-2) inhibitors, including but not limited to celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib and lumiracoxib; opioid analgesics, such as codeine, fentanyl, hydromorphone, levorphanol, pethidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine.

[0262] (21) Adrenergic neuron blockers, including but not limited to guanethidine and guanocyclidine.

[0263] (22) Imidazoline I-1 receptor agonists, including but not limited to rimenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.

[0264] (23) Potassium channel activators, including but not limited to pinacidil.

[0265] (24) Dopamine D1 agonists, including but not limited to fenoldopam mesylate; other dopamine agonists, such as ibopamine, dobutamine and doxercalciferol.

[0266] (25) 5-HT2 antagonists, including but not limited to ketanserin.

[0267] (26) Vasopressin antagonists, including but not limited to tolvaptan.

[0268] (27) Calcium channel sensitizers, including but not limited to levosimendan or activators such as nicorandil.

[0269] (28) Adenylate cyclase activators, including but not limited to colforsin dapropate hydrochloride.

[0270] (29) Positive inotropic agents, including but not limited to digoxin and methyldigoxin; metabolic cardiotonic agents, such as coenzyme Q10; brain natriuretic peptides, such as nesiritide.

[0271] (30) Drugs for treating erectile dysfunction, including but not limited to alprostadil, aviptadil, and phentolamine mesylate.

[0272] (31) Drugs for treating Alzheimer's disease and dementia, including but not limited to:

[0273] Acetylcholinesterase inhibitors, such as galantamine, rivastigmine, donepezil, and tacrine; and

[0274] NMDA receptor antagonists, such as memantine; and

[0275] Redox enzyme inhibitors, such as idebenone.

[0276] (32) Psychiatric drugs, including but not limited to:

[0277] Ziprasidone, risperidone, olanzapine, valproic acid;

[0278] Dopamine D4 receptor antagonists, such as clozapine;

[0279] Dopamine D2 receptor antagonists, such as nemonapride;

[0280] Mixed dopamine D1 / D2 receptor antagonists, such as zuclopenthixol;

[0281] GABA A receptor modulators, such as carbamazepine;

[0282] Sodium channel inhibitors, such as lamotrigine;

[0283] Monoamine oxidase inhibitors, such as moclobemide and indeloxazine; and

[0284] Primavanserin and perospirone.

[0285] (33) Drugs for treating movement disorders or symptoms, including but not limited to:

[0286] Catechol-O-methyltransferase inhibitors, such as entacapone;

[0287] Monoamine oxidase B inhibitors, such as selegiline;

[0288] Dopamine receptor modulators, such as levodopa;

[0289] Dopamine D3 receptor agonists, such as pramipexole;

[0290] Decarboxylase inhibitors, such as carbidopa;

[0291] Other dopamine receptor agonists, such as pergolide, ropinirole, cabergoline; ritigonide, itaciprant, talipexole; zonisamide and safinamide; and

[0292] Synaptic vesicle amine transporter inhibitors, such as tetrabenazine.

[0293] (34) Drugs for treating mood or emotional disorders or OCD, such as the following types:

[0294] Tricyclic antidepressants, such as amitriptyline, desipramine, imipramine, amoxapine, nortriptyline, doxepin, and clomipramine;

[0295] Selective serotonin reuptake inhibitors (SSRI), such as paroxetine, fluoxetine, sertraline, trazodone, and citalopram;

[0296] Atypical antidepressants, such as agomelatine;

[0297] Selective norepinephrine reuptake inhibitors (SNRI), such as venlafaxine, reboxetine, and atomoxetine; Dopaminergic antidepressants, such as bupropion and amifepramone.

[0298] (35) Drugs for enhancing synaptic plasticity, including but not limited to:

[0299] Nicotinic receptor antagonists, such as mecamylamine; and

[0300] Mixed 5-HT, dopamine, and norepinephrine receptor agonists, such as lurasidone.

[0301] (36) Drugs for treating ADHD, such as amphetamine; 5-HT receptor modulators, such as vortioxetine, and α-2 adrenergic receptor agonists, such as clonidine.

[0302] (37) Nitric oxide synthase cofactors, including but not limited to tetrahydrobiopterin, dihydrobiopterin, and sapropterin.

[0303] (38) Hypoglycemic drugs (also known as blood glucose control drugs or antidiabetic drugs), including but not limited to:

[0304] Biguanide drugs, such as metformin;

[0305] Sulfonylurea drugs, such as the combination of glyburide, glybenclamide, glipizide, gliclazide, gliquidone, glimepiride, atorvastatin calcium and glimerpiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, and tolazimide;

[0306] α-glucosidase inhibitors, such as acarbose, epalrestat, voglibose, and miglitol;

[0307] Insulin secretagogues, such as repaglinide, mitiglinide, and nateglinide;

[0308] Thiazolidinediones, such as rosiglitazone, troglitazone, ciglitazone, pioglitazone, englitazone, lobeglitazone sulfate, and balaglitazone;

[0309] DPP-4 inhibitors (or DPP-IV inhibitors), such as sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, the combination of alogliptin benzoate and metformin or metformin hydrochloride, allogliptin, teneligliptin, atorvastatin calcium and glimepiride, the combination of empagliflozin and linagliptin, gilteritinib, the combination of sitagliptin phosphate monohydrate and pioglitazone hydrochloride, the combination of sitagliptin and pioglitazone, the combination of sitagliptin and 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);

[0310] GLP-1 receptor agonists or incretin mimetics, such as exenatide, dulaglutide, liraglutide, semaglutide, lixisenatide, the combination of lixisenatide and insulin glargine, albiglutide, and pegapamodutide (TT-401), LY3298176 (dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist);

[0311] SGLT2 inhibitors (SGLT2is), such as empagliflozin, the combination of empagliflozin and linagliptin, the combination of empagliflozin and metformin, ipragliflozin, ipragliflozin L-proline, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, the combination of ertugliflozin and sitagliptin, the combination of ertugliflozin and metformin, sotagliflozin, canagliflozin, the combination of canagliflozin and metformin or metformin hydrochloride, dapagliflozin, the combination of dapagliflozin and metformin or metformin hydrochloride, and luseoglifozin, the combination of dapagliflozin and saxagliptin;

[0312] SGLT1 inhibitors or combinations of SGLT1 and SGLT2 inhibitors such as sotagliflozin;

[0313] Insulin therapy is one of various types of insulin, such as insulin lispro, insulin degludec, insulin lispro protamine, insulin aspart, insulin glargine, insulin detemir, isophane insulin, insulin mixtard (human insulin containing rapid-acting (soluble) and long-acting (isophane) insulin), the combination of insulin degludec and insulin aspart, inhalable powder of human insulin (rDNA origin), recombinant human insulin, liver-directed vesicular insulin, tregopi insulin (IN-105), the combination of insulin degludec and liraglutide, peglispro insulin (LY-2605541), and nodlin; and

[0314] Tolimidone (lyn kinase activator).

[0315] (39) Hypotensive drugs (also known as antihypertensive drugs), including but not limited to:

[0316] Diuretics, such as thiazide diuretics, chlorothiazide, chlorthalidone, hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xipamide, metolazone, indapamide, chlorthalidone, furosemide, toresamide, amiloride, spironolactone, potassium canrenoate, eplerenone, triamterene, acetazolamide, and carperitide;

[0317] β-blockers, such as acebutolol, atenolol, metoprolol, and nebivolol;

[0318] Angiotensin-converting enzyme (ACE) inhibitors, such as agents containing a sulfhydryl group (e.g., captopril, zofenopril), agents containing a dicarboxylate (e.g., enalapril, quinapril, ramipril, perindopril, lisinopril, and benazepril), agents containing a phosphate (e.g., fosinopril), naturally occurring ACE inhibitors (e.g., casokinins, lactokinins, the lactotripeptides Val-Pro-Pro and Ile-Pro-Pro), alacepril, delapril, cilazapril, imidapril, temocapril, moexipril, lisinopril, the combination of lisinopril and hydrochlorothiazide, trandolapril, and spirapril;

[0319] 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, the combination of amlodipine besylate and irbesartan, the combination of azilsartan and amlodipine besylate, the combination of cilnidipine and valsartan, nemonapride, the combination of irbesartan and atorvastatin, the combination of irbesartan and trichlormethiazide, the combination of losartan potassium with hydrochlorothiazide and / or amlodipine besylate, pratosartan, the combination of atorvastatin calcium and losartan potassium, nifedipine and candesartan cilexetil, the combination of sacubitril and valsartan, or LCZ-696, angiotensin AT2 antagonists, and TAK-591 and olmesartan medoxomil;

[0320] Endothelin receptor antagonists (ERAs), such as atrasentan, bosentan, sitaxentan, ambrisentan, actelion-1 (macitentan), cyclo(D-trp-D-asp-L-pro-D-val-L-leu) (BQ-123), sparsentan, and tezosentan disodium;

[0321] Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, the combination of amiloride hydrochloride and spironolactone, apararenone or MT-3995, eplerenone, and finerenone (BAY-94-8862);

[0322] Calcium channel blockers, such as amlodipine, arecalipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, diltiazem, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pradicipine, isradipine, verapamil, gallopamil, diltiazem, milradil, bepridil, fluspirilene, and fendiline;

[0323] Renin inhibitors, such as aliskiren;

[0324] Alpha blockers, such as doxazosin and prazosin;

[0325] Alpha-beta blockers, such as carvedilol and labetalol;

[0326] Centrally acting agents, such as clonidine, guanfacine, and methyldopa;

[0327] Vasodilators, such as nitroglycerin, hydralazine, and minoxidil; and

[0328] Aldosterone antagonists, such as finerenone, spironolactone, and eplerenone.

[0329] (40) Anti-hyperlipidemic drugs, including but not limited to:

[0330] Statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin;

[0331] Combinations of statins with another agent, such as amlodipine / atorvastatin, aspirin / pravastatin, ezetimibe / simvastatin, niacin / simvastatin, lovastatin / niacin, simvastatin / sitagliptin, and atorvastatin / ezetimibe;

[0332] Fibrates or fibric acid derivatives. Examples include but are not limited to fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate, and clofibrate;

[0333] Nicotinic acid (or niacin);

[0334] Bile acid sequestrants, such as cholestyramine, colesevelam, colestimide, and colestipol;

[0335] Ezetimibe, lomitapide, phytosterols, or orlistat; and

[0336] PCSK9 inhibitors, such as alirocumab and evolocumab;

[0337] (41) Neprilysin inhibitors (also known as endopeptidase inhibitors or NEP inhibitors or neprilysin inhibitors), including but not limited to sacubitril, or combinations of sacubitril with valsartan; neprilysin inhibitors TD-1439 or TD-0714 under development.

[0338] (42) Renal protective drugs, including but not limited to:

[0339] Budesonide;

[0340] ACE inhibitors, such as captopril;

[0341] ARBs, such as losartan or irbesartan;

[0342] SGLT2 inhibitors, such as canagliflozin,

[0343] GLP1 receptor agonists;

[0344] MRAs, such as finerenone;

[0345] ERAs, such as atrasentan; and apoptosis signal-regulating kinase 1 (ASK1) inhibitors, such as selonsertib.

[0346] (43) Hydroxycarbamide (HU, hydroxyurea).

[0347] (44) Anti-sickling agents, including but not limited to hydroxycarbamide, voxelotor or GBT-440.

[0348] (45) Anti-adhesion therapies, including but not limited to antibodies that block P-selectin, E-selectin, VLA-4, VCAM-1.

[0349] (46) Glutamine.

[0350] (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 (ESA), two examples of which are epoetin alfa and epoetin beta.

[0351] (48) Antibiotics, including but not limited to:

[0352] Penicillins and their derivatives, including but not limited to penicillin, amoxicillin, ampicillin, azlocillin, cloxacillin, penicillin G, penicillin V, procaine penicillin or benzathine penicillin, etc.

[0353] Cephalosporins, such as cephalexin, cefadroxil, cefaclor, cefuroxime and cefexime;

[0354] Macrolides, such as erythromycin, clarithromycin, azithromycin and roxithromycin;

[0355] Tetracyclines and their derivatives, such as demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline;

[0356] Sulfonamides, including but not limited to mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfasalazine, trimethoprim-sulfamethoxazole (co-trimoxazole) and sulfisoxazole; and

[0357] Quinolones, including but not limited to ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, and nalidixic acid.

[0358] (49) FXR agonists, including but not limited to obeticholic acid, cenicriviroc, enilicic acid, GR-MD-02, selonsertib, and elafibranor.

[0359] (50) Thyroid receptor-β agonists, including but not limited to MGL-3196.

[0360] (51) Acetyl-CoA carboxylase inhibitors, including but not limited to GS-0976.

[0361] (52) Therapeutic agents 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 (Carnitor); creatine; citrulline, and L-arginine.

[0362] (53) Treatment of epilepsy or seizures, including but not limited to phenytoin, valproic acid, phenobarbital, lamotrigine, carbamazepine, topiramate, oxcarbazepine, zonisamide, gabapentin, levetiracetam, pregabalin, clonazepam, lacosamide, ruclopride, and vigabatrin.

[0363] Packaging and kits

[0364] The pharmaceutical compositions (or formulations) used can be packaged in various ways depending on the method of administration. Generally, articles for distribution include a container having the pharmaceutical formulation placed therein in a suitable 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 may also include a tamper-proof assemblage to prevent inadvertent contact with the contents of the package. Additionally, the container has a label thereon that describes the contents of the container. Appropriate warnings may also be included on the label.

[0365] The compounds and pharmaceutical formulations described herein can be included in a kit. The kit can include two or more agents in single or multiple doses, each separately packaged or formulated, or two or more agents in single or multiple doses packaged or formulated together. Thus, one or more reagents can be present in a first container, and the kit can optionally include one or more reagents in a second container. The one or more containers are placed within a package, and the package can optionally include administration or dosage instructions. The kit can include additional components, such as a syringe or other device for administering the reagent and 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 contain instructions that describe the method of using the pharmaceutical composition in one or more of the methods described herein (e.g., for preventing or treating one or more of the diseases and disorders described herein). The kit can optionally contain a second pharmaceutical composition comprising one or more additional reagents for combination therapy described herein, a pharmaceutically acceptable carrier, vehicle, or diluent. The pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit can optionally be combined in the same pharmaceutical composition. Examples

[0366] All references provided in the Examples are incorporated herein by reference. As used herein, all abbreviations, symbols, and conventions are consistent with those used in contemporary scientific literature. See, for example, Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997, which is incorporated herein by reference in its entirety.

[0367] Various embodiments of the invention are described below.

[0368] Definitions of abbreviations used in the Examples section are provided in the table below.

[0369]

[0370]

[0371] Synthesis Section

[0372] Example 1: Synthesis of Compounds in Tables I - IV

[0373] The present invention also provides methods for synthesizing the compounds of Tables I-IV, which represent another aspect of the present invention. The compounds of the present invention can be prepared according to the general and specific syntheses described herein, synthetic procedures reported in the chemical literature, or methods known to those skilled in the art. As will be understood by those skilled in the art, the optimal reaction conditions, which can be determined during experimentation, can vary based on the type of reaction and the specific reagents used in the reaction. Thus, unless otherwise specified, those skilled in the art can readily select and modify reaction conditions, such as pressure, temperature, relative proportions of reagents, solvents, and reaction time, without undue experimentation. The compounds and intermediates of the present invention can be purified by purification methods known to those skilled 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 on RP-HPLC can be carried out using a suitable gradient on a suitable reverse-phase column (e.g., Waters XBridge OBD C18, 5 μm, 19 x 150 mm) selected from a gradient of 0% to 100% acetonitrile / water containing an additive (e.g., 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 mixtures of enantiomers by resolution using chiral HPLC. The progress of the reaction can be monitored by methods known to those skilled in the art, such as thin-layer chromatography, reverse-phase HPLC, or tandem reverse-phase HPLC-mass spectrometry (LC-MS).

[0374] The starting materials used in the syntheses described herein are available from commercial sources or can be prepared by those skilled in the art using methods reported in the chemical literature or methods cited herein.

[0375] 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. Thus, they are not intended to impose any limitation on the subject matter and scope of the compounds claimed in the present invention.

[0376] All references provided in the Examples are incorporated herein by reference. As used herein, all abbreviations, symbols, and conventions are consistent with those used in contemporary scientific literature. See, for example, G.M. Banik, G. Baysinger, P.V. Kamat, N.J. Pienta, eds., The ACS Guide to Scholarly Communication, Washington, D.C.: American Chemical Society, 2020 (https: / / pub.acs.org / doi / book / 10.1021 / acsguide), which is incorporated herein by reference in its entirety.

[0377] General Procedure 1:

[0378]

[0379] The compounds of Tables I-IV can be prepared using the general synthesis described in Scheme 1. X, J C , J C1 , J B , J D1 and J D2 are each as defined above, or a precursor, intermediate, or protected form thereof. Specific variants of each compound will be apparent to those skilled in the art and, in some instances, are shown below.

[0380] Synthesis of 2-(8-(2,4-difluorobenzyl)-3-mercaptoimidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (I-2) Synthesis:

[0381]

[0382] Compound I-2-1 is converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound undergoes a 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 bis(diphenylphosphino)ferrocene palladium(II) dichloride to give compound I-2-4. PMBSH is 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 is reacted with ammonium chloride to give compound I-2-6. The amidine of compound I-2-6 is condensed with compound I-2-7 to give the cyclized compound I-2-8. Finally, the protected thiol of compound I-2-8 is deprotected to give compound I-2.

[0383] Synthesis of 6-(5-fluoro-4-hydroxypyrimidin-2-yl)-8-(2,4,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-2-carbonitrile (I-3) Synthesis:

[0384]

[0385] Compound I-3-1 was converted to the corresponding organozinc compound using zinc, 1,2-dibromoethane, and TMSCl. The organozinc compound was subjected to Negishi coupling in the presence of compound I-3-2 to afford 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 in the presence of heat to afford the 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 afford the cyclized compound I-3-9. The carboxylic acid of compound I-3-9 was converted to the corresponding amide, and then dehydrated to give the nitrile compound I-3.

[0386] Synthesis of I-3-3

[0387] 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) at 50 °C for 10 min under a nitrogen atmosphere, and then TMSCl (0.43 mL, 3.364 mmol, 0.05 equiv) was added dropwise at 50 °C. Then 1-(bromomethyl)-2,4,5-trifluorobenzene (I-3-1, 15 g, 66.664 mmol, 1.00 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. 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) were added to the above mixture 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 x 400 mL). The combined organic layers were washed with brine (2 x 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), gradient from 0% to 100% in 10 min; and detector UV 254 nm to give 5-bromo-3-[(2,4,5-trifluorophenyl)methyl]pyrazin-2-amine (I-3-3, 13.9 g, yield 65.5%) as a yellow solid. LC-MS: (ESI) m / z 318.00 [M+H].

[0388] Synthesis of I-3-4

[0389] 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)2 (5.13 g, 43.697 mmol, 1.00 equiv), Zn (0.57 g, 8.739 mmol, 0.20 equiv) and Pd(dppf)Cl2 (0.80 g, 1.093 mmol, 0.03 equiv) in DMF (250 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was then cooled to room temperature. The reaction was quenched by the addition of water (200 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (2 x 100 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 / water (0.1% FA), gradient from 0% to 100% in 10 min; and detector UV 254 nm, to give 5-amino-6-[(2,4,5-trifluorophenyl)methyl]pyrazine-2-carbonitrile (I-3-4, 10 g, yield 86.6%), which was a brown solid. LC-MS: (ESI) m / z 262.9 [M+H].

[0390] Synthesis of I-3-6

[0391] 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 x 200 mL), and the combined organic layers were washed with brine (2 x 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 / water (0.1% FA), gradient from 0% to 100% in 8 min; and detector UV 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, yield 42%), which was a yellow solid. LC-MS: (ESI) m / z 361.1 [M+H].

[0392] Synthesis of I-3-7

[0393] 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. NH4Cl (1.68 g, 31.464 mmol, 2 equiv) was added to the above mixture at 45 °C, and the resulting mixture was stirred at 45 °C for another 2 h. The reaction was quenched with water (50 mL) at room temperature. The aqueous layer was extracted with CH2Cl2 / IPA in a ratio of 3 / 1 (3 x 150 mL). The combined organic extracts were then washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give methyl 6-formamido-8-[(2,4,5-trifluorophenyl)methyl]imidazo[1,2-a]pyrazine-2-carboxylate (I-3-7, 5 g, crude), which was a yellow solid. LC-MS: (ESI) m / z 364.1 [M+H].

[0394] Synthesis of I-3-9

[0395] To a stirred solution of methyl 6-formamido-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) at room temperature and under a nitrogen atmosphere was added dropwise NaOMe (5.90 g, 32.757 mmol, 3.50 equiv, 30% wt in MeOH). The resulting mixture was stirred at 70 °C for another 4 h. Then the mixture was 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 x 120 mL). The combined organic layers were washed with brine (2 x 120 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 / water (0.1% FA), gradient from 0% to 100% in 10 min; and detector UV 254 nm to give 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, yield 15.3%), which was a yellow solid. LC-MS: MS (ESI) m / z 420.1 [M+H].

[0396] Synthesis of I-3

[0397] At room temperature and under a nitrogen atmosphere, TEA (434 mg, 4.289 mmol, 3.00 equiv) and NH3(g) (0.95 mL, 1.240 mmol, 4 equiv, 1.3 M in THF) were added dropwise 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). The resulting mixture was stirred at room temperature for an additional 4 h. The resulting mixture was then extracted with EtOAc (3 x 60 mL), and the combined organic layers were washed with brine (2 x 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), gradient from 0% to 100% in 10 min; and detector UV 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, yield 33.5%), which was a yellow solid. LC-MS: (ESI) m / z 419.15 [M+H].

[0398] 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) prepared as above in phosphoryl chloride (2 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with 1,4-dioxane (5 mL) and then concentrated under reduced pressure. NaOH (2.5 mL, 2 mmol) and dioxane (2 mL) were added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 2 h. Then the resulting mixture was extracted with EtOAc (3 x 20 mL), and the combined organic layers were washed with brine (2 x 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 / water (0.1% FA), gradient from 0% to 100% in 10 min; and detector UV 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, yield 4%, purity 80.4%), which was an off-white solid.

[0399] LC-MS: (ESI) m / z 410.10 [M+H].

[0400] 1 1H 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).

[0401] 19 19F 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.

[0402] 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]pyrazine- 8-yl)methyl)-5-methylbenzonitrile (I-32):

[0403]

[0404] Compound I-4-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound was subjected to Negishi coupling in the presence of compound I-4-2 to afford 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 the amidine compound I-4-5. The amidine of compound I-4-5 was condensed with compound I-4-6 in NaOMe / MeOH to afford the cyclized compound I-4-7 and compound I-32-1. Both cyclization products were carried forward. The aryl bromide of compound I-4-7 was reacted with compound I-32-1 in the presence of zinc, zinc cyanide, Pd2(dba)3, and diphenylphosphinoferrocene to give the cyano compounds I-4 and I-32, respectively.

[0405] Synthesis of 1-4-1

[0406] 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 was added dropwise BH3-THF (30.25 mL, 30.254 mmol, 1.5 equiv, 1 M in THF). The mixture was stirred at 50 °C for 3 h. The reaction was quenched by the addition of water (100 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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 afford (4-bromo-5-fluoro-2-methylphenyl)methanol (4.5 g, crude), which was a grayish-white solid. 1 1H 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).

[0407] At 0 °C, phosphorus tribromide (0.93 g, 3.424 mmol, 0.5 equiv) was added to a stirred solution of (4-bromo-5-fluoro-2-methylphenyl)methanol (1.5 g, 6.848 mmol, 1 equiv) in diethyl ether (20 mL). The mixture was stirred at 25 °C for 4 h. The reaction was quenched by the addition of water (50 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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 1-bromo-4-(bromomethyl)-2-fluoro-5-methylbenzene (I-4-1, 2.1 g, crude), which was a grayish-white solid. It was used directly in the next step without further purification.

[0408] Synthesis of I-4-2

[0409] At 25 °C, 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 (9.59 g, 27.084 mmol, 1.5 equiv). The mixture was stirred at 60 °C for 10 h. The reaction was quenched by the addition of water (200 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 300 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 6,8-dibromo-3-fluoroimidazo[1,2-a]pyrazine (I-4-2, 1.5 g, yield 28%), which was a pale yellow solid. LC-MS: (ESI) m / z 295.9 [M+H]. 1 1H NMR: (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.58 (d, J = 6.8 Hz, 1H).

[0410] Synthesis of I-4-3

[0411] At 25 °C and under a nitrogen atmosphere, dibromoethane (31.8 mg, 0.170 mmol, 0.1 equiv) was added dropwise to a stirred solution of Zn (221.7 mg, 3.390 mmol, 2 equiv) in anhydrous THF (5 mL). The mixture was stirred at 50 °C for 10 min under a nitrogen atmosphere. Then TMSCl (18.42 mg, 0.170 mmol, 0.1 equiv) was added, and the mixture was cooled to ambient temperature. Then, 1-bromo-4-(bromomethyl)-2-fluoro-5-methylbenzene (I-4-1, 717.0 mg, 2.542 mmol, 1.5 equiv) was added dropwise at 0 °C still under a nitrogen atmosphere. The mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h. 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 still under a nitrogen atmosphere. The mixture was stirred at 50 °C under a nitrogen atmosphere for 4 h. The reaction was quenched by adding water (50 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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, yield 85%), which was a pale yellow solid. LC-MS: (ESI) m / z 417.9 [M+H]. 1 1H 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).

[0412] Synthesis of I-4-4

[0413] Under a nitrogen atmosphere at 25 °C, zinc cyanide (101.3 mg, 0.863 mmol, 0.6 eq), Zn (18.8 mg, 0.288 mmol, 0.2 eq) and Pd(dppf)Cl2 (26.3 mg, 0.036 mmol, 0.025 eq) were added 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 eq) in anhydrous DMF (5 mL). The mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. Then the reaction was quenched by adding water (100 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4, 365 mg, yield 70%), which was a grayish-white solid. LC-MS: (ESI) m / z 363.0 [M+H]. 1 1H 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).

[0414] Synthesis of I-4-5

[0415] At 25 °C, NaOMe (18.1 mg, 0.100 mmol, 0.1 eq., 30% wt in MeOH) was added 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 eq.) in MeOH (5 mL). The mixture was stirred at 70 °C for 4 h, at which time NH4Cl (107.5 mg, 2.010 mmol, 2 eq.) 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 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carboximidamide (I-4-5, 392 mg, crude), which was a brown solid. LC-MS: (ESI) m / z 380.0 [M+H].

[0416] Synthesis of I-4-6

[0417] At 0 °C, EtOH (0.05 mL, 0.943 mmol, 0.1 eq.) was added to a stirred solution of NaH (0.23 g, 9.425 mmol, 1 eq.) in Et2O (50 mL). The mixture was stirred at 0 °C for 10 min. Ethyl 2-fluoroacetate (1 g, 9.425 mmol, 1 eq.) and ethyl formate (0.70 g, 9.425 mmol, 1 eq.) were added at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and then concentrated under reduced pressure to afford ethyl 2-fluoro-3-oxopropionate (I-4-6, 1.5 g, crude), which was a light yellow solid and could be used directly in the next step.

[0418] Synthesis of I-4-7

[0419] At 25 °C, 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) was added ethyl 2-fluoro-3-oxopropionate (I-4-6, 275.1 mg, 2.052 mmol, 2 equiv) and NaOMe (369.4 mg, 2.052 mmol, 2 equiv, 30% in MeOH). The mixture was stirred at 70 °C for 8 h. The reaction was quenched by adding water (50 mL) at room temperature, and then acidified to pH 3 - 4 with concentrated HCl (10 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-4-7, 280 mg, yield 60.5%), which was a brown solid.

[0420] LC-MS: (ESI) m / z 449.95 [M+H].

[0421] Synthesis of I-4

[0422] Under a nitrogen atmosphere at 25 °C, 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)2 (138.2 mg, 1.178 mmol, 2 equiv), Zn (7.7 mg, 0.118 mmol, 0.2 equiv) and Pd(dppf)Cl2 (43.0 mg, 0.059 mmol, 0.1 equiv). The mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. Then the mixture was 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 / water (10 mmol / L NH4HCO3), gradient from 5% to 80% in 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, purity 91%, yield 18%), which was an off-white solid.

[0423] 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。

[0424] Compound I-32 can also be isolated according to the above protocol. It is an impurity derived from I-32-1, which is formed in the step of synthesizing I-4-7, or it can be prepared by a different method as described below.

[0425] Synthesis of 2-fluoro-4-((6-(5-fluoro-4-hydroxypyrimidin-2-yl)-3-methoxyimidazo[1,2-a]pyrazin-8-yl)meth yl)-5-methylbenzonitrile (I-32):

[0426]

[0427] Compound I-32 can be prepared in the following manner summarized in the above protocol. Compound I-4-1 is converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound undergoes a Negishi coupling in the presence of compound I-4-2-1 to give compound I-4-3-1. Compound I-4-3-1 further reacts in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give compound I-4-4-1. Using selectfluor TM Compound I-4-4-1 is fluorinated to give compound I-4-4. The nitrile of compound I-4-4 reacts with ammonium chloride in methanol in the presence of sodium methoxide to give the amidine compound I-4-5-1. The amidine of compound I-4-5-1 condenses with compound I-4-6 in NaOMe / MeOH to give the cyclized compound I-32-1. The aryl bromide of compound I-32-1 reacts in the presence of zinc, zinc cyanide, and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride to give the cyano compound I-32.

[0428] Synthesis of I-4-3-1

[0429] Under a nitrogen atmosphere, dibromoethane (DBE, 0.17 g, 0.906 mmol, 0.1 eq) was added to a stirred solution of Zn (1.19 g, 18.128 mmol, 2 eq) in anhydrous THF (40 mL) at 25 °C. The mixture was stirred at 50 °C for 10 min under a nitrogen atmosphere. TMSCl (0.10 g, 0.906 mmol, 0.1 eq) was added and the mixture was cooled to ambient temperature. Then 1-bromo-4-(bromomethyl)-2-fluoro-5-methylbenzene (I-4-1, 3.83 g, 13.596 mmol, 1.5 eq) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. Then 6,8-dibromoimidazo[1,2-a]pyrazine (I-4-2-1, 2.51 g, 9.064 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.13 g, 0.181 mmol, 0.02 eq) were added at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 4 h under a nitrogen atmosphere. Then the reaction was quenched by adding water (100 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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, yield 96%), which was a grayish-white solid. LC-MS: (ESI) m / z 399.9 [M+H].

[0430] Synthesis of I-4-4-1

[0431] 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)Cl2 (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 by the addition of water (200 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4-1, 2.2 g, yield 73.5%), which was a pale yellow solid. LC-MS: (ESI) m / z 345.0 [M+H].

[0432] Synthesis of I-4-4

[0433] At 25 °C under a nitrogen atmosphere, 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 (4.52 g, 12.748 mmol, 2 equiv) and NaHCO3 (1.34 g, 15.935 mmol, 2.5 equiv). The mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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 8-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (I-4-4, 1.3 g, yield 56%), which was an off-white solid. LC-MS: MS(ESI) m / z363.0 [M+H].

[0434] Synthesis of I-4-5-1

[0435] At 25 °C, NaOMe (48.5 mg, 0.270 mmol, 0.1 eq., 30% wt in MeOH) was added 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 eq.) in MeOH (5 mL). The mixture was stirred at 70 °C for 3 h. Then, MeONa (437.3 mg, 8.094 mmol, 3 eq.) was added, and the mixture was stirred at 70 °C for another 4 h. Then, NH4Cl (288.6 mg, 5.396 mmol, 2 eq.) was added, and the mixture was stirred at 70 °C for another 5 h. The reaction was quenched by the addition of saturated NaHCO3 (aqueous solution) (20 mL) at room temperature, and the resulting mixture was extracted with IPA / DCM = 1:3 (3 x 100 mL). The combined organic layers were washed with brine (1 x 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), which was a brown solid. LC-MS (ESI) m / z 392.0 [M+H].

[0436] Synthesis of I-32-1

[0437] At 25 °C, ethyl 2-fluoro-3-oxopropionate (I-4-6, 940.2 mg, 7.010 mmol, 2.5 eq.) and NaOMe (1.51 g, 8.412 mmol, 3 eq., 30% wt in MeOH) were added 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 eq.) in MeOH (6 mL). The mixture was stirred at 70 °C for 8 h. Then, the reaction was quenched by the addition of 1 M HCl (aqueous solution) (10 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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-[(4-bromo-5-fluoro-2-methylphenyl)methyl]-3-methoxyimidazo[1,2-a]pyrazin-6-yl}-5-fluoropyrimidin-4-ol (I-32-1, 402 mg, yield 31%), which was an off-white solid. LC-MS (ESI) m / z 462.0 [M+H].

[0438] Synthesis of I-32

[0439] Under a nitrogen atmosphere at 25 °C, Zn(CN)2 (101.6 mg, 0.866 mmol, 2 equiv), Pd(dppf)Cl2 (6.3 mg, 0.009 mmol, 0.02 equiv), and Zn (5.6 mg, 0.087 mmol, 0.2 equiv) were added 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). The mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. Then the mixture was 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 / H2O (0.1% TFA), gradient from 5% to 80% in 10 min; and detector UV 254 / 220 nm, to give 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, yield 22%), which was a grayish-white solid. LC-MS (ESI) m / z 409.10 [M+H]. 1 1H 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 19F NMR: (376 MHz, DMSO-d6) δ -113.38, -153.49.

[0440] 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): Synthesis of 2-(8-(4-chloro-2,5-difluorobenzyl)-3-methylimidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidine-4,6-

[0441]

[0442] Compound I-5-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound was subjected to 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 the amidine compound I-5-5. The amidine of compound I-5-5 was condensed with compound I-5-6 to give the cyclized compound I-5 and compound I-44.

[0443] Synthesis of I-5-6

[0444] Under a nitrogen atmosphere at room temperature, NaH (282.7 mg, 11.783 mmol, 2.5 equiv, 60% mineral oil) was added portionwise to a stirred solution of ethyl 2-fluoroacetate (500 mg, 4.713 mmol, 1 equiv) in Et2O (10 mL). The resulting mixture was stirred at 40 °C for 4 h under a nitrogen atmosphere. Then the mixture was cooled to room temperature. The reaction was quenched by adding water / ice (40 mL) and concentrated H2SO4 (1 mL) at 0 °C. The resulting mixture was extracted with Et2O (3 x 20 mL), and the combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. 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), which was a pale yellow oil.

[0445] Synthesis of I-5-1

[0446] Under a nitrogen atmosphere at 0 °C, BH3-THF (499.2 mg, 5.810 mmol, 2 equiv, 1 M in THF) was added dropwise to a stirred solution of 2,5-difluoro-4-methylbenzoic acid (500 mg, 2.905 mmol, 1 equiv) in THF (2.5 mL). The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched by adding brine (10 mL) at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 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, yield 83%), which was an off-white solid. 1 1H 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).

[0447] Under a nitrogen atmosphere at 0 °C, phosphorus tribromide (260.2 mg, 0.961 mmol, 0.4 eq) was added to a stirred solution of the above-prepared (2,5-difluoro-4-methylphenyl)methanol (380 mg, 2.403 mmol, 1 eq) in Et2O (5 mL). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched by the addition of water / ice (20 mL) at room temperature. The organic layer was washed with saturated NaHCO3 (1 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(bromomethyl)-2,5-difluoro-4-methylbenzene (I-5-1, 350 mg, crude), which was a pale yellow oil. 1 1H 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).

[0448] Synthesis of I-5-3

[0449] Under a nitrogen atmosphere, dibromoethane (14.9 mg, 0.079 mmol, 0.05 equiv) was added dropwise to a stirred mixture of Zn (155.3 mg, 2.374 mmol, 1.5 equiv) in THF (5 mL) at 50 °C. The resulting mixture was stirred at 50 °C for 10 min under a nitrogen atmosphere. Then, TMSCl (8.6 mg, 0.079 mmol, 0.05 equiv) was added to the above mixture, and the resulting mixture was stirred at room temperature for another 10 min. 1-(Bromomethyl)-2,5-difluoro-4-methylbenzene (I-5-1, 350 mg, 1.583 mmol, 1 equiv) was added to this mixture at 0 °C. Then the resulting mixture was stirred at 0 °C for an additional 15 min and then at room temperature for 2 h. Then, 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) were added to this mixture at room temperature. The final resulting mixture was stirred at 40 °C for 1 h, after which it was filtered. The filter cake was washed with THF (1 x 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 / water (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector UV 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, yield 45%), which was a light yellow solid. LC-MS: (ESI) m / z 338.85 [M+H].

[0450] Synthesis of I-5-4

[0451] At room temperature under a nitrogen atmosphere, Pd(dppf)Cl2 (13.0 mg, 0.018 mmol, 0.025 equiv) and Zn (9.3 mg, 0.142 mmol, 0.2 equiv) were added 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)2 (49.9 mg, 0.425 mmol, 0.6 equiv) in DMF (4 mL). The resulting mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. Then the mixture was 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 / H2O (0.1% formic acid), gradient from 0% to 100% in 10 min; 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, yield 67%), which was a light yellow solid. LC-MS (ESI) m / z 286.10 [M+H].

[0452] Synthesis of I-5-5

[0453] At room temperature under a nitrogen atmosphere, NaOMe (2.6 mg, 0.048 mmol, 0.1 equiv, 30% wt in MeOH) was added 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). The resulting mixture was stirred at 40 °C for 3 h under a nitrogen atmosphere. Then at room temperature, NH4Cl (51.0 mg, 0.954 mmol, 2 equiv) was added to the above mixture and the resulting mixture was stirred at 40 °C overnight. The mixture was cooled to room temperature. The reaction was quenched by adding saturated sodium bicarbonate at room temperature, and the resulting mixture was diluted with water (20 mL) and extracted with CH2Cl2 / IPA = 3 / 1 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. 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), which was a pale yellow solid. LC-MS: (ESI) m / z 303.20 [M+H].

[0454] Synthesis of Compounds I-5 and I-44

[0455] At room temperature under a nitrogen atmosphere, NaOMe (232.3 mg, 1.290 mmol, 3 equiv., 30% wt in MeOH) was added 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). The resulting mixture was stirred at 70 °C for 1.5 h under a nitrogen atmosphere. Then the reaction was quenched by adding water (1 mL) at room temperature and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% formic acid), gradient from 0% to 100% in 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-fluoro-6-(fluoromethyl)pyrimidin-4-ol (I-5, 44.0 mg, yield 25%), which is 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, yield 16%), which is an off-white solid.

[0456] I-5 = LC-MS: (ESI) m / z 405.15 [M+H].

[0457] 1 1H 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).

[0458] 19 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).

[0459] I-44 = LC-MS: (ESI) m / z 431.20 [M+H].

[0460] 11H 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).

[0461] 19 19F NMR: (376 MHz, DMSO-d6) δ -123.10 (d, J = 18.1 Hz), -123.21 (d, J = 18.3 Hz), -151.04.

[0462] diol (I-6) and 2,5-difluoro-4-((6-(5-fluoro-4,6-dihydroxypyrimidin-2-yl)-3-methylimidazo[1,2-a]pyrazine- 8-yl)methyl)benzonitrile (I-42): 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:

[0463]

[0464] Compound I-6-1 was converted to the corresponding organozinc compound using zinc, 1,2-dibromoethane, and TMSCl. Compound I-6-2 was synthesized by cyclizing compound I-6-2-1 with 2-bromo-1,1-diethoxypropane. The organozinc compound was subjected to Negishi coupling in the presence of compound I-6-2 to afford compound I-6-3. Compound I-6-3 was further reacted in the presence of zinc, zinc cyanide, and palladium(II) dichloride bis(1,1'-bis(diphenylphosphino)ferrocene) to give compound I-6-4. The nitrile of compound I-6-4 was reacted with ammonium chloride to afford the amidine compound I-6-5. The amidine of compound I-6-5 was condensed with compound I-6-6 to give the cyclized compound I-6. The aryl chloride of I-6 was reacted in the presence of zinc, zinc cyanide, Pd2(dba)3, and diphenylphosphinoferrocene to give the cyano compound I-42.

[0465] Synthesis of I-6-1

[0466] 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 was added LiAlH4 (867.2 mg, 22.851 mmol, 2.2 equiv) portionwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (3 x 20 mL). 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 (4-chloro-2,5-difluorophenyl)methanol (1.7 g, 92% yield) as a colorless oil. 1 1H 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).

[0467] To a stirred solution of (4-chloro-2,5-difluorophenyl)methanol (1.7 g, 9.55 mmol, 1.0 equiv) prepared as above in anhydrous Et2O (25 mL) at 0 °C was added PBr3 (1.28 g, 4.77 mmol, 0.5 equiv). The resulting mixture was stirred at room temperature for 0.5 h. The reaction was then quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give 1-(bromomethyl)-4-chloro-2,5-difluorobenzene (I-6-1, 2.28 g, crude) as a colorless oil. 1 1H NMR (400 MHz, chloroform-d) δ 7.23 - 7.13 (m, 2H), 4.43 (s, 2H).

[0468] Synthesis of I-6-2

[0469] 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 x 10 mL) to give 6,8-dibromo-3-methylimidazo[1,2-a]pyrazine (I-6-2, 700 mg, crude) as a white solid. The crude product was used in the next step without further purification. LC-MS: MS (ESI) m / z 291.9 [M+H].

[0470] Synthesis of I-6-3

[0471] To a stirred solution of Zn (211.2 mg, 3.23 mmol, 2.0 equiv) in anhydrous THF (4 mL) at 50 °C was added 1,2-dibromoethane (12.1 mg, 0.065 mmol, 0.04 equiv). The resulting mixture was stirred for a period of 10 min at 50 °C. Then, TMSCl (8.7 mg, 0.081 mmol, 0.05 equiv) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred for another 10 min at room temperature 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 for 2 h at room temperature. 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 for 2 h at 45 °C. The mixture was cooled to room temperature and then diluted with water (5 mL). The aqueous layer was extracted with EtOAc (3 x 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 and eluted 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, yield 63%), which was a yellow solid. LC-MS (ESI) m / z 374.0 [M+H].

[0472] Synthesis of I-6-4

[0473] At room temperature, Zn(CN)2 (58.3 mg, 0.496 mmol, 0.5 equiv) and Pd(dppf)Cl2 (20.1 mg, 0.025 mmol, 0.025 equiv) were added 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). The resulting mixture was stirred at 120 °C for 2 h. Then the mixture was cooled to room temperature and quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 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 (1:1) to afford 8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carbonitrile (I-6-4, 260 mg, 82% yield), which was a white solid. LC-MS: (ESI) m / z 319.10 [M+H].

[0474] Synthesis of I-6-5

[0475] At room temperature, NaOMe (2.8 mg, 0.016 mmol, 0.10 equiv, 30% wt in methanol) was added 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), and the resulting mixture was stirred at 45 °C for 2 h. Then NH4Cl (78.9 mg, 1.474 mmol, 2.0 equiv) was added, and the mixture was stirred at 45 °C for an additional 2 h. The reaction was quenched by adding water (5 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The combined organic layers were dried in vacuo to afford (8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carboxamidine (I-6-5, 240 mg, crude), which was a brown solid. LC-MS: (ESI) m / z 335.9 [M+H].

[0476] Synthesis of Compound I-6

[0477] At room temperature, 2-fluoromalonic acid 1,3-dimethyl ester (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) were added to a stirred solution of 8-[(4-chloro-2,5-difluorophenyl)methyl]-3-methylimidazo[1,2-a]pyrazine-6-carboxamidine (I-6-5, 230 mg, 0.685 mmol, 1 equiv) in anhydrous MeOH (5 mL). The resulting mixture was stirred at 70 °C for 2 h and then allowed to cool to room temperature. The crude product was precipitated by the addition of 1 M HCl (5 mL) and purified by trituration with DMSO (5 mL) to give 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, yield 21%), which was 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, 1H), 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.

[0478] Compound I-6 was reacted in the presence of zinc, zinc cyanide, Pd2(dba)3 and ferrocenyldiphenylphosphine to give the cyano compound I-42.

[0479] Synthesis of 1-(8-(2,5-difluorobenzyl)-6-(5-fluoro-4-hydroxy-6-methylpyrimidin-2-yl)imidazo[1,2-a]pyrazine- 3-yl)ethan-1-one (I-8) and 2-(8-(2,5-difluorobenzyl)-3-(1-hydroxyethyl)imidazo[1,2-a]pyrazin-6-yl)-

[0480]

[0481] Compound I-7-4 was prepared by a method similar to that of Compound I-4-4. The nitrile of Compound I-7-4 was reacted with ammonium chloride in NaOMe / MeOH to give Compound I-7-5 and Compound I-46-5. The amidines of Compound I-7-5 and I-46-5 were condensed with Compound I-7-6 to give the 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-trioxatriangulane in the presence of palladium to give Compound I-7 and I-46.

[0482] Synthesis of Compound I-7

[0483] Under a nitrogen atmosphere at room temperature, SPhos (19.7 mg, 0.048 mmol, 0.1 eq), SPhos Palladacycle Gen.3 (37.35 mg, 0.048 mmol, 0.1 eq) and K2CO3 (132.3 mg, 0.958 mmol, 2 eq) were added 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 eq) and trimethyl-1,3,5,2,4,6-trioxatriborinane (120.2 mg, 0.958 mmol, 2 eq) in dioxane (4 mL). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere and then cooled to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector: UV 254 nm, to give 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), which was a pale gray solid. LC-MS (ESI): m / z 398.15 [M+H]. 1 H NMR: (400 MHz, DMSO-d6) δ 11.85 (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 F NMR: (376 MHz, DMSO-d6) δ -123.12 (dd, J = 26.2, 18.8 Hz), -129.25 。

[0484] 5-fluoro-6-methylpyrimidin-4-ol (I-31): Synthesis of 1-(4-((3-chloro-6-(5-fluoro-4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyrazin-8-yl)methyl)-3-fluoro phenyl)ethan-1-one (I-9) and 2-(3-chloro-8-(2-fluoro-4-(1-hydroxyethyl)benzyl)imidazo[1,2-a]pyrazin-6-

[0485]

[0486] Compound I-8-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound was subjected to 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 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 the amidine compound I-8-5. The amidine of compound I-8-5 was condensed with compound I-8-6 to give the 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 ethoxyvinyltin 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.

[0487] Synthesis of I-8-3

[0488] Under a nitrogen atmosphere at 25 °C, dibromoethane (90.7 mg, 0.483 mmol, 0.05 equiv) was added to a stirred solution of Zn (0.95 g, 14.491 mmol, 1.5 equiv) in anhydrous THF (20 mL). The mixture was stirred under a nitrogen atmosphere at 50 °C for 10 min. 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 under a nitrogen atmosphere at 25 °C for 2 h. Then 6,8-dibromoimidazo[1,2-a]pyrazine (I-8-2, 1.87 g, 6.763 mmol, 0.7 equiv) and Pd(PPh3)2Cl2 (135.6 mg, 0.193 mmol, 0.02 equiv) were added at 25 °C under a nitrogen atmosphere. The mixture was stirred under a nitrogen atmosphere at 50 °C for 2 h. Then the reaction was quenched by adding water (50 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine (I-8-3, 1.82 g, 58% yield), which was a grayish-white solid. LC-MS: (ESI) m / z 323.9 [M+H]. 11H 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).

[0489] Synthesis of I-8-4

[0490] Under a nitrogen atmosphere at 25 °C, Zn (80.6 mg, 1.234 mmol, 0.2 equiv), Zn(CN)2 (434.7 mg, 3.702 mmol, 0.6 equiv) and Pd(dppf)Cl2 (112.8 mg, 0.154 mmol, 0.025 equiv) were added 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), and the resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 h. The reaction was quenched by adding water (200 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 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 (3:1) to give 8-[(2,5-difluorophenyl)methyl]imidazo[1,2-a]pyrazine-6-carbonitrile (I-8-4, 1.72 g, crude), which was a pale yellow solid. The crude product was used in the next step without further purification. LC-MS: (ESI) m / z 271.0 [M+H].

[0491] Synthesis of I-8-5

[0492] At 25 °C, NaOMe (0.11 g, 0.629 mmol, 0.1 eq, 30% wt in MeOH) was added 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 eq) in MeOH (20 mL). The mixture was stirred at 50 °C for 4 h, then NH4Cl (0.67 g, 12.582 mmol, 2 eq) was added. The resulting mixture was stirred at 50 °C for 4 h. Then the reaction was quenched by adding saturated NaHCO3 (aqueous solution) (100 mL) at room temperature, and the resulting mixture was extracted with IPA / DCM = 1:3 (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. 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, yield 74%), which was a brown oil. It was used in the next step without further purification. LC-MS: (ESI) m / z 288.1 [M+H].

[0493] Synthesis of I-8-7

[0494] At 25 °C, ethyl 2-fluoro-3-oxobutanoate (I-8-6, 1.01 g, 6.788 mmol, 1.5 eq) and NaOMe (0.18 g, 0.996 mmol, 0.22 eq, 30% wt in MeOH) were added 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 eq) in MeOH (20 mL). The mixture was stirred at 70 °C for 8 h. The reaction was quenched by adding water (50 mL) at room temperature, and then 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 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 / water (0.1% NH3.H2O), gradient from 10% to 80% in 10 min; and detector UV 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, yield 42%), which was a light yellow solid. LC-MS: (ESI) m / z 372.1 [M+H].

[0495] Synthesis of I-8-8

[0496] At 25 °C, NBS (316.3 mg, 1.778 mmol, 1.1 eq) was added 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 eq) in CHCl3 (10 mL). The mixture was stirred at 25 °C for 3 h. The reaction was quenched by the addition of water (50 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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), which was a yellow solid. LC-MS: (ESI) m / z 450.0 [M+H].

[0497] Synthesis of I-8-9

[0498] Under a nitrogen atmosphere at 25 °C, tributyl(1-ethoxyvinyl)stannane (673.8 mg, 1.866 mmol, 1.2 eq) and Pd(PPh3)4 (179.6 mg, 0.155 mmol, 0.1 eq) were added 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 eq) in toluene (10 mL). The mixture was stirred at 80 °C for 12 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 x 100 mL). The combined organic layers were washed with brine (1 x 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-ethoxyvinyl)imidazo[1,2-a]pyrazin-6-yl}-5-fluoro-6-methylpyrimidin-4-ol (I-8-9, 600 mg, yield 87%), which was a brown solid.

[0499] LC-MS: (ESI) m / z 442.1 [M+H].

[0500] Synthesis of Compound I-8

[0501] Under a nitrogen atmosphere at 25 °C, 2 M HCl (10 mL) was added to a stirred solution of 2-{8-[(2,5-difluorophenyl)methyl]-3-(1-ethoxyvinyl)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). The mixture was stirred at 25 °C for 4 h. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 100 mL) and the combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% NH3.H2O), gradient from 10% to 80% in 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, yield 18%), which was a pale gray solid. LC-MS: (ESI) m / z 414.15 [M+H].v 1 1H 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).

[0502] 19 19F NMR: (376 MHz, CDCl3) δ -118.49 (d, J = 17.6 Hz), -122.25 (d, J = 17.5 Hz), -149.61.

[0503] Synthesis of I-31

[0504] At 0 °C, NaBH4 (15.1 mg, 0.399 mmol, 3 eq) was added 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 eq) in THF (1 mL) and MeOH (0.2 mL). The mixture was stirred at 25 °C for 2 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, ACN / H2O (0.1% TFA), gradient from 10% to 80% in 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, yield 63%), which was a white solid. LC-MS: (ESI) m / z 416.20 [M+H]. 1 1H 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 19F NMR: (376 MHz, CDCl 3 ) δ -118.77 (d, J = 17.9 Hz), -122.41 (d, J = 17.9 Hz), -150.57.

[0505] yl)-5-fluoropyrimidin-4-ol (I-33): ​ ​

[0506]

[0507] 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 afford 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 reacted with ammonium chloride to provide compound I-9-5. The amidine of compound I-9-5 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 afford compound I-9-9. The amide moiety of compound I-9-9 reacted with methylmagnesium reagent to give compound I-9. The ketone of the resulting compound I-9 was reduced to a secondary alcohol to afford compound I-33.

[0508] Synthesis of I-9-3

[0509] To a stirred solution of Zn (1.59 g, 24.285 mmol, 1.5 equiv) in THF (25 mL) at room temperature under a nitrogen atmosphere, 1,2-dibromoethane (0.15 g, 0.810 mmol, 0.05 equiv) was added dropwise. The resulting mixture was stirred at 50 °C for 10 min under a nitrogen atmosphere. Then, TMSCl (0.09 g, 0.810 mmol, 0.05 equiv) was added dropwise to the above mixture. The mixture was cooled to 0 °C. Then, methyl 4-(bromomethyl)-3-fluorobenzoate (I-9-1, 4 g, 16.190 mmol, 1 equiv) was added dropwise to the above mixture at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min under a nitrogen atmosphere and then stirred at room temperature for another 2 h still under a nitrogen atmosphere. At room temperature, 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) were added to the above mixture, and the resulting mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution) (30 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 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 / water (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector UV 254 nm, to give methyl 4-({6-bromoimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-3, 2.18 g, yield 37%), which was a yellow solid. LC-MS (ESI) m / z 364.00 [M+H].

[0510] Synthesis of I-9-4

[0511] At room temperature under a nitrogen atmosphere, Pd(dppf)Cl2 (0.10 g, 0.137 mmol, 0.025 equiv) was added 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)2 (0.39 g, 3.295 mmol, 0.6 equiv) and Zn (0.07 g, 1.098 mmol, 0.2 equiv) in DMF (40 mL). 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 x 50 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 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 (2:1) to give methyl 4-({6-cyanoimidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-4, 1.26 g, yield 74%), which was a pale gray solid. LC-MS: (ESI) m / z 311.09 [M+H].

[0512] Synthesis of I-9-5

[0513] Under a nitrogen atmosphere at room temperature, NaOMe (0.06 g, 0.351 mmol, 0.1 equiv, 30% wt in MeOH) was added dropwise 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). The resulting mixture was stirred at 40 °C for 3 h under a nitrogen atmosphere. NH4Cl (0.38 g, 7.026 mmol, 2 equiv) was added to the above mixture at 40 °C, and the resulting mixture was stirred at 40 °C overnight. The reaction was quenched with saturated NaHCO3 (aqueous solution) (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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-({6-carbamimidoyl imidazo[1,2-a]pyrazin-8-yl}methyl)-3-fluorobenzoate (I-9-5, 822 mg, 71.5%), which was a yellow solid. LC-MS: (ESI) m / z 328.11 [M+H].

[0514] Synthesis of I-9-7

[0515] At room temperature under a nitrogen atmosphere, NaOMe (716.3 mg, 3.979 mmol, 3.5 equiv, 30% wt in MeOH) was added dropwise to a stirred solution of methyl 4-({6-formamimidazol[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). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. Then the mixture was acidified to pH 4 with 1 M HCl (aqueous solution) (2 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 60 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 / water (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector, UV 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, yield 27.5%), which was a pale yellow solid. LC-MS: (ESI) m / z 384.08 [M+H].

[0516] Synthesis of I-9-8

[0517] At room temperature under a nitrogen atmosphere, Weinreb amine (19.1 mg, 0.313 mmol, 1.2 equiv) was added 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). The resulting mixture was stirred at room temperature for 1 h 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 / water (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector: UV 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, yield 30%), which was a yellow solid. LC-MS: (ESI) m / z 427.13 [M+H].

[0518] Synthesis of I-9-9

[0519] At room temperature and under a nitrogen atmosphere, NCS (32.1 mg, 0.241 mmol, 0.6 eq) was added 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 eq) in DMF (3 mL). 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 / H2O (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector, UV 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), which was a pale gray solid. LC-MS: (ESI) m / z 461.09 [M+H].

[0520] Synthesis of I-9

[0521] At 0 °C and under a nitrogen atmosphere, 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 eq) in THF (2 mL) was added dropwise to a stirred solution of bromo(methyl)magnesium (0.25 mL, 0.760 mmol, 5 eq, 2 M in THF). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was then quenched by the addition of saturated NH4Cl (aqueous solution) (5 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 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 / H2O (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector, UV 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), which was a yellow solid. The reaction was repeated 3 more times and a total of 53 mg of product was obtained. LC-MS: (ESI) m / z 416.05 [M+H]. 11H 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 19F NMR: (376 MHz, DMSO-d6) δ -115.84, -151.89.

[0522] 2-(8-(4-Ethyl-2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoro-6-methoxy pyrimidin-4-ol (I-10) and the synthesis of 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):

[0523]

[0524] Compound I-10-1 was converted to the corresponding organozinc compound using zinc, 1,2-dibromoethane, and TMSCl. The organozinc compound was subjected to Negishi coupling in the presence of compound I-10-2 to give compound I-10-3. Compound I-10-3 could be further reacted in the presence of zinc, zinc cyanide, and palladium(II) dichloride bis(diphenylphosphino)ferrocene to give compound I-10-4. The nitrile of compound I-10-4 could be reacted with ammonium chloride to give the amidine compound I-10-5. The amidine of compound I-10-5 could be condensed with compound I-10-6 to give the cyclized compound I-10-7. The aryl alcohol of compound I-10-7 could be converted to the aryl chloride in the presence of POCl3 to give compound I-10-8. Compound I-10-8 could be partially hydroxylated in the presence of sodium hydroxide to give compound I-10-9. The remaining aryl chloride of compound I-10-9 could be converted to compound I-10 using sodium methoxide or to compound I-34 using SHMe.

[0525] The synthesis of 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-(8-(4,5-difluoro-2-(methylthio)benzyl)-3-(fluoromethyl)imi dazo[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):

[0526]

[0527] Compound I-11-1 was converted to the corresponding organozinc compound using zinc, 1,2-dibromoethane, and TMSCl. The organozinc compound was subjected to Negishi coupling with Compound I-11-2 to give Compound I-11-3, which was further reacted in the presence of zinc, zinc cyanide, and tris(dibenzylideneacetone)dipalladium(0) to give Compound I-11-4. The nitrile of Compound I-11-4 could react with ammonium chloride to give the amidine compound I-11-5. The amidine of Compound I-11-5 could condense with Compound I-11-6 to give the cyclized compound I-11-7, which could be converted to an aromatic aldehyde in the presence of POCl3 to give Compound I-11-8, and Compound I-11-8 could be reduced with sodium borohydride to give Compound I-39. The primary alcohol of Compound I-39 could be halogenated with DAST to give Compound I-11. Compounds I-40 and I-41 could be prepared in a similar manner.

[0528] The 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]py razin-6-yl)-5-methylpyrimidine-4,6-diol (I-38):

[0529]

[0530] The nitrile of Compound I-7-4 reacted with NaSMe to form the higher intermediate I-7-4-1, which reacted in situ with ammonium chloride to give the amidine compound I-12-5. The amidine of Compound I-12-5 condensed with Compound I-12-6 to form the cyclized compound I-38. The aryl alcohol on the pyrimidine of I-38 was converted to bromine using POBr3 to give the dibromo compound I-12-7. In the presence of sodium methoxide, a single aryl bromide on the pyrimidine ring of Compound I-12-7 was converted to –OMe to give Compound I-12-8. The compound I-12-8 was dealkylated to give the hydroxy compound I-12.

[0531] Synthesis of I-12-5

[0532] At room temperature, sodium methanethiolate (185.3 mg, 2.648 mmol, 2.0 equiv) was added 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), and the resulting mixture was stirred at 45 °C for 2 h. NH4Cl (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. Then the reaction was quenched with water (20 mL) at room temperature, and the aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give (8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylthio)imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 360 mg, crude), which was a brown solid. It was used in the next step without further purification. LC-MS: (ESI) m / z 348.05 [M+H].

[0533] Synthesis of I-38

[0534] At room temperature, diethyl 2-methylmalonate (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) were added to a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylthio)imidazo[1,2-a]pyrazine-6-carboximidamide (I-12-5, 360 mg, 1.036 mmol, 1.0 equiv) in anhydrous MeOH (6 mL), 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-(methylthio)imidazo[1,2-a]pyrazine-6-yl}-5-methylpyrimidine-4,6-diol (I-38, 400 mg, crude), which was a white solid. LC-MS: (ESI) m / z 430.05 [M+H].

[0535] Synthesis of I-12-7

[0536] At room temperature, POBr3 (1.08 g, 3.76 mmol, 4.0 equiv) was added to a stirred solution of 2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylthio)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), 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 x 20 mL). 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 (1:1) to afford 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, yield 85%), which was a yellow solid. LC-MS: (ESI) m / z 556.00 [M+H].

[0537] Direct synthesis of I-12 from I-12-7

[0538] At room temperature, 2 M aqueous NaOH (5.60 mL, 11.194 mmol, 22.21 equiv) was added to a stirred solution of 4,6-dibromo-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylthio)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), 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 CH2Cl2 (3 x 10 mL). 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 CH2Cl2 / ethyl acetate (10:1) to afford 6-bromo-2-{8-[(2,5-difluoro-4-methylphenyl)methyl]-3-(methylthio)imidazo[1,2-a]pyrazin-6-yl}-5-methylpyrimidin-4-ol (I-12, 100 mg, yield 40%), which was a white solid. LC-MS: (ESI) m / z 493.95 [M+H]. 11H 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).

[0539] 19 19F NMR: (282 MHz, chloroform-d) δ -123.03 (d, J = 16.8 Hz), -123.09 (d, J = 17.8 Hz).

[0540] The synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(methoxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoro pyrimidin-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):

[0541]

[0542] Compound I-13-5 was synthesized in a similar manner to compound I-8-5. The amidine of compound I-13-5 was condensed with compound I-12-6 to give the cyclized compound I-13-7, which was then converted to the bromide using N-bromosuccinimide. The brominated compound I-13-8 was 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 was protected using MOMBr to give compound I-13-10. The ester of compound I-13-10 was reduced with sodium borohydride to give the alcohol compound I-13-11, which was then alkylated on oxygen to give compound I-13-12. Deprotection of the MOM group of compound I-13-12 gave compound I-13. Alternatively, compound I-13-11 could be deprotected to give compound I-35.

[0543] The synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(methoxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoro pyrimidin-4-ol (I-13):

[0544]

[0545] Alternatively, compound I-13 could be prepared as follows. The aryl alcohol on the pyrimidine of I-13-9 was converted to chloro using POCl3 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 using MeI and NaH, and then the arylmethoxy on the pyrimidine was dealkylated using HCl to give compound I-13.

[0546] Synthesis of compound I-47 from compound I-35

[0547]

[0548] Compound I-35 was prepared according to the following scheme shown below. This compound can be converted to I-13 in the last step of the above scheme. Alternatively, it can be converted to I-47 by using the method described below.

[0549] 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) at 0 °C 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). The mixture was stirred at 25 °C for 4 h. The reaction was quenched by adding 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 / water (0.1% TFA), gradient from 5% to 80% in 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), which was an off-white solid. LC-MS: (ESI) m / z 416.05 [M+H].

[0550] 1 1H 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).

[0551] 19 19F NMR: (376 MHz, CDCl3) δ -122.51 (d, J = 17.4 Hz), -123.36 (d, J = 17.6 Hz), -149.44.

[0552] The synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-(hydroxymethyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyri midin-4-ol (I-35):

[0553] Alternative Route 1: Alternative Route 2:

[0554] Alternatively, Compound I-35 is prepared from Compound I-13-8 by using Alternative Route 1 or Alternative Route 2.

[0555] Alternative Route 1: In the presence of a palladium catalyst, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, I-13-8 is esterified with carbon monoxide and methanol to obtain Compound I-13-9. The ester of Compound I-13-9 is reduced with sodium borohydride to directly obtain the alcohol Compound I-35.

[0556] Alternative Route 2: In the presence of a palladium catalyst, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, I-13-8 is carbonylated with carbon monoxide and triethylsilane to obtain Compound I-13-9-0. The aldehyde of Compound I-13-9-0 is reduced with sodium borohydride to directly obtain the alcohol Compound I-35.

[0557] Synthesis of I-13-7

[0558] 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) at 25 °C was added ethyl 2-fluoro-3-oxo-2-sodium propionate (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). The mixture was stirred at 70 °C for 8 h. The reaction was quenched by the addition of 1 M HCl (aqueous solution) (50 mL) at room temperature and the resulting mixture was extracted with IPA / DCM = 1:3 (3 x 100 mL). The combined organic layers were washed with brine (1 x 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 afford 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), which is a yellow solid. LC-MS: (ESI) m / z 372.1 [M+H].

[0559] Synthesis of I-13-8

[0560] At 25 °C, NBS (1.27 g, 7.109 mmol, 1.1 eq) was added 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 eq) in CHCl3 (50 mL). The mixture was stirred at 25 °C for 8 h. Then the reaction was quenched by adding water (100 mL) at room temperature and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was triturated with ACN (10 mL) for purification. The precipitated solid was collected by filtration, washed with ACN (3 mL), and the resulting solid was 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, yield 48%), which was a light yellow solid. LC-MS: (ESI) m / z 450.0 [M+H].

[0561] Synthesis of I-13-9-0 (Alternative Route 2)

[0562] In a pressure vessel, Et3SiH (0.85 g, 7.329 mmol, 3 eq), Pd(dppf)Cl2 (0.18 g, 0.244 mmol, 0.1 eq) and TEA (0.74 g, 7.329 mmol, 3 eq) were added 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 eq) in anhydrous DMF (10 mL). The mixture was purged with nitrogen for 1 min and then pressurized with carbon monoxide to 10 atm at 80 °C for 12 h. The reaction mixture was cooled to room temperature, the insoluble solids were filtered off, 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, yield 25%, purity 35%), which was a light yellow solid. LC-MS: (ESI) m / z 400.05 [M+H].

[0563] Synthesis of Compound I-35

[0564] At 0 °C, NaBH4 (198.9 mg, 5.259 mmol, 3 eq) was added to a stirred solution of the above-obtained 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 eq) in THF (20 mL). The mixture was stirred at 25 °C for 2 h. The reaction was quenched by adding 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 / H2O (0.1% formic acid), gradient from 5% to 80% in 10 min; detector, UV 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, yield 6.4%), which was a pale gray solid. LC-MS: (ESI) m / z 402.10 [M+H]. 1 1H 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 19F NMR: (376 MHz, DMSO-d6) δ -123.08 (d, J = 17.7 Hz), -123.35, -152.58.

[0565] The 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):

[0566]

[0567] 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 obtain compound I-15-5. Compound I-15-5 can be esterified in the presence of carbon monoxide, palladium, and methanol to obtain compound I-15-6. The nitrile of compound I-15-6 can react with ammonium chloride to obtain the amidine compound I-15-7. The amidine of compound I-15-7 can condense with compound I-15-8 to obtain the cyclized compound I-15-9. The aryl alcohol of compound I-15-9 can be converted to aryl chloride in the presence of POCl3 to obtain compound I-15-10. One of the pyrimidine chlorides in compound I-15-10 can be converted to methyl thioether in the presence of NaSMe to obtain compound I-15-11, and compound I-15-11 is reduced in the presence of sodium borohydride to obtain compound I-15-12. Compound I-15-12 is hydroxylated in the presence of sodium hydroxide to obtain compound I-15.

[0568] The synthesis of 2-(8-(2,5-difluoro-4-hydroxybenzyl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-5-fluoro-6-hydroxypyri midine-4-carbonitrile (I-16):

[0569]

[0570] Compound I-16-1 can be converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound undergoes Negishi coupling in the presence of compound I-16-2 to obtain 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 obtain compound I-16-4. The nitrile of compound I-16-4 can react with ammonium chloride to obtain the amidine compound I-16-5. The amidine of compound I-16-5 can condense with compound I-16-6 to obtain the cyclized compound I-16-7. The aryl alcohol of compound I-16-7 can be converted to aryl chloride in the presence of POCl3 to obtain compound I-16-8. A single aryl chloride on the pyrimidine ring of compound I-16-8 can be converted to –OMe in the presence of sodium methoxide to obtain 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.

[0571] 2-(8-(2,5-Difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-hydroxypyrimidine-5- Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-hydroxypyrimidine-5-carbonitrile (I-17):

[0572]

[0573] The nitrile of compound I-7-4 reacts with ammonium chloride to give the amidine compound I-17-5; the amidine of compound I-17-5 reacts with compound I-17-6 to give the cyclized compound I-17-7; the ester of compound I-17-7 is converted to the amide in the presence of ammonia to give compound I-17-8, and then converted to the cyano group in the presence of TFAA to give compound I-17.

[0574] Synthesis of I-17-7

[0575] At 25 °C, 2-(ethoxymethylene) malonic acid 1,3-diethyl ester (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) were added to a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]-3-fluoroimidazo[1,2-a]pyrazine-6-carboxamidine (I-17-5, 370 mg, 1.159 mmol, 1 equiv) in MeOH (5 mL) obtained as shown elsewhere in the present disclosure. The mixture was stirred at 70 °C for 8 h. The mixture was cooled to room temperature and then acidified to pH 3 with 1 M HCl (10 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with brine (1 x 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 DCM / MeOH (30:1) to give 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), which was a yellow solid. LC-MS: (ESI) m / z 430.1 [M+H].

[0576] Synthesis of I-17-8

[0577] At 25 °C, NH3(g) (60 mL, 420.000 mmol, 494.06 eq., 7 M in MeOH) was added 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 eq.) in MeOH (10 mL). The mixture was stirred at 90 °C for 24 h. Then the mixture was 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), which was a yellow solid and was used directly in the next step. LC-MS: (ESI) m / z 415.1 [M+H].

[0578] Synthesis of Compound I-17

[0579] 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 eq.). 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 H2O (2 mL). Then 2 M NaOH (1.1 mL, 2.028 mmol, 2 eq.) was added and the mixture was stirred at 25 °C for 4 h. Then the resulting mixture was diluted with water (10 mL) and acidified to pH 3 with 1 M HCl (10 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 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, purity 97%, yield 13%), which was a light yellow solid. LC-MS: (ESI) m / z 397.15 [M+H].

[0580] 11H 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).

[0581] 19 19F NMR: (376 MHz, DMSO-d6) δ -122.44, -123.15.

[0582] 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): 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): 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):

[0583]

[0584] Compound I-18-1 can be converted into the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound undergoes Negishi coupling in the presence of compound I-18-2 to give compound I-18-3. Compound I-18-3 further reacts 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 react with ammonium chloride to give the amidine compound I-18-5. The amidine of compound I-18-5 can condense with compound I-18-6 to give the cyclized compound I-36. Compound I-36 can be alkylated by a cross-coupling reaction in the presence of palladium to give compound I-18.

[0585] 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): Synthesis of 5-chloro-2-(8-(2,5-difluorobenzyl)-3-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (I-29):

[0586]

[0587] Compound I-20-1 can be converted into the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound can undergo Negishi coupling in the presence of compound I-20-2 to give compound I-20-3. Compound I-20-3 can further react 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 reacted with selctfluor TMIn the presence of [substance], it is fluorinated to obtain Compound I-20-5. The nitrile of Compound I-20-5 can react with ammonium chloride to obtain the amidine compound I-20-6. The amidine of Compound I-20-6 can condense with Compound I-20-7 to obtain the cyclized compound I-20-8. The aryl hydroxyl group of I-20-8 can be converted to chlorine in the presence of POCl3 to obtain Compound I-20-9. The acyl substituent of Compound I-20-9 can be fluorinated in the presence of DAST to obtain Compound I-20-10, and then it is deprotected in the presence of a strong base to obtain Compound I-20.

[0588] 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): Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-(hydroxymethyl)pyrimidin-4-ol (I-25): Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)-6-(2-hydroxyethyl)pyrimidin-4-ol (I-26):

[0589]

[0590] Compound I-12-5 is synthesized in a manner similar to Compound I-8-5. The amidine of Compound I-12-5 condenses with Compound I-21-6 or I-27-6 to obtain Compounds I-21 or I-27 respectively.

[0591] Synthesis of I-21-6

[0592] At -78 °C under a nitrogen atmosphere, LDA (19.2 mL, 38.422 mmol, 2 equivalents, 2 M in THF) and ethyl 2-fluoroacetate (1.85 g, 17.482 mmol, 0.91 equivalent) were added dropwise to a stirred solution of methyl methoxyacetate (2 g, 19.211 mmol, 1 equivalent) in THF (40 mL). The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction was quenched with 1 M HCl (aqueous solution) (10 mL) at room temperature, and the resulting mixture was extracted with Et2O (3 x 40 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 4-fluoro-2-methoxy-3-oxobutyrate (I-21-6, 1.17 g, yield 37%), which was a yellow oil. The crude product was used directly in the next reaction without further purification.

[0593] Synthesis of Compound I-21

[0594] At room temperature and under a nitrogen atmosphere, a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboximidamide (prepared as shown elsewhere in this disclosure) (I-12-5, 20 mg, 0.066 mmol, 1.00 equivalent) and methyl 4-fluoro-2-methoxy-3-oxobutanoate (I-21-6, 43.6 mg, 0.264 mmol, 4 equivalents) in MeOH (1 mL) was added dropwise with NaOMe (41.8 mg, 0.231 mmol, 3.5 equivalents, 30% wt in MeOH). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. Then the resulting mixture was concentrated under vacuum, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN / water (0.1% formic acid), gradient from 0% to 100% in 10 min; and detector: UV 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, yield 54%), which was an off-white solid. The reaction was repeated 2 times, and a total of 27.5 mg of the product was obtained. LC-MS: (ESI) m / z 416.20 [M+H].

[0595] 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).

[0596] 19 F NMR: (376 MHz, DMSO-d6) δ -73.40, -123.13 (d, J = 18.1 Hz), -123.39 (d, J = 18.1 Hz).

[0597] Synthesis of I-27-6

[0598] At -78 °C under a nitrogen atmosphere, LDA (4.8 mL, 9.606 mmol, 2 equiv, 2 M in THF) was added dropwise to a stirred solution of methyl methoxyacetate (500 mg, 4.803 mmol, 1 equiv) in THF (10 mL). The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction was quenched at room temperature with 1 M HCl (aqueous solution) (10 mL), and the resulting mixture was extracted with Et2O (3 x 15 mL). The combined organic layers were washed with brine (2 x 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2,4-dimethoxy-3-oxobutanoate (I-27-6, 190 mg, 22% yield, crude), which was a yellow oil. The crude product was used directly in the next step without further purification.

[0599] Synthesis of Compound I-27

[0600] At room temperature under a nitrogen atmosphere, NaOMe (117.1 mg, 0.651 mmol, 3.5 equiv, 30% wt in MeOH) was added dropwise 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). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. Then the mixture was acidified to pH 4 with 1 M HCl (aqueous solution) (1 mL), and it was extracted with EtOAc (3 x 10 mL) and dried over anhydrous Na2SO4. 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), which was an off-white solid. LC-MS: (ESI) m / z 428.05 [M+H]. 1 H 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).

[0601] 19 19F NMR: (377 MHz, DMSO-d6) δ -74.24, -123.27 (dd, J = 98.5, 18.1 Hz).

[0602] Example 2: cGMP measurement results in primary rat neurons ​

[0603]

[0604] Compound I-12-5 was synthesized in a similar manner to compound I-8-5. The amidine of compound I-12-5 was condensed with compound I-22-6 to give the cyclized compound I-22-7. The aryl hydroxyl group of compound I-22-7 was converted to chloro in the presence of POCl3 to give compound I-22-8. The single aryl chloro of compound 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 by a cross-coupling reaction in the presence of palladium to give compound I-22-10, and compound I-22-10 was dealkylated to give compound I-22.

[0605] Synthesis of I-22-7

[0606] 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 dimethyl 2-fluoromalonate (I-22-6, 1.49 g, 9.957 mmol, 1.5 equiv) in MeOH (20 mL) prepared as described elsewhere in this disclosure was added NaOMe (3.59 g, 19.914 mmol, 3 equiv, 30% in MeOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 1.5 h 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 (aqueous solution), and the precipitated solid was collected by filtration and washed with water (2 x 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%), which was a light yellow solid. LC-MS: (ESI) m / z 388.10 [M+H].

[0607] Synthesis of I-22-8

[0608] At room temperature under a nitrogen atmosphere, phosphorus oxychloride (989.6 mg, 6.455 mmol, 5 equiv) was added portionwise 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). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was then quenched by the addition of water (20 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. 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), which was a pale yellow solid. LC-MS: (ESI) m / z 424.0 [M+H].

[0609] Synthesis of I-22-9

[0610] At room temperature under a nitrogen atmosphere, sodium methoxide (382.0 mg, 2.121 mmol, 1.5 equiv, 30% wt in MeOH) was added portionwise 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure and then diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. 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), which was a pale yellow solid. LC-MS: (ESI) m / z 420.10 [M+H].

[0611] Synthesis of I-22-10

[0612] At room temperature and under a nitrogen atmosphere, K3PO4 (202.2 mg, 0.952 mmol, 2 equiv) and Pd(Amphos)2Cl2 (67.4 mg, 0.095 mmol, 0.2 equiv) were added 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)-λ4-borate (144.8 mg, 0.952 mmol, 2 equiv) in dioxane (5 mL) and H2O (1 mL). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The mixture was then cooled to room temperature and filtered. The filter cake was washed with THF (3 x 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 / water (0.1% formic acid), gradient from 0% to 100% in 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%), which was a light yellow solid. LC-MS: (ESI) m / z 430.20 [M+H].

[0613] Synthesis of Compound I-22

[0614] 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 a 1,4-dioxane solution (2 mL) of HCl (gas) was stirred at 60 °C overnight under a nitrogen atmosphere. 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 / water (0.1% formic acid), gradient from 0% to 100% in 10 min; detector, UV 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, yield 54.5%), which was an off-white solid. LC-MS: (ESI) m / z 416.15 [M+H].

[0615] 11H 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).

[0616] ​ ​

[0617]

[0618] The amidine of compound I-7-5 was condensed with compound I-29-6 to obtain the cyclized compound I-29.

[0619] Synthesis of I-7-5

[0620] Under nitrogen atmosphere at room temperature, NaOMe (1.0 g, 5.559 mmol, 3 equiv., 30% in MeOH) was added 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). The resulting mixture was stirred overnight at 50 °C under nitrogen atmosphere. NH4Cl (198.2 mg, 3.706 mmol, 2 equiv.) was added to the above mixture at 50 °C. The resulting mixture was stirred for another 2 h at 70 °C. Then the mixture was cooled to room temperature. The reaction was quenched by adding saturated NaHCO3 (aqueous solution) (40 mL) at room temperature, and the resulting mixture was extracted with CH2Cl2 / IPA (3 / 1) (3 x 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), which was a brown solid. It was used directly in the next step without further purification. LC-MS: (ESI) m / z 332.05 [M+H].

[0621] Synthesis of compound I-29

[0622] Under a nitrogen atmosphere at room temperature, NaOMe (173.9 mg, 0.966 mmol, 2 equiv, 30% wt in MeOH) was added 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). The resulting mixture was stirred at 70 °C for 3 h 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%), which was 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 F NMR: (376 MHz, chloroform-d) δ -123.12 (d, J = 2.8 Hz), -150.71.

[0623] ​ ​ ​

[0624]

[0625] Compound I-12-5 was synthesized in a similar manner to compound I-8-5. The carboximidamide of compound I-12-5 was cyclized with compound I-28-6 to give compound I-24. The aryl hydroxyl group 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.

[0626] Synthesis of Compound I-24

[0627] At room temperature under a nitrogen atmosphere, 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-(ethoxymethylene)-3-oxobutanoate (I-28-6, 124 mg, 0.666 mmol, 1.00 equiv) for 5 min, and then NaOMe (418 mg, 2.321 mmol, 3.50 equiv, 30% wt in MeOH) was added dropwise at 70 °C. The resulting mixture was stirred at 70 °C for an additional 4 h and then 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, yield 30%), which was a yellow solid. LC-MS: (ESI) m / z 396.15 [M+H]. 1 1H 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 19F NMR: (377 MHz, DMSO-d6) δ -123.03 (d, J = 18.1 Hz), -123.46 (d, J = 18.0 Hz).

[0628] Synthesis of Compound I-28-7

[0629] At 0 °C under a nitrogen atmosphere, DIEA (1.14 g, 8.852 mmol, 2.5 eq) was added dropwise 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 eq) and bromomethoxymethane (0.88 g, 7.082 mmol, 2 eq) in DCM (25 mL). 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 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 / water (0.1% FA), gradient from 0% to 100% in 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), which was a white solid. LC-MS: (ESI) m / z 440.2 [M+H].

[0630] Synthesis of Compound I-28-8

[0631] At 0 °C under a nitrogen atmosphere, NaBH4 (176 mg, 4.652 mmol, 3.01 eq) was added portionwise 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 eq) in THF (14 mL). The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by the addition of water (40 mL) at 0 °C, 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 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 / water (10 mmol / L NH4HCO3), gradient from 0% to 100% in 10 min, 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%), which was a yellow solid.

[0632] LC-MS: (ESI) m / z 442.0 [M+H].

[0633] Synthesis of Compound I-28

[0634] To a 50 mL round-bottom flask at room temperature 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). The resulting mixture was stirred at room temperature for 1 h. Then the resulting mixture was diluted with DCM (2 x 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 / water (10 mmol / L NH4HCO3), gradient from 0% to 100% in 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-(1-hydroxyethyl)pyrimidin-4-ol (I-28, 50 mg, 47.5%), which was a yellow solid. LC-MS (ESI) m / z 398.05 [M+H]. 1 1H 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 19F NMR: (376 MHz, DMSO-d6) δ -73.40, -123.12 (d, J = 17.7 Hz).

[0635] ​ ​

[0636]

[0637] Compound I-12-5 was synthesized in a similar manner to Compound I-8-5. The amidine of Compound I-12-5 was condensed with Compound I-25-6 to give the 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.

[0638] Synthesis of I-25-7

[0639] 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 diethyl 2-(ethoxymethylene)malonate (I-25-6, 1.44 g, 6.638 mmol, 1 equiv) for 5 min under a nitrogen atmosphere at room temperature, and then NaOMe (4.18 g, 23.233 mmol, 3.5 equiv, 30% wt in MeOH) was added dropwise at 70 °C. The resulting mixture was stirred at 70 °C for an additional 4 h. 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 cake was washed with water (3 x 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, yield 76.5%), which was a yellow solid. LC-MS: (ESI) m / z 412.2 [M+H].

[0640] Synthesis of I-25

[0641] 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) was added LiAlH4 (184.5 mg, 4.860 mmol, 4 equiv) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was then quenched with Na2SO4·10H2O (50 mg) at room temperature, and the resulting mixture was filtered. The cake was washed with THF (3 x 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 / water (0.1% formic acid), gradient from 0% to 100% in 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-(hydroxymethyl)pyrimidin-4-ol (I-25, 80.6 mg, 17%), which was a white solid. LC-MS: (ESI) m / z 384.15 [M+H]. 11H 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 19F NMR - PH - CYCN - CYC - 025 - 0: (376 MHz, DMSO-d6) δ -123.12 (d, J = 18.2 Hz), -123.22 – -123.54 (m).

[0642] ​ ​

[0643]

[0644] Compound I - 12 - 5 was synthesized in a similar manner to compound I - 8 - 5. The amidine of compound I - 12 - 5 was condensed with compound I - 26 - 6 to obtain the cyclized compound I - 26 - 7. The aryl ester of compound I - 26 - 7 was reduced in the presence of lithium aluminum hydride to obtain compound I - 26.

[0645] Synthesis of I - 26 - 7

[0646] 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 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 afford 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 product), which was a white solid. MS (ESI) m / z 426.15 [M + H].

[0647] Synthesis of I - 26

[0648] At 0 °C, LiAlH4 (98.1 mg, 2.60 mmol, 2.2 equiv) was added portionwise 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). The mixture was stirred at room temperature for 2 h. The reaction was then quenched by adding water (10 mL) at 0 °C. The aqueous layer was extracted with CH2Cl2 (3 x 10 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 (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%), which was 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.

[0649] 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)

[0650]

[0651] Compound I-45-1 was converted to the corresponding organozinc compound using zinc, dibromoethane, and TMSCl. The organozinc compound was subjected to Negishi coupling in the presence of compound I-45-2 to afford compound I-45-3. Compound I-45-3 was further reacted in the presence of zinc, zinc cyanide, and 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 the amidine compound I-45-5. The amidine of compound I-45-5 was condensed with compound I-45-6 to give the cyclized compound I-45 and the by-product compound I-43.

[0652] These compounds were synthesized by procedures similar to those used for the synthesis of compounds I-5 and I-44, but starting from the azido version of I-4-2-1 instead of the core I-5-2. These procedures were also similar to those used for the preparation of compounds I-21 and I-27, but different condensation reagents were used in different cases.

[0653] Compound I-30

[0654]

[0655] To a stirred solution of 8-[(2,5-difluoro-4-methylphenyl)methyl]imidazo[1,2-a]pyrazine-6-carboxamidine (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). Methyl 3-oxopentanoate (I-30-1, 324.0 mg, 2.489 mmol, 1.5 equiv) was added to the above mixture 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 x 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, yield 23%), which was a light yellow solid. The reaction was repeated 3 more times, and a total of 381.5 mg of the product was obtained. LC-MS: (ESI) m / z 382.15 [M+H]. 11H 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 19F NMR: (377 MHz, DMSO-d6) δ -123.13 (d, J = 18.1 Hz), -123.40 (d, J = 18.1 Hz).

[0656] ​

[0657] Rat primary neurons were isolated from timed-pregnant female Sprague-Dawley (SD) rats, washed once with HBSS containing calcium and magnesium, and then incubated at 37 °C for 15 min with HBSS solution (80 μL / well) containing 0.5 mM 3-isobutyl-1-methylxanthine (IBMX). Next, a 5X stock solution (20 μl) of the test compound was added to the wells together with a fixed concentration of DETA (diethylenetriamine NONOate) to give a concentration of the test compound solution of x nM and a concentration of the DETA solution of 30 μM, where x was 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 min. At the end of the incubation, 100 μL of lysis buffer (Molecular Devices) was added to the cells. The CatchPointTM Cyclic-GMP fluorescence assay kit was used together with the ID3 multimode plate reader from Molecular Devices. The sample cGMP concentration was inferred from the standard curve using Softmax Pro 7 software. A well-characterized, potent sGC stimulator was included in all assay runs and used as a positive control.

[0658] Using GraphPad Prism version 9.4.1, the test compound (“agonist”) concentration was plotted and analyzed relative to the inferred cGMP concentration (“response”). Curve fitting was used for each data set; non-linear log(agonist) vs. response variable slope (four parameters). EC 50Obtained by curve fitting interpolation and defined as the concentration at which the compound elicits 50% of its maximum response. When the experiment is conducted more than twice, the geometric mean is reported; otherwise, the arithmetic mean is shown. To increase the accuracy of EC 50 calculation, the top and bottom parameters are constrained when consistent with the data observed in a given assay run. For example, in an assay run where the cGMP response values are consistent across plates in the absence of the test article, the mean of all these wells is used as the bottom constraint in the calculation. In an assay run where the maximum cGMP response is consistent with the positive control, a top constraint equal to the maximum cGMP response of the positive control is applied. If there is significant variability in the cGMP response in the compound-free wells or variation in the maximum response across plates, no constraints are imposed. For compounds with a response > 50% of the positive control that do not reach the top constraint (if a top constraint is applied) or compounds that do not show a plateau in response at higher concentrations (in the absence of a top constraint), the EC of the test article 50 is defined as > 30 μM (the highest concentration tested). The EC of compounds that do not show a dose response 50 is qualified as ND (not determined).

[0659] Table A.

[0660]

[0661] Neuron-based cell assay. EC 50 ≤ 100 nM = A; 100 nM < EC 50 ≤ 1000 nM = B; 1000 nM < EC 50 = C ≤ 5000 nM; EC 50 > 5000 nM = D.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: Wherein: X is N or C(J C1 ); J C selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein said C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and said C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R; J C1 selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR and –C(O)R; n is an integer selected from 0, 1, 2 or 3; Each J B is independently selected from halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R; J D1 Selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl is optionally and independently substituted with 1 to 3 halogen atoms, and the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R; J D2 Selected from hydrogen, halogen, C 1-6 alkyl, -OH, -OR, -SH, -SR, -CN, -C(O)R, and C 3-5 cycloalkyl, wherein said C 3-5 cycloalkyl is optionally and independently substituted by 1 to 3 halogen atoms, and said C 1-6 alkyl is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -OR, -SR, and –C(O)R; Each occurrence of R is independently C 1-4 alkyl, optionally substituted with 1 to 3 independently selected halogen atoms; Wherein when J D2 is hydrogen and n is 1, 2 or 3, then at least one of J C , J C1 , J D1 and J B is -OH, -OR, -SH, -SR, -CN, -C(O)R, cycloalkyl optionally and independently substituted by 1 to 3 halogen atoms or C 3-5 alkyl substituted by 1 to 3 substituents independently selected from -OH, -OR, -SR and -C(O)R; 1-6 alkyl; When J D2 is hydrogen and n is 0, then at least one of J C , J C1 and J D1 is -OH, -OR, -SH, -SR, -CN, -C(O)R, a C 3-5 cycloalkyl optionally and independently substituted with 1 to 3 halogen atoms, or a C 1-6 alkyl substituted with 1 to 3 substituents independently selected from -OH, -OR, -SR and -C(O)R; and Provided that the compound is not one of the following:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula IA:

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

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein J C1 is selected from hydrogen, -F, -Cl, -CN, -CH3, -CH2F, -SH, -CH2OH, -CH2OCH3, -SCH3, -CH(OH)CH3, -C(O)CH3, and -OCH3.

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

6. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein J C1 is selected from hydrogen, -F, -Cl, -CH3 and -CH2F.

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

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula IB:

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

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

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

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

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

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

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

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein each J B is independently selected from -F, -Cl, -Br, -CN, -CH3, -CF3, -CH2F, -CHFCH3, -CH2CH2F, -C(O)CH3, -CH(OH)CH3, -CH2CH3, -SCH3, -OCH3, -OH, -CH2OCH3 and -CH2OH.

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

18. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3, and each J B is independently selected from -F, -Cl, -CH3, -CF3, -CN, -OH and -OCH3. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 2; and each J B is independently selected from -F, -CH3 and -CF3. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 2; and one of J B is –CH3 or –CF3 and the other J B is -F.

21. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 2; and both J B are -F. The compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein n is 3; and each J B is independently selected from -F, -OH, -CH3, -CH2F, and -CF3. The compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein n is 3; and one of the J B is -F, the second J B is -CH3 or -CH2F, and the others are selected from -F, -OH, -CH3 and -CH2F.

24. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 1; and J B is selected from halogen, -OR and C 1-3 alkyl optionally substituted by 1 to 3 independently selected halogen substituents. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 1; and J B is selected from -F, -OR and C 1-3 alkyl optionally substituted with 1 to 3 independently selected halogen substituents. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein n is 1; and J B is selected from -F, -CH3, -CF3 and -OCH3.

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

28. The compound or a pharmaceutically acceptable salt thereof according to claim 27, wherein J D2 is selected from hydrogen, -F, -Cl, -Br, -CH3, -SCH3, -OH, -CH2F, -CH2OCH2CH3, -OCH3, -CH2OCH3 and -CH2CH2OH.

29. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein J D2 is selected from hydrogen, halogen, -OR and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and -C(O)R. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein J D2 is selected from hydrogen, -F and -Cl.

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

33. The compound according to any one of claims 1-32 or a pharmaceutically acceptable salt thereof, wherein J C is selected from hydrogen, -F, -Cl, -CH3, -CH2F, -OCH3, -SCH3, -C(O)CH3, -CH2OCH3, -CH2OH, and -CN.

34. The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein J C is selected from hydrogen, -F, -Cl, -CH3 and -CH2F.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-26, 33 and 34, wherein the compound is represented by formula IIA:

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 8-26, 33 and 34, wherein the compound is represented by formula IIB:

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

38. The compound or a pharmaceutically acceptable salt thereof according to claim 37, wherein J D1 is selected from hydrogen, -F, -CH3, -CN, -SCH3, -CHF2, -OCH3, -C(O)CH3, -CH(OH)CH3 or -CH2CH2OH.

39. The compound according to claim 37 or a pharmaceutically acceptable salt thereof, wherein J D1 is selected from hydrogen, halogen, -OR and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and –C(O)R. The compound or a pharmaceutically acceptable salt thereof according to claim 37, wherein J D1 is selected from hydrogen, -F and -Cl. The compound according to claim 37 or a pharmaceutically acceptable salt thereof, wherein J D1 is a halogen. The compound according to claim 37 or a pharmaceutically acceptable salt thereof, wherein J D1 is -F.

43. The compound according to any one of claims 1-42 or a pharmaceutically acceptable salt thereof, wherein each occurrence of R is independently C 1-4 alkyl.

44. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

45. The compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein the compound is selected from:

46. The compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein the compound is selected from:

47. The compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein the compound is selected from:

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

49. A method of treating a disease in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-47 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 48, alone or in combination therapy; wherein the disease or disorder is a disease or disorder that would benefit from sGC stimulation or from an increase in the concentration of NO and / or cGMP.

50. The method according to claim 49, wherein the method is for treating a CNS disease, a CNS health condition or a CNS disorder.

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

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

53. The method according to claim 50, wherein the CNS disease is a cognitive disorder.

54. The method according to claim 50, wherein the CNS disease is dementia.

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

56. The method according to claim 50, wherein the CNS disease is cognitive aging.

57. The method according to claim 50, wherein the CNS disease is vascular dementia.

58. The method according to claim 50, wherein the CNS disease is mixed dementia.

59. The method according to claim 50, wherein the CNS disease is Parkinson's disease.

60. The method according to claim 50, wherein the CNS disease is mild cognitive impairment.

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

62. The method according to claim 50, wherein the CNS disease is stroke.

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

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

65. The method according to claim 49, wherein the method is for treating mitochondrial diseases.

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

67. The method according to claim 66, wherein the mitochondrial diseases of the genetic disorder are selected from Alpers disease, 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 mutation.

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

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