Novel host-targeted pan-respiratory antiviral small molecule therapeutics

Abstract

Described herein are compounds, pharmaceutical compositions, and methods of using these compounds and pharmaceutical compositions for the treatment and / or prevention of conditions, such as those caused by any of the viral families that cause respiratory viral disease, including, inter alia, coronaviruses and influenza viruses.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 270,918, filed October 22, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] There is a need for compounds that are useful as host-targeted pan-respiratory antiviral compounds.

[0003] Certain compounds described herein have now been discovered to be effective pan-respiratory antiviral small molecule therapeutics, and these compounds can be used to inhibit the antiviral activity of the pan-respiratory virus family, including in particular coronaviruses and influenza viruses, and diseases caused by these virus families, as described herein.

[0004] Early compounds in this class have demonstrated significant barriers to the development of viral resistant mutants, and a novel molecular basis for targeting the host without host toxicity has been demonstrated (https: / / www.biorxiv.org / content / 10.1101 / 2021.01.17.426875v1). Summary of the Invention [Means for solving the problem]

[0005] In one embodiment, the compound of formula (I): [ka] or a pharma- ceutically acceptable salt, hydrate or solvate thereof, 1 and R 2 is independently alkyl, alkenyl, cycloalkyl or cycloalkenyl; R 3is -H or alkyl; a is 1, 2 or 3; R 4 is -H, halo, alkyl, -OR 7 ;R 5 is -H, halo, alkyl, substituted alkyl, [ka] , -C(O)NR 76 R 77 , -NR 78 R 79 , -NHC(O)R 80 , -OR 11 b is 0, 1, 2 or 3; R 6 is -H, alkyl, [ka] -OR 15 c is 1, 2 or 3; X is [ka] , substituted aryl, heteroaryl, substituted heteroaryl; R 8 -H, -C(O)NR 16 R 17 , -CH 2 OC(O)NR 18 R 19 , -NR 20 R 21 , -CH 2 NR 22 R 23 or -SO 2 R 24 R 25 ;R 9 -H, -C(O)NR 26 R 27 , -CH 2 OC(O)NR 28 R 29 , -NR 30 R 31 , -CH 2 NR 32 R 33 or -SO 2 R34 R 35 ;R 10 -H, -C(O)NR 36 R 37 , -CH 2 OC(O)NR 38 R 39 , -NR 40 R 41 , -CH 2 NR 42 R 43 or -SO 2 R 44 R 45 ;R 12 -H, -C(O)NR 46 R 47 , -CH 2 OC(O)NR 48 R 49 , -NR 50 R 51 , -CH 2 NR 52 R 53 or -SO 2 R 54 R 55 ;R 13 is -H, substituted alkyl, -C(O)NR 56 R 57 , -CH 2 OC(O)NR 58 R 59 , -NR 60 R 61 or -CH 2 NR 62 R 63 or -SO 2 R 64 R 65 ;R 14 -H, -C(O)N 66 R 67 , -CH 2 OC(O)NR 68 R 69 , -NR 70 R 71 or -CH 2 NR 72 R 73 or -SO 2 R 74 R 75 ;R 7 , R 11 and R15 is independently alkyl, substituted alkylalkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl; R 16 and R 17 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 18 and R 19 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 20 and R 21 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 22 and R 23 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 24 and R 25 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 26 and R 27 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 28 and R 29 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 30 and R 31 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 32 and R 33 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 34 and R 35 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 36 and R 37 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 38 and R 39 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 40 and R 41 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 42 and R 43 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 44 and R45 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 46 and R 47 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 48 and R 49 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 50 and R 51 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 52 and R 53 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 54 and R 15 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 56 and R 57 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 58 and R 59 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 60 and R 61 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 62 and R 63 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 64 and R 65 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 66 and R 67 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 68 and R 69 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 70 and R 71 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 72 and R 73 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 74 and R 75together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 76 , R 77 , R 78 , or R 79 is independently alkyl, substituted alkylalkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl; or R 76 and R 77 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring, and / or R 78 , or R 79 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 80 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, aryl, or substituted aryl; 5 or R 6 At least one of the following is not -H, but R 8 -R 10 At least one of the following is not -H, but R 12 -R 14 at least one of which is not -H) is provided.

[0006] Derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites and prodrugs of the compounds described herein are also provided.In addition, pharmaceutical compositions are provided that include the compounds provided herein and a pharma-ceutically acceptable vehicle.Methods of treating, preventing or ameliorating the symptoms of medical disorders, such as various pan-respiratory antiviral infections and diseases, are also provided herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0008] As used herein, the terms "about" and "approximately," when used in connection with a property with a numerical value or a numerical range, unless otherwise specified, indicate that the numerical value or numerical range may deviate from the stated property by a reasonable amount to one of ordinary skill in the art. Specifically, the terms "about" and "approximately" as used in this context indicate that the numerical value or numerical range may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the stated numerical value or numerical range. Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those of ordinary skill in the art.

[0009] A line that is not between two letters or symbols is used to indicate a point of attachment for a substituent, for example, -C(O)NH 2 are attached through a carbon atom. Lines at the beginning or end of chemical groups are for convenience only, and chemical groups may be represented with or without one or more lines without loss of ordinary meaning. Wavy lines drawn with lines in structures indicate points of attachment of the groups. No directionality is implied or indicated by the order of depiction or naming of chemical groups, except where chemically or structurally necessary.

[0010] Prefix “C” u-v " indicates that the subsequent group has u through v carbon atoms. It should be understood that u through v carbons includes u+1 through v, u+2 through v, u+3 through v, etc. carbons, u+1 through u+3 through v, u+1 through u+4 through v, u+2 through u+4 through v, etc. carbons, covering all possible variations of u and v.

[0011] "Alkyl" by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl, such as propan-1-yl, propan-2-yl; butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl; and the like. In some embodiments, an alkyl group contains 1 to 20 carbon atoms (C 1 -C 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C 1 -C 10 In yet other embodiments, the alkyl group contains 1 to 6 carbon atoms (C 1 -C 6 alkyl).

[0012] "Alkenyl" by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond. Exemplary alkenyl groups include, but are not limited to, ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, and cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, and cyclobuta-1,3-dien-1-yl; and the like. In some embodiments, the alkenyl group contains 1 to 20 carbon atoms (C 1 -C 20In another embodiment, the alkenyl group contains 1 to 10 carbon atoms (C 1 -C 10 In yet other embodiments, the alkenyl group contains 1 to 6 carbon atoms (C 1 -C 6 alkenyl).

[0013] "Alkynyl" by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In some embodiments, an alkynyl group contains 1 to 20 carbon atoms (C 1 -C 20 In another embodiment, the alkynyl group contains 1 to 10 carbon atoms (C 1 -C 10 In yet other embodiments, the alkynyl group contains 1 to 6 carbon atoms (C 1 -C 6 alkynyl).

[0014] "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system as defined herein. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In some embodiments, an aryl group contains 6 to 20 carbon atoms (C 6 -C 20 In another embodiment, the aryl group contains 6 to 15 carbon atoms (C 6 -C 15 In yet another embodiment, the aryl group contains 6 to 10 carbon atoms (C 6 -C 10 aryl).

[0015] "Arylalkyl," by itself or as part of another substituent, refers to an alkyl group consisting of a carbon atom (typically a terminal or sp 3 It refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to (C carbon atom) is replaced with an aryl group as defined herein. Exemplary arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. In some embodiments, an arylalkyl group is a (C 6 -C 30 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C 1 -C 10 ) alkyl, and the aryl portion is (C6 -C 20 In another embodiment, the arylalkyl group is (C 6 -C 20 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C 1 -C 8 ) alkyl, and the aryl portion is (C 6 -C 12 In yet other embodiments, the arylalkyl group is (C 6 -C 15 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C 1 -C 5 ) alkyl, and the aryl portion is (C 6 -C 10 ) aryl.

[0016] "Arylalkenyl," by itself or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In some embodiments, an arylalkenyl group is an alkyl group such as (C 6 -C 30 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C 1 -C 10 ) alkenyl, and the aryl moiety is (C 6 -C 20 In other embodiments, the arylalkenyl group is (C 6 -C 20 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C 1 -C 8 ) alkenyl, and the aryl moiety is (C 6 -C 12 In yet other embodiments, the arylalkenyl group is (C 6 -C 15 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C 1 -C 5 ) alkenyl, and the aryl moiety is (C 6-C 10 ) aryl.

[0017] "Arylalkynyl" by itself or as part of another substituent refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In some embodiments, an arylalkynyl group is (C6-C30)arylalkynyl, e.g., the alkynyl moiety of the arylalkynyl group is (C1-C10)alkynyl and the aryl moiety is (C6-C20)aryl. In other embodiments, an arylalkynyl group is (C6-C20)arylalkynyl, e.g., the alkynyl moiety of the arylalkenyl group is (C1-C8)alkynyl and the aryl moiety is (C6-C12)aryl. In yet other embodiments, an arylalkynyl group is (C6-C15)arylalkynyl, e.g., the alkynyl moiety of the arylalkynyl group is (C1-C5)alkynyl and the aryl moiety is (C6-C10)aryl.

[0018] "Cycloalkyl" by itself or as part of another substituent refers to a saturated cyclic monovalent hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In some embodiments, cycloalkyl groups contain 3 to 20 carbon atoms (C 1 -C 15 In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C 1 -C 10 In yet other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C 1 -C 8 The term "cyclic monovalent hydrocarbon radical" also includes polycyclic hydrocarbon ring systems having a single radical and 3 to 12 carbon atoms. Exemplary polycyclic cycloalkyl rings include, for example, norbornyl, vinyl, and adamantyl.

[0019] "Cycloalkenyl" by itself or as part of another substituent refers to an unsaturated cyclic monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkene. Exemplary cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, and the like. In some embodiments, a cycloalkenyl group contains 3 to 20 carbon atoms (C1-C20 cycloalkenyl). In other embodiments, a cycloalkenyl group contains 3 to 10 carbon atoms (C1-C10 cycloalkenyl). In yet other embodiments, a cycloalkenyl group contains 3 to 8 carbon atoms (C1-C8 cycloalkenyl). The term "cyclic monovalent hydrocarbon radical" also includes polycyclic hydrocarbon ring systems having single radicals and 3 to 12 carbon atoms.

[0020] "Cycloheteroalkyl" by itself or as part of another substituent refers to a cycloalkyl group, as defined herein, in which one or more carbon atoms (and optionally associated hydrogen atoms) have been replaced, each independently of the other, with the same or different heteroatom or heteroatom group defined below under "heteroalkyl." In some embodiments, a cycloheteroalkyl group contains 3 to 20 carbon atoms and heteroatoms (1-20 cycloheteroalkyl). In other embodiments, a cycloheteroalkyl group contains 3 to 10 carbon atoms and heteroatoms (1-10 cycloheteroalkyl). In yet other embodiments, a cycloheteroalkyl group contains 3 to 8 carbon atoms and heteroatoms (1-8 cycloheteroalkyl). The term "cyclic monovalent heteroalkyl radical" also includes single radicals and polycyclic heteroalkyl ring systems having 3 to 12 carbons and at least one heteroatom.

[0021] "Cycloheteroalkenyl" by itself or as part of another substituent refers to a cycloalkenyl group, as defined herein, in which one or more carbon atoms (and optionally associated hydrogen atoms) have been replaced, each independently of the other, with the same or different heteroatom or heteroatom group, as defined below under "heteroalkenyl". In some embodiments, a cycloheteroalkenyl group contains 3 to 20 carbon atoms and heteroatoms (1-20 cycloheteroalkenyl). In other embodiments, a cycloheteroalkenyl group contains 3 to 10 carbon atoms and heteroatoms (1-10 cycloheteroalkenyl). In yet other embodiments, a cycloheteroalkenyl group contains 3 to 8 carbon atoms and heteroatoms (1-8 cycloheteroalkenyl). The term "cyclic monovalent heteroalkenyl radical" also includes single radicals and polycyclic heteroalkenyl ring systems having 3 to 12 carbons and at least one heteroatom.

[0022] "Compound" refers to a compound encompassed by the structural formulas disclosed herein, including specific compounds within these formulas whose structures are disclosed herein. Compounds may be identified by chemical structure and / or chemical name. The chemical structure determines the identity of the compound. Compounds described herein may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, chemical structures depicted herein encompass stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) depicted in the structure. Chemical structures depicted herein also encompass enantiomeric and stereoisomeric derivatives of the depicted compounds. Enantiomeric and stereoisomeric mixtures can be separated into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. Compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomers of the depicted compounds. The compounds described also include isotopically labeled compounds in which one or more atoms have an atomic mass different from that conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, and the like. The compounds may exist in unsolvated and solvated forms, including hydrated forms. In general, the compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. Additionally, when a substructure of a compound is depicted, it is to be understood that a parenthetical indicates the point of attachment of the substructure to the remainder of the molecule.

[0023] "Halo" by itself or as part of another substituent refers to the radicals -F, -Cl, -Br, or -I.

[0024] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and optionally associated hydrogen atoms) are replaced, each independently of the other, with the same or different heteroatoms or heteroatom groups. Exemplary heteroatoms or heteroatom groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatoms or heteroatom groups can be located at any interior position of the alkyl, alkenyl, or alkynyl group. Exemplary heteroatom groups that may be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR501R502, =NN=, -N=N-, -N=N-NR503R404, -PR505-, -P(O)2-, -POR506-, -OP(O)2-, -SO-, -SO2-, -SnR507R508, and the like, where R501, R502, R503, R504, R505, R506, R507, and R508 are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkyl group contains 1 to 20 carbon atoms and heteroatoms (1-20 heteroalkyl). In other embodiments, the heteroalkyl group contains 1 to 10 carbon atoms and heteroatoms (1-10 heteroalkyl). In yet other embodiments, a heteroalkyl group contains 1 to 6 carbon atoms and heteroatoms (1-6 heteroalkyl).

[0025] "Heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and optionally associated hydrogen atoms) are replaced, each independently of the other, with the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatom groups that can replace the carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, etc., and combinations thereof. The heteroatoms or heteroatom groups can be located at any interior position of the alkyl, alkenyl, or alkynyl group. Exemplary heteroatom groups that may be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR501R502, =NN=, -N=N-, -N=N-NR503R404, -PR505-, -P(O)2-, -POR506-, -OP(O)2-, -SO-, -SO2-, -SnR507R508, and the like, where R501, R502, R503, R504, R505, R506, R507, and R508 are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkenyl group contains 1 to 20 carbon atoms and heteroatoms (1-20 heteroalkenyl). In other embodiments, a heteroalkenyl group contains from 1 to 10 carbon atoms and heteroatoms (1-10 heteroalkenyl). In yet other embodiments, a heteroalkenyl group contains from 1 to 6 carbon atoms and heteroatoms (1-6 heteroalkenyl).

[0026] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Typical heteroaryl groups include those derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, heteroaryl groups contain from 5 to 20 ring atoms (5-20 membered heteroaryls). In other embodiments, heteroaryl groups contain from 5 to 10 ring atoms (5-10 membered heteroaryls). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0027] "Heteroarylalkyl," by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkyl portion of the heteroarylalkyl is (C1-C6)alkyl and the heteroaryl portion is a 5-15 membered heteroaryl. In other embodiments, the heteroarylalkyl group is a 6-13 membered heteroarylalkyl, e.g., the alkyl portion is (C1-C3)alkyl and the heteroaryl portion is a 5-10 membered heteroaryl.

[0028] "Heteroarylalkenyl," by itself or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, a heteroarylalkenyl group is a 6-21 membered heteroarylalkyl, e.g., the alkenyl moiety of the heteroarylalkenyl is a (C1-C6)alkenyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, a heteroarylalkenyl is a 6-13 membered heteroarylalkenyl, e.g., the alkenyl moiety is a (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0029] "Heteroarylalkynyl" by itself or as part of another substituent refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, a heteroarylalkynyl group is a 6-21 membered heteroarylalkyl, e.g., the alkynyl moiety of the heteroarylalkynyl is a (C1-C6)alkynyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, a heteroarylalkynyl is a 6-13 membered heteroarylalkynyl, e.g., the alkynyl moiety is a (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0030] "Hydrate" refers to the incorporation of water in a stoichiometric proportion into the crystal lattice of a compound described herein to form an adduct. Methods for making hydrates include, but are not limited to, storage in an atmosphere containing water vapor, a dosage form containing water, or a typical pharmaceutical processing step, such as crystallization (i.e., from water or mixed aqueous solvents), lyophilization, wet granulation, aqueous film coating, or spray drying. Under certain circumstances, hydrates may form from crystalline solvates when exposed to water vapor or when anhydrous materials are suspended in water. Hydrates may also crystallize in multiple forms, resulting in hydrate polymorphs. See, for example, Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999. The above methods for preparing hydrates are within the knowledge of one of ordinary skill in the art and are completely conventional and do not require experimentation beyond that which is typical in the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition, many commercial companies routinely offer services that include the preparation and / or characterization of hydrates, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0031] "Parent Aromatic Ring System" refers to an unsaturated ring or polycyclic ring system having a conjugated pi-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Exemplary parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0032] "Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Exemplary parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0033] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbiphenyl ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0034] "Prophylaxis" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., preventing at least one clinical symptom of a disease from developing in a patient who may have been exposed to or is susceptible to the disease, but who has not yet experienced or shown symptoms of the disease). The application of a therapy to prevent or prevent a disease or disorder is known as "prophylaxis." In some embodiments, the compounds provided herein provide superior prophylactic benefits due to low long-term side effects over a long period of time.

[0035] As used herein, "prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug.

[0036] As used herein, a "promoiety" refers to a form of protecting group that, when used to mask a functional group within a drug molecule, converts the drug into a prodrug. Typically, a promoiety is attached to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means.

[0037] "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group during chemical synthesis. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry", (Wiley, 2nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), etc. Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxy group is acylated or alkylated, such as benzyl, trityl ether, alkyl ether, tetrahydropyranyl ether, trialkylsilyl ether, and allyl ether.

[0038] "Solvate" refers to the incorporation of a solvent into the crystal lattice of a compound described herein in stoichiometric proportions to form an adduct. Methods for making solvates include, but are not limited to, storage in an atmosphere containing the solvent, a dosage form containing the solvent, or a typical pharmaceutical processing step, such as crystallization (i.e., from a solvent or mixture of solvents), vapor diffusion, etc. Under certain circumstances, a solvate may form from other crystalline solvates or hydrates when exposed to a solvent or when a substance is suspended in a solvent. A solvate may crystallize in more than one form, resulting in solvate polymorphism. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above methods for preparing solvates are within the knowledge of one of ordinary skill in the art and are completely conventional and do not require experimentation beyond that which is typical in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition, many commercial companies routinely offer services that include the preparation and / or characterization of solvates, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0039] "Substituted," when used to modify a particular group or radical, means that one or more hydrogen atoms of the particular group or radical are each replaced, independently of one another, with the same or different substituents.Useful substituents for replacing saturated carbon atoms in a specified group or radical include Ra, halo, -O-, =O, -ORb, -SRb, -S-, =S, -NRcRc, =NRb, =N-ORb, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-ORb, -N-NRcRc, -NRbS(O)2Rb, =N2, -N3, -S(O)2Rb, -S(O)2NRbRb, -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, -OS(O)2ORb, -OS(O)2NRcN Rc, -P(O)(O-)2, -P(O)(ORb)(O-), -P(O)(ORb)(ORb), -C(O)Rb, -C(O)NRb-ORb-C(S)Rb, -C(NRb)Rb, -C(O)O-, -C(O)ORb, -C(S)ORb, -C(O)NRcRc, - C(NRb)NRcRc, -OC(O)Rb, -OC(S)Rb, -OC(O)O-, -OC(O)ORb, -OC(O)NRcRc, -OC(NCN)NRcRc-OC(S)ORb, -NRbC(O)Rb, -NRbC(S)Rb, -NRbC(O)O-, -NRb and -NRbC(NRb)NRcRc, where each Ra is independently aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl; each Rb is independently aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl; each Rc is independently hydrogen, alkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl; each Rc is independently Rb, or two Rc together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, or cycloheteroalkyl fused to an aryl group which may optionally contain 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S.As specific examples, -NRcRc is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for replacing saturated carbon atoms in the specified groups or radicals include Ra, halo, -ORb, -NRcRc, trihalomethyl, -CN, -NRbS(O)2Rb, -C(O)Rb, -C(O)NRb-ORb, -C(O)ORb, -C(O)NRcRc, -OC(O)Rb, -OC(O)ORb, -OS(O)2NRcNRc, -OC(O)NRcRc, and -NRbC(O)ORb, where each Ra is independently alkyl, aryl, heteroaryl and each Rb is independently hydrogen, Ra, heteroalkyl, arylalkyl, heteroarylalkyl; each Rc is independently Rb, or two Rc together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring.

[0040] Useful substituents for replacing unsaturated carbon atoms in a specified group or radical include, but are not limited to, -Ra, halo, -O-, -ORb, -SRb, -S-, -NRcRc, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2ORb, -OS(O)2O-, -P(O)(O-)2, -P(O)(ORb)(O-), -P(O)(ORb)(ORb), -C(O)Rb, -C(S)Rb, -C(NRb)Rb, -C(O)O-, -C(O)ORb, -C(S)ORb, -C(O)NRcRc, -C(NRb)NRcRc, -OC(O)Rb, -OC(S)Rb, -OC(O)O-, -OC(O)ORb, -OC(S)ORb, -OC(O)NRcRc, -OS(O)NRcNRc, -NRbC(O)Rb, -NRbC(S)Rb, -NRbC(O)O-, -NRbC(O)ORb, -NRbS(O)ORa, -NRbS(O)Ra, -NRbC(S)ORb, -NRbC(O)NRcRc, -NRbC(NRb)Rb and -NRbC(NRb)NRcRc, where Ra, Rb and Rc are as defined above. In other embodiments, substituents useful for replacing the unsaturated carbon atom in a specified group or radical include -Ra, halo, -ORb, -SRb, -NRcRc, trihalomethyl, -CN, -S(O)2ORb, -C(O)Rb, -C(O)ORb, -C(O)NRcRc, -OC(O)Rb, -OC(O)ORb, -OS(O)2NRcNRc, -NRbC(O)Rb, and -NR b C(O)OR b where R a , R b and R c is as defined above.

[0041] In some embodiments, useful substituents for replacing a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include -R a , -O - , -OR b , -SR b , -S - , -NR C R C , trihalomethyl, -CF3 , -CN, -NO, -NO 2 , -S(O) 2 R b , -S(O) 2 O - , -S(O) 2 OR b , -OS(O) 2 R b , -OS(O) 2 O - , -OS(O) 2 OR b , -P(O)(O - ) 2 , -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)OR b , -C(S)OR b , -C(O)NR C R C , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)OR b , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)OR b , -NR b C(S)OR b , -NR b C(0)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c In particular, but not limited to, a , R b and Rc is as defined above. In some embodiments, useful substituents for substituting a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include R a , Halo, -OR b , -NR C R C , trihalomethyl, -CN, -S(O) 2 OR b , -OS(O) 2 R b , -OS(O) 2 OR b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR C R C , -OC(O)R b , -OC(O)OR b , -OS(O) 2 NR C NR C , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as defined above.

[0042] Substituents from the above list that are useful to replace other particular groups or atoms will be apparent to those of skill in the art.

[0043] The substituents used to substituted a particular group may be further substituted with one or more of the same or different groups typically selected from the various groups identified above.

[0044] The terms "subject," "individual," or "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, including, but not limited to, murines, rodents, simians, humans, farm animals, sport animals, and pets.

[0045] "Treating" a disease or disorder or "treatment" thereof, in some embodiments, refers to ameliorating the disease or disorder (i.e., arresting or reducing the progression of the disease or at least one clinical symptom thereof). Treatment is also contemplated to include preemptive or prophylactic administration to ameliorate, arrest, or prevent the progression of the disease or at least one clinical symptom thereof. In a further feature, the treatment provided has a low likelihood of long-term side effects over multiple years. In other embodiments, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the patient. In yet other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0046] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, excretion, etc., of the patient being treated.

[0047] "Vehicle" refers to a diluent, excipient, or carrier used in administering a compound to a subject. In some embodiments, the vehicle is pharma- ceutically acceptable.

[0048] compound As used herein, in one aspect, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, hydrate or solvate thereof, 1 and R 2 is independently alkyl, alkenyl, cycloalkyl or cycloalkenyl; R 3 is -H or alkyl; a is 1, 2 or 3; R 4 is -H, halo, alkyl, -OR7 ;R 5 is -H, halo, alkyl, substituted alkyl, [ka] , -C(O)NR 76 R 77 , -NR 78 R 79 , -NHC(O)R 80 , -OR 11 b is 0, 1, 2 or 3; R 6 is -H, alkyl, [ka] -OR 15 c is 1, 2 or 3; X is [ka] , substituted aryl, heteroaryl, substituted heteroaryl; R 8 -H, -C(O)NR 16 R 17 , -CH 2 OC(O)NR 18 R 19 , -NR 20 R 21 , -CH 2 NR 22 R 23 or -SO 2 R 24 R 25 ;R 9 -H, -C(O)NR 26 R 27 , -CH 2 OC(O)NR 28 R 29 , -NR 30 R 31 , -CH 2 NR 32 R 33 or -SO 2 R 34 R 35 ;R 10 -H, -C(O)NR36 R 37 , -CH 2 OC(O)NR 38 R 39 , -NR 40 R 41 , -CH 2 NR 42 R 43 or -SO 2 R 44 R 45 ;R 12 -H, -C(O)NR 46 R 47 , -CH 2 OC(O)NR 48 R 49 , -NR 50 R 51 , -CH 2 NR 52 R 53 or -SO 2 R 54 R 55 ;R 13 is -H, substituted alkyl, -C(O)NR 56 R 57 , -CH 2 OC(O)NR 58 R 59 , -NR 60 R 61 or -CH 2 NR 62 R 63 or -SO 2 R 64 R 65 ;R 14 -H, -C(O)N 66 R 67 , -CH 2 OC(O)NR 68 R 69 , -NR 70 R 71 or -CH 2 NR 72 R 73 or -SO 2 R 74 R 75 ;R 7 , R 11 and R 15is independently alkyl, substituted alkylalkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl; R 16 and R 17 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 18 and R 19 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 20 and R 21 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 22 and R 23 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 24 and R 25 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 26 and R 27 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 28 and R 29 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 30 and R 31 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 32 and R 33 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 34 and R 35 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 36 and R 37 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 38 and R 39 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 40 and R 41 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 42 and R 43 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 44 and R 45together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 46 and R 47 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 48 and R 49 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 50 and R 51 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 52 and R 53 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 54 and R 15 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 56 and R 57 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 58 and R 59 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 60 and R 61 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 62 and R 63 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 64 and R 65 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 66 and R 67 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 68 and R 69 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 70 and R 71 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 72 and R 73 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 74 and R 75 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R76 , R 77 , R 78 , or R 79 is independently alkyl, substituted alkylalkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl; or R 76 and R 77 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring, and / or R 78 , or R 79 together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R 80 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, aryl, or substituted aryl; 5 or R 6 At least one of the following is not -H, but R 8 -R 10 At least one of the following is not -H, but R 12 -R 14 at least one of which is not -H) is provided.

[0049] In some embodiments, the formula (II) [ka] The compound of formula (1) is provided.

[0050] In some embodiments, the compound of formula (III) [ka] The compound of formula (1) is provided.

[0051] In some embodiments, formula (IV) [ka] The compound of formula (1) is provided.

[0052] In some embodiments, formula (V) [ka] The compound of formula (1) is provided.

[0053] In some embodiments, R 1 and R 2 is independently alkyl or cycloalkyl.

[0054] In some embodiments, a, b and c are 1.

[0055] In some embodiments, R7 is alkyl or substituted alkyl.

[0056] In some embodiments, R9 is heterocycle or substituted heterocycle or alkyl substituted with haloalkyl.

[0057] In some embodiments, R11 is heterocycle or substituted heterocycle or alkyl substituted with haloalkyl.

[0058] In some embodiments, R1 and R2 are independently alkyl or cycloalkyl, a, b, and c are 1, R7 is alkyl or substituted alkyl, R11 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle, and R15 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

[0059] In some embodiments of Formula (II), R 5 is -H, halo or -OR 9 In another embodiment of formula (II), R 9 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle. In yet another embodiment of formula (II), R 6 teeth, [ka] -OR 15 In yet another embodiment of formula (II), R 11 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

[0060] In some embodiments of Formula (II), R 5 is -H or halo. In another embodiment of formula (II), R 5 teeth, [ka] -OR 11 In yet another embodiment of formula (II), R 1 and R 2 is independently alkyl or cycloalkyl and a is 1.

[0061] In some embodiments of Formula (III), R 6 teeth, [ka] -OR 15 R 9 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle. In another embodiment of formula (III), R 1 and R 2 is independently alkyl or cycloalkyl, and a is 1. In still other embodiments of Formula (III), R 6 teeth, [ka] -OR 15 In yet another embodiment of formula (III), R 11 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle. In yet another embodiment of formula (III), R 1 and R 2 is independently alkyl or cycloalkyl and a is 1.

[0062] In some embodiments of Formula (V), R 5 teeth, [ka] -OR 11 In another embodiment of formula (V), R 9 is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle. 1 and R 2 is independently alkyl or cycloalkyl and a is 1.

[0063] In some of the above embodiments, R 12 and R 13 is hydrogen. In some of the above embodiments, R 8 and R 9 is hydrogen.

[0064] Exemplary compounds are shown in Table 1 below.

[0065] [Table 1-1]

[0066] [Table 1-2]

[0067] [Table 1-3]

[0068] [Table 1-4]

[0069] [Table 1-5]

[0070]

Table 1-6

[0071]

Table 1-7

[0072]

Table 1-8

[0073]

Table 1-9

[0074]

Table 1-10

[0075]

Table 1-11

[0076]

Table 1-12

[0077]

Table 1-13

[0078]

Table 1-14

[0079]

Table 1-15

[0080]

Table 1-16

[0081]

Table 1-17

[0082]

Table 1-18

[0083]

Table 1-19

[0084]

Table 1-20

[0085]

Table 1-21

[0086]

Table 1-22

[0087]

Table 1-23

[0088]

Table 1-24

[0089]

Table 1-25

[0090]

Table 1-26

[0091] [Table 1-27]

[0092] [Table 1-28]

[0093] [Table 1-29]

[0094] [Table 1-30]

[0095] [Table 1-31]

[0096] [Table 1-32]

[0097] [Table 1-33]

[0098] The above compounds can be made by well-known procedures, some of which are exemplified in the experimental section.

[0099] Compositions and Methods of Administration The compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein and a vehicle that is useful for preventing, treating, or improving one or more symptoms of the diseases or disorders described herein.Vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art to be suitable for a particular method of administration.Furthermore, the compounds may be formulated as the only active ingredient in the composition or may be combined with other active ingredients.

[0100] The composition contains one or more compounds provided herein.In some embodiments, the compound is formulated into suitable preparations such as solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation or elixir for oral administration, or sterile solution or suspension for parenteral administration, topical administration, transdermal administration, and oral inhalation by nebulizer, pressurized metered dose inhaler, dry powder inhaler.In some embodiments, the compound is formulated into composition using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0101] In the composition, an effective concentration of one or more compounds or derivatives thereof is mixed with a suitable medium. The compound may be derivatized as the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate or prodrug before formulation, as described above. The concentration of the compound in the composition is effective to deliver an amount that, upon administration, treats, prevents, or ameliorates one or more symptoms of the disease or disorder described herein. In some embodiments, the composition is formulated for single administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected medium at an effective concentration so that the condition being treated is improved, prevented, or one or more symptoms are ameliorated.

[0102] The active compound is included in the medium in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the treated patient.The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then the dosage for humans can be extrapolated therefrom.The human dosage is then typically fine-tuned in clinical trials and titrated according to response.

[0103] The concentration of the active compound in the composition depends on the absorption, inactivation and excretion rate of the active compound, the physicochemical properties of the compound, the administration schedule and the dosage, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of the disease or disorder described herein.

[0104] In the case where the solubility of the compound is insufficient, methods for solubilizing the compound can be used, such as using liposomes, prodrugs, complexation / chelation, nanoparticles, emulsions, or tertiary templates.Such methods are known to those skilled in the art and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants or surface modifiers such as TWEEN®, using complexing agents such as cyclodextrins, or dissolving by enhanced ionization (i.e., dissolving in aqueous sodium bicarbonate).Derivatives of the compound, such as prodrugs of the compound, can also be used in formulating effective compositions.

[0105] Upon mixing or addition of the compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder, or condition being treated and may be empirically determined.

[0106] The compositions are provided for administration to humans and animals in dosage forms suitable for the indication, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / bioerodible strips, tablets or capsules, powders, granules, troches, lotions, ointments, suppositories, fast dissolving agents, transdermal patches or other transdermal application devices / formulations, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil-water emulsions, and the like, containing the appropriate amount of the compound or its derivatives. The therapeutically active compounds and its derivatives are in some embodiments formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms as used herein refer to physically discrete units suitable for human and animal subjects and individually packaged, as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, together with the necessary vehicle. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. Unit dosage forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in one container for administration in separate unit dosage forms.Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.Therefore, a multiple dose form is a multiple of the unit dosage that is not separated in packaging.

[0107] Liquid compositions can be prepared, for example, by dissolving, dispersing, or mixing the active compound defined above and optional auxiliary agents in a vehicle such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension, a colloidal dispersion, an emulsion, or a liposomal preparation. If desired, the composition to be administered can also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizers, pH buffers, etc., such as acetates, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such substances.

[0108] Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions).

[0109] Dosage forms or compositions may be prepared containing active ingredient in the range of 0.005%-100%, with the remainder consisting of a vehicle or carrier. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, and in another embodiment 0.4-10% active ingredient.

[0110] In certain embodiments, the composition is a lactose-free composition containing excipients known in the art and described, for example, in the United States Pharmacopoeia (USP) 25-NF20 (2002). In general, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in suitable amounts. A particular lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0111] Further provided are anhydrous compositions and dosage forms containing active ingredients, since water can accelerate the decomposition of some compounds.For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as shelf life or stability over time of formulations.See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.In fact, water and heat accelerate the decomposition of some compounds.Therefore, the effect of water on formulations is very important, since they often encounter moisture and / or humidity during the process of manufacturing, handling, packaging, storage, shipping, and use of formulations.

[0112] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0113] Anhydrous composition must be prepared and stored in such a way that its anhydrous nature is maintained.Therefore, anhydrous composition is usually packaged using a material known to prevent exposure to water so that it can be included in a suitable formulary kit.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0114] Oral dosage forms are either solid, gel or liquid. Solid dosage forms are tablets, capsules, granules, bulk powders. Types of oral tablets include compressed chewable lozenges and tablets that may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with combinations of other ingredients known to those skilled in the art.

[0115] In certain embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc. may contain one or more of the following ingredients: binders, lubricants, diluents, glidants, disintegrants, colorants, sweeteners, flavorings, wetting agents, enteric coatings, film coatings, release control agents, or compounds of similar nature. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth gum, glucose solution, acacia gum mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, starch, and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, carboxymethylcellulose. Coloring agents include, for example, approved certified water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate, and high-grade coloring agents or anti-counterfeiting color / opalescence additives known to those skilled in the art. Sweeteners include sucrose, lactose, mannitol and artificial sweeteners such as saccharin, as well as various spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic mixtures of compounds that produce a pleasant sensation or mask unpleasant tastes, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, cellulose acetate phthalates.Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Release controlling agents include polymers such as the Eudragit® series and cellulose esters.

[0116] The compound or its derivatives can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0117] When the dosage unit form is a capsule, it may contain, in addition to the above-mentioned types of materials, liquid carriers such as fatty oils.Furthermore, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar and other enteric agents.The compound may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, etc.Syrup may contain, in addition to the active ingredient, sucrose as a sweetener, certain preservatives, dyes, colorings, and flavorings.

[0118] The active substance may be mixed with other active substances that do not impair the desired action, or with antacids, H 2 It may also be mixed with substances that supplement the desired action, such as blockers and diuretics. The active ingredient is a compound described herein or a derivative thereof. High concentrations of the active ingredient, up to about 98% by weight, may be included.

[0119] In all embodiments, the tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient, and thus may be coated with conventional enterically digestible coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

[0120] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0121] Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small droplets throughout another liquid. Carriers used in emulsions are non-aqueous liquids, emulsifying agents, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[0122] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Sweetening agents include sucrose, syrup, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include the approved certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds which produce a pleasant taste sensation.

[0123] For solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils, or triglycerides, is in some embodiments encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patents 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, the solution, for example in polyethylene glycol, can be diluted with a sufficient quantity of liquid medium, for example water, so that it can be easily measured for administration.

[0124] Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those described in U.S. Patents RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound described herein, a dialkylated mono- or polyalkylene glycol (including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol)), and one or more antioxidants (such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates).

[0125] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetals.The alcohols used in these formulations are any water-miscible solvents with one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.Acetals include, but are not limited to, the di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0126] In some embodiments, parenteral administration is also contemplated herein, characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients include, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0127] Implantation of a slow-release or sustained-release system such that a constant dosage is maintained is also contemplated herein (see, e.g., U.S. Pat. No. 3,710,795). Briefly, the compounds provided herein are delivered to the patient via an outer polymeric membrane that is insoluble in body fluids (e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol ternary copolymers, and ethylene. The compound is dispersed in a solid internal matrix (e.g., hydrophilic polymers such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate) surrounded by a polymeric membrane (e.g., ethylene / vinyloxyethanol copolymer). The compound diffuses through the outer polymer membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[0128] Parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration.Preparations for parenteral administration include sterile solutions for injection, sterile dry soluble products (including subcutaneous tablets) such as freeze-dried powders that are mixed with solvents immediately before use, sterile suspensions for injection, sterile dry insoluble products that are mixed with media immediately before use, and sterile emulsions.Solutions can be either aqueous or non-aqueous.

[0129] For intravenous administration, suitable carriers include physiological saline or phosphate buffered saline (PBS), as well as solutions containing viscosity enhancing and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0130] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetic agents, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other substances.

[0131] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Parenteral preparations packaged in multi-dose containers require the addition of antibacterial agents in bacteriostatic or fungistatic concentrations, including phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citric acid. Antioxidants include sodium bisulfite. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). Sequestering or chelating agents for metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol as water-miscible vehicles; sodium hydroxide, hydrochloric acid, citric acid, or lactic acid as pH adjusters.

[0132] The concentration of the compound is adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dose will vary with the age, weight, body surface area and condition of the patient or animal, as is known in the art.

[0133] Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. All preparations for parenteral administration must be sterile, as known and practiced in the art.

[0134] For example, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective method of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material injected as necessary to produce the desired pharmacological effect.

[0135] Injectables are designed for local and systemic administration. In some embodiments, a therapeutically effective dose is formulated to contain at least about 0.01% w / w to about 90% w / w or more of the active compound to the tissue to be treated, and in certain embodiments, greater than 0.1% w / w.

[0136] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product, or to produce a prodrug. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate symptoms, and may be empirically determined.

[0137] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; Nos. 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500; and 6,740,634. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide desired release profiles at various rates. Suitable controlled release formulations known to those of skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0138] All controlled release products have a common goal of improving drug therapy compared to that achieved by non-controlled release products. Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by the use of a minimum amount of drug and the cure or control of symptoms in the shortest time possible. Advantages of controlled release formulations include extended drug action, reduced dosing frequency, and improved patient compliance. In addition, controlled release formulations can be used to affect other characteristics, such as the time of onset of action or blood levels of the drug, thereby affecting the occurrence of side effects (e.g., adverse effects).

[0139] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, and then slowly and continuously release another amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant drug level in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of active ingredients can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, and other physiological conditions or compounds.

[0140] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other methods of administration. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, a polymeric material may be used. In other embodiments, a controlled release system may be placed near the therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, a controlled release device is introduced into the subject near a site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer, Science 249:1527-1533 (1990).The active ingredient is contained within an outer polymeric membrane that is insoluble in body fluids (e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol ternary copolymers, and ethylene / vinyl oxidase). The active ingredient may be dispersed in a solid internal matrix (e.g., polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate) surrounded by a polyvinyl alcohol copolymer (polyvinyl alcohol copolymer). The active ingredient then diffuses through the outer polymer membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on their specific nature, as well as the needs of the subject.

[0141] Lyophilized powders are also contemplated herein, which can be reconstituted for administration as solutions, emulsions, and other mixtures. They may also be reconstituted and formulated as solids or gels.

[0142] Sterile lyophilized powders are prepared by dissolving a compound provided herein or a derivative thereof in a suitable solvent. The solvent may contain excipients or other pharmacological ingredients that improve the stability of the powder or reconstituted solutions prepared from the powder. Excipients that may be used include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipients are selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer such as citric acid, sodium phosphate, potassium phosphate, or other buffers known to those of skill in the art (pH values ​​near neutral). The solution is then sterile filtered, followed by lyophilization under standard conditions known to those of skill in the art to obtain the desired formulation. In some embodiments, the resulting solution is apportioned into vials for lyophilization. Each vial contains a single dose or multiple doses of the compound. The lyophilized powders can be stored under appropriate conditions, such as at about 4° C. to room temperature.

[0143] This lyophilized powder is reconstituted with water for injection to provide a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other appropriate carrier. Exact amounts will vary with the compound selected. Such amounts can be empirically determined.

[0144] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and may be formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, wash, spray, suppository, bandage, skin patch, or other formulation suitable for topical administration.

[0145] The compound or its derivatives can be formulated as an aerosol for topical application, such as by inhalation (see, for example, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be administered alone or in combination with an inert carrier, such as lactose, in the form of an aerosol or solution for nebulizers, or in the form of ultrafine powder for inhalation. In such cases, the particles of the formulation have a mass median geometric diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0146] Oral inhalation formulations of the compound or derivative suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid formulations for administration from a nebulizer or metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, the crystalline form of the compound or derivative is the preferred physical form of the drug to provide longer product stability.

[0147] In addition to particle size reduction methods known to those skilled in the art, crystalline particles of the compound or derivative can be produced using supercritical fluid processing, which offers great advantages in the production of such particles for inhalation delivery by producing respirable particles of the desired size in a single step (e.g., WO 2005 / 025506). The particle size of the microcrystals can be controlled to ensure that a significant proportion of the compound or derivative is deposited in the lungs. In some embodiments, the mass mean aerodynamic diameter of these particles is about 0.1 to about 10 microns, in other embodiments, about 1 to about 5 microns, and in yet other embodiments, about 1.2 to about 3 microns.

[0148] The inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane), provided alone or in a ratio that matches the density of the crystalline particles of the compound or derivative. The ratios are also selected so that the product suspension avoids deleterious settling or creaming (which can precipitate irreversible aggregates) and instead promotes a loosely aggregated system that disperses easily when shaken. The loosely aggregated system is believed to provide optimal stability in pMDI cans. As a result of the properties of the formulation, it contains no ethanol and no surfactants / stabilizers.

[0149] The compounds can be formulated for local or external application, such as topical application to the skin and mucous membranes (including the eye), application to the eye, or intracisternal or intrathecal application, in the form of gels, creams, and lotions.Topical administration is contemplated for transdermal delivery, as well as for administration to the eye or mucous membranes, or for inhalation therapy.Nasal solutions of the active compounds alone or in combination with other excipients can also be administered.

[0150] For nasal administration, the formulation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier for aerosol spray, particularly an aqueous carrier. The carrier may contain a solubilizing or suspending agent, such as propylene glycol, a surfactant, an absorption enhancer, such as lecithin or cyclodextrin, or a preservative.

[0151] Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions (pH about 5 to 7.4) containing appropriate salts.

[0152] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein.

[0153] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art.For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0154] For example, dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories as used herein refer to solid bodies inserted into the rectum that melt or soften at body temperature and release one or more pharmacologically or therapeutically active ingredients. Substances used in rectal suppositories are bases or vehicles and agents that raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and suitable mixtures of mono-, di- and triglycerides of fatty acids. Combinations of various bases may be used. Substances that raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared by either compression or molding. In one embodiment, the weight of a rectal suppository is about 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same substances and methods as formulations for oral administration.

[0155] The compounds provided herein, or derivatives thereof, may be formulated to target specific tissues, receptors, or other areas of the body of the subject to be treated. Many such targeting methods are well known to those skilled in the art. All such targeting methods are contemplated herein for use in the compositions of the present invention. Non-limiting examples of targeting methods are described, for example, in U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060, See US Pat. Nos. 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0156] In some embodiments, liposomal suspensions, including tissue-targeted liposomes such as tumor-targeted liposomes, may also be suitable as carriers. These may be prepared according to methods known to those skilled in the art. For example, liposomal formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) may be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) in a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0157] The compound or derivative may be packaged as an article of manufacture containing packaging material, within the packaging material, a compound or derivative thereof as described herein that is effective for the treatment, prevention or amelioration of one or more symptoms of the disease or disorder described above, and a label indicating that the compound or composition or derivative thereof is used for the treatment, prevention or amelioration of one or more symptoms of the disease or disorder described above.

[0158] The product provided herein contains packaging material. The packaging material used to package the product is well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging material include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended administration and treatment method. A wide range of formulations of the compounds and compositions provided herein are contemplated, as are various treatments for any disease or disorder described herein.

[0159] Dosage For use in the treatment or prevention of infectious diseases, the compounds described herein or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount. In human treatment, the physician will determine the most appropriate dosing regimen depending on the preventive or therapeutic treatment, and the age, weight, stage of the disease, and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein is effective for the prevention or treatment of infectious diseases, but will vary depending on the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary depending on factors specific to each subject, depending on the specific therapeutic agent (e.g., therapeutic or prophylactic agent) administered, the severity of the infection, the route of administration, and the age, size, weight, response, and past medical history of the subject.

[0160] Exemplary dosage amounts of the formulations include milligram or microgram amounts of active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 micrograms per kilogram to about 5 milligrams per kilogram).

[0161] In some embodiments, a therapeutically effective dosage produces a serum concentration of active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. In other embodiments, the compositions provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg, and in some embodiments, about 10 mg to about 500 mg of active ingredient or a combination of essential ingredients per dosage unit form.

[0162] The active ingredient may be administered once or divided into several smaller doses administered at intervals. It is understood that the exact dosage and duration of treatment vary according to the disease being treated and can be empirically determined using known testing protocols or can be determined by extrapolating from in vivo or in vitro test data or subsequent clinical trials. It is noted that concentration and dosage can also vary according to the severity of the condition being improved. It is further understood that for a particular subject, specific dosage regimens must be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0163] As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein. Furthermore, the clinician or treating physician will know when and how to interrupt, adjust, or terminate treatment depending on the subject's response.

[0164] For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays, e.g., IC determined in cell culture, animal models, or 50 (i.e., the concentration of test compound that is lethal to 50% of the cell cultures), or the IC determined in cell culture. 100 A dose can be formulated to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal to 100% of the cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0165] Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can readily optimize human dosing based on animal data.

[0166] Alternatively, the IC of certain compounds disclosed herein 50 , MIC, and / or I 100 Initial dosages can also be determined from the dosages of known drugs by comparing the initial dosages to those of known drugs and adjusting the initial dosages accordingly. Optimal dosages can be obtained from these initial values ​​by routine optimization.

[0167] In cases of local administration or selective uptake, the effective local concentration of the compound used may not be related to plasma concentration. Those skilled in the art will be able to optimize therapeutically effective local doses without undue experimentation.

[0168] Ideally, a therapeutically effective amount of the compounds described herein will provide a therapeutic effect without causing substantial toxicity. Toxicity of the compounds can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50(the dose lethal to 50% of the population) or LD 100 The therapeutic index can be determined by determining the dose that is lethal to 100% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a dosage range that can be used in subjects without toxicity. The dosage of the compounds described herein is preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage can vary within this range depending on the dosage form employed and the route of administration used. The exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition (see, for example, Fingl el al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p.1).

[0169] Treatment may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, and administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0170] Methods of Use of the Compounds and Compositions Described herein are methods of treating, preventing, or ameliorating symptoms of medical disorders, such as various respiratory antiviral infections and related diseases, including, inter alia, coronaviruses and influenza viruses, using the disclosed compounds and pharmaceutical compositions. Also described herein are methods of using the disclosed compounds and pharmaceutical compositions as antiviral agents. In practicing these methods, a therapeutically effective amount of the compounds or compositions described herein above is administered to a patient having a disorder or condition.

[0171] Combination therapy The compounds and compositions disclosed herein may be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination with or sequentially with another therapeutic agent. Such other therapeutic agents include those known to treat, prevent, or ameliorate one or more symptoms associated with various pan-respiratory antiviral infections and diseases. Other therapeutic agents include those known to treat, prevent, or ameliorate one or more symptoms of viral infections.

[0172] It should be understood that any suitable combination of the compounds and compositions provided herein with one or more of the therapeutic agents described above, and optionally with one or more additional pharmacologically active substances, is considered to be within the scope of the present disclosure. In some embodiments, the compounds and compositions provided herein are administered before or after one or more additional active ingredients.

[0173] Finally, it should be noted that there are alternative ways of implementing the invention, and therefore the present embodiments should be considered as illustrative rather than restrictive, and the invention is not limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

[0174] All publications and patents cited herein are incorporated by reference in their entirety.

[0175] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. EXAMPLES

[0176] Scheme 1 illustrates the preparation of compound 205. [ka]

[0177] Preparation of amine 203 [ka]

[0178] To a solution of aldehyde 201 (10 g, 65.79 mmol, 1.0 equiv) in toluene was added 2,4-dimethoxybenzylamine 202 (10.99 g, 65.79 mmol, 1.0 equiv) and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was taken up in MeOH and cooled using an ice bath. Sodium borohydride (4.97 g, 131.58 mmol, 2.0 equiv) was then added slowly and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed and the residue was taken up in ethyl acetate and then saturated NaHCO 3 The organic layer was separated and dried (MgSO 4 ), and the solvent was removed to give amine 203, which was used in the next step without further purification.

[0179] Preparation of amide 205 [ka]

[0180] To a solution of crude amine 203 (5.0 g, 19.1 mmol, 1.0 equiv) in DMF (25 mL) was added acid 204 (3.17 g, 19.1 mmol, 1.0 equiv), HBTU (8.7 g, 22.92 mmol, 1.2 equiv), and DIEA (12.32 g, 95.5 mmol, 5.0 equiv), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was dissolved in MeOH and then 2 CO 3(2.64 g, 19.1 mmol, 1.0 equiv) was added and stirred at room temperature for 12 h. The solvent was removed and the residue was dissolved in ethyl acetate and washed with 10% HCl (1x). The organic layer was separated, dried and the solvent was removed to give the crude material, which was purified by column chromatography (EtOAc / Hexanes) to give compound 205. Mass Spectrum (LCMS, ESI Pos.) C 25 H 30 N 3 O 5 Calculated value for: 452.0(M + H), actual value 452.0.

[0181] Scheme 2 illustrates the preparation of piperazine 208. [ka]

[0182] Preparation of bromide 206 [ka]

[0183] To a solution of compound 205 (5.0 g, 11.0 mmol, 1.0 equiv) in DMF (25 mL) was added cesium carbonate (7.2 g, 22.0 mmol, 2.0 equiv) and the reaction mixture was stirred at room temperature for 10 min. Then, 1,3-dibromopropane (4.44 g, 22.0 mmol, 2.0 equiv) was added to the reaction mixture and stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water (3 times). The organic layer was dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (hexane / EtOAc) to give bromide 206. Mass Spectrum (LCMS, ESI Pos.): 28 H 35 BrN 3 O 5 Calculated value for: 572.0(M + H), actual value 572.0.

[0184] Preparation of piperazine 208 [ka]

[0185] To a solution of bromide 206 (247 mg, 0.433 mmol, 1.0 equiv) in DMF (10 mL) was added Cs 2 CO 3 (211 mg, 0.650 mmol, 1.5 equiv) and N-Boc-piperazine (121 mg, 0.650 mmol, 1.5 equiv) were added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water (3 times). The organic layer was collected, dried and the solvent was removed to give crude 207, which was immediately treated with 95% TFA and stirred at room temperature for 12 h. The TFA was removed and the crude material was purified by column chromatography (DCM / MeOH) to give piperazine compound 208. Mass Spectrum (LCMS, ESI Pos.): C 24 H 38 N 5 O 3 Calculated value for: 444.0(M + H), actual value 444.0.

[0186] Example 1: Preparation of Compound 24 [ka]

[0187] Isobutylsulfonyl chloride (0.024 g, 0.15 mmol, 1.5 equiv) was added to a solution of piperazine 208 (0.043 g, 0.1 mmol, 1.0 equiv) and DIEA (0.039 mL, 0.3 mmol, 3.0 equiv) in DCM (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, DCM was added, and the organic layer was washed with saturated NaHCO 3 The solution was washed with 10% HCl, water, brine, dried and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired sulfonamide 24. Mass Spectrum (LCMS, ESI Pos.): C 27 H 42 N 5 O 5 Calculated value for S: 548.0 (M+ H), actual value 548.0.

[0188] Scheme 3 illustrates the preparation of amide 9. [ka]

[0189] Preparation of ester 210 [ka]

[0190] To a stirred solution of amide 205 (1.0 g, 2.22 mmol, 1.0 equiv) and cesium carbonate (1.08 g, 3.33 mmol, 1.5 equiv) in DMF (15 mL) was added methyl 4-(chloromethyl)benzoate 209 (559 mg, 2.44 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate and washed with water (3 times). The organic layer was dried, concentrated and the residue was stirred in a 1:1 mixture of TFA:DCM for 12 h. After concentration, chromatographic purification (hexane / EtOAc) gave the desired ester 210. Mass Spectrum (LCMS, ESI Pos.): C 34 H 37 FN 3 O 7 Calculated value for: 600.0(M + H), actual value 600.0.

[0191] Preparation of Acid 212 [ka]

[0192] Ester 210 (500 mg, 0.84 mmol) was dissolved in a 1:1 mixture of TFA:DCM (20 mL), the reaction mixture was stirred at room temperature for 18 h, and evaporated in vacuo to give a residue which was dissolved in ethyl acetate and saturated NaHCO 3 The organic layer was dried and concentrated to give the crude ester 211, which was used directly in the next step.2 To a stirred solution of ester 211 (0.84 mmol, 1.0 equiv) in a 3:1 mixture of 2H2O (12 mL) was added LiOH (40 mg, 1.68 mmol, 2.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected and purified by HCl chromatography. 2 O (1x), dried and concentrated to give crude acid 212. Mass Spectrum (LCMS, ESI Pos.): C 24 H 25 N 3 O 5 Calculated value for: 436.0(M + H) Actual value: 436.0.

[0193] Example 2: Preparation of amide 9 [ka]

[0194] To a solution of piperazine sulfonamide 213 (68 mg, 0.552 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid 212 (200 mg, 0.46 mmol, 1.0 equiv), HATU (210 mg, 0.552 mmol, 1.2 equiv), and DIEA (0.300 mg, 2.3 mmol, 5.0 equiv), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired compound 9. Mass Spectrum (LCMS, ESI Pos.): 29 H 35 N 5 O 6 Calculated value for S: 582.0 (M + H), actual value 582.0.

[0195] Scheme 4 illustrates the preparation of amide 39. [ka]

[0196] Preparation of Chloride 216 [ka]

[0197] To a stirred solution of compound 205 (0.25 g, 0.55 mmol) and cesium carbonate (0.45 g, 1.37 mmol) in DMF (5 mL) was added 1,4-bis(chloromethyl)benzene 213 (0.14 g, 0.82 mmol) and the reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate and washed with water (3 times). The organic layer was dried and concentrated to give the crude ether 215, which was then stirred in a 1:1 mixture of TFA:DCM for 12 h. After concentration, chromatographic purification (hexanes / EtOAc) gave the desired chloride 216.

[0198] Example 4: Preparation of Compound 39 [ka]

[0199] To a solution of chloride 216 (200 mg, 0.34 mmol) in DMF (10.0 mL), 2 CO 3 (332 mg, 1.02 mmol, 3.0 equiv.) and N-methylpiperazine 217 (0.68 mmol, 2.0 equiv.) were added and the reaction mixture was stirred at 60° C. for 18 h, diluted with ethyl acetate and washed with water (3×). The organic layer was collected, dried and evaporated to give a viscous liquid which was purified by column chromatography to give the desired amine 39.

[0200] Scheme 5 illustrates the preparation of compound 4. [ka]

[0201] Preparation of Compound 220 [ka]

[0202] To a stirred solution of compound 205 (1.0 g, 2.22 mmol, 1.0 equiv.) and cesium carbonate (1.08 g, 3.33 mmol, 1.5 equiv.) in DMF (15 mL) was added methyl 3-(bromomethyl)benzoate 219 (450 mg, 2.44 mmol, 1.2 equiv.) and the reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate and washed with water (3 times). The organic layer was dried and concentrated to give crude ether 220, which was stirred in a 1:1 mixture of TFA:DCM for 12 h. After concentration, chromatographic purification (hexane / EtOAc) gave the desired ester 220. Mass Spectrum (LCMS, ESI Pos.): C 34 H 37 FN 3 O 7 Calculated value for: 600.0 (M+H), measured value 600.0.

[0203] Preparation of Compound 222 [ka]

[0204] Ester 220 (500 mg, 0.84 mmol) was dissolved in a 1:1 mixture of TFA:DCM (20 mL), and the reaction mixture was stirred at room temperature for 18 h and evaporated in vacuo to give a residue which was dissolved in ethyl acetate and saturated NaHCO 3 The organic layer was dried and concentrated to give crude ester 221, which was used directly in the next step. 2 To a stirred solution of ester 221 (0.84 mmol, 1.0 equiv) in a 3:1 mixture of 2H2O (12 mL) was added LiOH (40 mg, 1.68 mmol, 2.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected and purified by HCl chromatography. 2The mixture was washed with O (1×), dried and concentrated to give the crude acid 222. Mass Spectrum (LCMS, ESI Pos.): C 24 H 25 N 3 O 5 Calculated value for: 436.0(M + H), actual value 436.0.

[0205] Example 5: Preparation of Compound 4 [ka]

[0206] To a solution of amine 223 (68 mg, 0.552 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid 222 (200 mg, 0.46 mmol, 1.0 equiv), HATU (210 mg, 0.552 mmol, 1.2 equiv), and DIEA (0.300 mg, 2.3 mmol, 5.0 equiv), and the reaction mixture was stirred at room temperature for 12 h, diluted with EtOAc, washed with 10% aqueous HCl (once), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired sulfonamide 4. Mass Spectrum (LCMS, ESI Pos.): 29 H 35 N 5 O 6 Calculated for S: 582.0 (M+H), found 582.0.

[0207] Scheme 6 illustrates a general procedure for the preparation of sulfonamides, specifically compound 227. [ka]

[0208] To a stirred solution of N-Boc piperazine 224 (500 mg, 2.69 mmol, 1 equiv) in DCM (5 ml) at 0° C., DIEA (451 mg, 3.48 mmol, 1.3 equiv), DMAP (32.7 mg, 0.269 mmol, 0.1 equiv) and isobutylsulfonyl chloride 225 (462 mg, 2.9 mmol, 1.1 equiv) were added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with DCM and diluted with saturated NaHCO 3 The aqueous solution was extracted with DCM (x2) and the combined organic layers were washed with water, brine, dried (Na 2 SO 4 ) and evaporated under vacuum to give sulfonamide 226. Sulfonamide 226 was taken up in 4M HCl in dioxane (5 ml) and the reaction mixture was stirred at room temperature for 12 h. The reaction mass was evaporated under vacuum to give a colourless solid 227 which was used in the next step without further purification.

[0209] Scheme 7 illustrates the preparation of compound 40. [ka]

[0210] Example 6: Preparation of Compound 40

[0211] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), piperazine-1-sulfonic acid dimethylamide 228 (22 mg, 0.114 mmol, 1.0 equiv) and HTAU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 40. Mass Spectrum (LCMS, ESI Pos.) 30 H39 N 6 O 6 Calculated for S: 610.0 (M+H), found 610.0.

[0212] Scheme 8 illustrates the preparation of compound 41. [ka]

[0213] Example 7: Preparation of Compound 41

[0214] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), 1-(pyrrolidine-1-sulfonyl)piperazine 229 (25 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 41. Mass Spectrum (LCMS, ESI Pos.) 32 H 41 N 6 O 6 Calculated for S: 637.0 (M+H), found 637.0.

[0215] Scheme 9 illustrates the preparation of compounds 42 and 43. [ka]

[0216] Example 8: Preparation of Compound 42

[0217] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), amine 231 (23 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ), and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 42.

[0218] Example 9: Preparation of Compound 43

[0219] Amide 42 was dissolved in a minimum amount of DCM, then 4 mL of 4M HCl in dioxane was added and the reaction mixture was stirred for 12 h. Removal of the solvent afforded amine 232 as the HCl salt, which was used directly in the next step. To a stirred solution of amine 232 (40 mg, 0.073 mmol, 1 equiv) and TEA (37 mg, 0.365 mmol, 5 equiv) in DCM (5 mL) at 0° C., methanesulfonyl chloride (0.010 g, 0.093 mmol, 1.2 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO 3 The organic layer was dried (NaSO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give compound 43. Mass Spectrum (LCMS, ESI Pos.) 30 H 36 N 5 O 6 Calculated for S: 594.0 (M+H), found 594.0.

[0220] Scheme 10 illustrates the preparation of compound 44. [ka]

[0221] Preparation of compound 234

[0222] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), amine 233 (24 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ), and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 234.

[0223] Example 10: Preparation of Compound 44

[0224] Amide 234 was dissolved in a minimum amount of DCM, then 4 mL of 4M HCl in dioxane was added and the reaction mixture was stirred for 12 h. Removal of the solvent afforded amine 235 as the HCl salt, which was used directly in the next step. To a stirred solution of amine 235 (44 mg, 0.073 mmol, 1 equiv) and TEA (37 mg, 0.365 mmol, 5 equiv) in DCM (5 mL) at 0° C., methanesulfonyl chloride (0.010 g, 0.093 mmol, 1.2 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO 3 The organic layer was dried (NaSO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give compound 44. Mass Spectrum (LCMS, ESI Pos.) 31 H 38 N 5 O 6 Calculated for S: 608.0 (M+H), found 608.0. [ka]

[0225] Example 11: Preparation of Compound 45

[0226] Compound 45 was prepared using the synthetic procedure used for the synthesis of compound 9. The triazole carboxylic acid was prepared using a literature procedure (Chemistry of Heterocyclic Compounds 2022, 58(2 / 3), 116-128). Mass Spectrum (LCMS, ESI Pos.) C 29 H 35 N 6 O 6 Calculated for S: 583.0 (M+H), found 583.0. [ka]

[0227] Example 12: Preparation of Compound 46

[0228] Compound 46 was prepared using the synthetic procedure used to synthesize compound 9. The required triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. Mass Spectrum (LCMS, ESI Pos.) C 29 H 36 N 5 O 6 Calculated for S: 582.0 (M+H), found 582.0. [ka]

[0229] Example 13: Preparation of Compound 47

[0230] Compound 47 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 4-methylbromocrotonic acid. Mass Spectrum (LCMS, ESI Pos.) C25 H 34 N 5 O 6 Calculated for S: 532.0 (M+H), found 532.0.

[0231] Scheme 11 illustrates the preparation of compound 237. [ka]

[0232] Preparation of compound 237

[0233] To a mixture of 3-cyclopropyl-1H-pyrazole-5-carboxylic acid 236 [1 g (6.5 mmol)] in 30 ml of EtOH, thionyl chloride [0.95 ml (13 mmol)] was added dropwise. The resulting mixture was stirred at 60 °C for 3 h, cooled to room temperature, and then diluted with 100 ml of ice water. The mixture was extracted with methylene chloride, and the extract was then washed with 50 ml of water, 50 ml of saturated NaHCO 3 Wash with 100 ml of water, dry and (Na 2 SO 4 ), and the solvent was removed to give 1.08 g (91%) of ethyl 3-cyclopropyl-1H-pyrazole-5-carboxylate 237.

[0234] Scheme 12 illustrates the preparation of compound 240. [ka]

[0235] A solution of 238 [500 mg (3.3 mmol)] of 3-hydroxy-2-methoxybenzaldehyde in 5 ml of DMF was added to the 2 CO 3 [910 mg (6.6 mmol)] was added. Benzyl bromide 239 [430 ul (3.6 mmol)] was then added. The resulting mixture was stirred at room temperature for 12 hours and then diluted with 30 ml of EtOAc. The reaction was then washed twice with water (50 ml) and the organic layer was dried (Mg 2 SO 4), the solvent was removed on a rotary evaporator, and the crude material was then carried on to the next step.

[0236] The crude benzyl ether from the previous step was dissolved in 10 ml of EtOH and this was mixed with NaBH 4 [125 mg (3.3 mmol)] was added. After stirring at room temperature for 1 h, the reaction was quenched with 1N HCl (2 ml) and further diluted with 30 ml of water. The mixture was extracted with 40 ml of EtOAc, dried (Mg 2 SO 4 ), and the solvent was removed on a rotary evaporator to give the desired crude benzyl alcohol, which was carried on to the next step.

[0237] CH at 0℃ 2 CI 2 To the crude benzyl alcohol in 15 ml of water, add PBr 3 [152ul (1.6mmol)] was added dropwise. After stirring for 40 minutes, the reaction was quenched with 10ml of water. The organic layer was removed and the aqueous layer was 2 CI 2 (30 ml) and combined with CH 2 CI 2 The extract was dried (Na 2 SO 4 ), removal of the solvent afforded 970 mg (97%) of 1-benzyloxy-3-(bromomethyl)-2-methoxybenzene 241 after ISCO purification with hexane / EtOAc.

[0238] Scheme 13 illustrates the preparation of compound 243. [ka]

[0239] CH at 0℃ 2 CI 2 To a solution of 4-(bromomethyl)benzoyl chloride 241 [1 g (4.33 mmol)] in 40 mL of ethyl acetate, add a small amount of CH 2 CI 2A mixture of 1.9 ml (10.75 mmol) of DIEA and 710 mg (4.3 mmol) of 1-methylsulfonylpiperazine 242 dissolved together in 100 ml of water was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction was quenched with 20 ml of water, the organic phase was removed, dried (Na 2 SO 4 ), and the solvent was removed to give 774 mg (50%) of the desired [4-(bromomethyl)phenyl]-(4-methylsulfonylpiperazin-1-yl)methanone 243, which was used without further purification.

[0240] Scheme 14 illustrates the preparation of compound 48. [ka]

[0241] Preparation of compound 245

[0242] To a mixture of ethyl 3-cyclopropyl-1H-pyrazole-5-carboxylate [500 mg (2.7 mmol)] 237 in 20 ml DMF, 2-(Boc-amino)-ethyl bromide 244 [0.670 g (4.2 mmol)] was added, followed by Cs2CO3 [1.1 g (3.4 mmol)]. The mixture was stirred at room temperature for 16 h, filtered through Celite and the pad was washed with EtOAc (40 ml). The filtrate was then washed twice with water (50 ml), the organic layer was dried (Mg2SO4) and the solvent removed on a rotary evaporator to give 660 mg (76%) of ethyl 2-[2-(tert-butoxycarbonylamino)ethyl]-5-cyclopropylpyrazole-3-carboxylate 245 after ISCO purification with hexane / EtOAc. The structure was confirmed by LCMS.

[0243] Preparation of compound 246

[0244] To ethyl 2-[2-(tert-butoxycarbonylamino)ethyl]-5-cyclopropyl-pyrazole-3-carboxylate 246 [660 mg (2.0 mmol)] was added 8 ml of 4N HCl in dioxane. The mixture was stirred at room temperature for 1 h, then basified with saturated Na2CO3, stirred for an additional 10 min, and then diluted with CHCl2 (20 ml). The reaction mixture was dried (Na2SO4) and the solvent removed to give 322 mg (94%) of 2-cyclopropyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one 246 after ISCO purification with hexane / EtOAc. The structure was confirmed by LCMS.

[0245] Preparation of compound 247

[0246] To a suspension of 48 mg (1.2 mmol) of 60% NaH in 3 ml of DMF at 0° C., 150 mg (0.85 mmol) of 2-cyclopropyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one 246 was added. After stirring for 1 h at 0° C., 285 mg (0.93 mmol) of 1-benzyloxy-3-(bromomethyl)-2-methoxybenzene 240 was added and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with 10 ml of water and diluted with CH 2 CI 2 (20 ml twice). The combined CH 2 CI 2 The extract was dried (Na 2 SO 4 ), removal of the solvent gave, after ISCO purification with hexane / EtOAc, 60 mg (18%) of 5-[(3-benzyloxy-2-methoxyphenyl)methyl]-2-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one 247. The structure was confirmed by LCMS.

[0247] Example 14: Preparation of Compound 48

[0248] To a mixture of 5-[(3-benzyloxy-2-methoxyphenyl)methyl]-2-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one 247 [60 mg (0.15 mmol)] in 10 ml of MeOH was added 20 mg of Pd / C 10%. The mixture was aspirated and then H 2 After stirring at room temperature for 1 h, the removal of the benzyl group was complete. The reaction mixture was filtered through a plug of Celite and dried on a rotary evaporator. The residue was taken up in 3 ml of DMF and this solution was added with [4-(bromomethyl)phenyl]-(4-methylsulfonylpiperazin-1-yl)methanone 243 [54 mg (0.15 mmol)] and K 2 CO 3 [41 mg (0.3 mmol)] was added. The reaction was stirred at room temperature overnight and then diluted with 20 ml of EtOAc. The mixture was washed with water (10 ml) and dried (Mg 2 SO 4 ), the solvent was removed on a rotary evaporator to give, after ISCO purification with hexanes / EtOAc, 38 mg (43%) of 2-cyclopropyl-5-[[2-methoxy-3-[[4-(4-methylsulfonylpiperazine-1-carbonyl)phenyl]methoxy]phenyl]methyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one 48. The structure was confirmed by LCMS.

[0249] [ka] Example 14: Preparation of Compound 49

[0250] Compound 49 was prepared using the synthetic procedure used to synthesize compound 9. The required triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. Mass Spectrum (LCMS, ESI Pos.) C 29 H 36 N 5 O 6 Calculated for S: 582.0 (M+H), found 582.0.

[0251] [ka] Example 15: Preparation of Compound 50

[0252] Compound 50 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is methyl 5-(bromomethyl)-2-fluorobenzoate. Mass Spectrum (LCMS, ESI Pos.) C 29 H 35 FN 5 O 6 Calculated for S: 600.0 (M+H), found 600.0.

[0253] [ka] Example 16: Preparation of Compound 51

[0254] Compound 51 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is methyl 2-bromomethylbenzoate. Mass Spectrum (LCMS, ESI Pos.) C 29 H 36 N 5 O 6 Calculated for S: 582.0 (M+H), found 582.0.

[0255] [ka] Example 17: Preparation of Compound 52

[0256] Compound 52 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(isopropylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 31 H 40 N 5 O 6 Calculated for S: 610.0 (M+H), found 610.0.

[0257] [ka] Example 18: Preparation of Compound 53

[0258] Compound 53 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(Butylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 32 H 42 N 5 O 6 Calculated for S: 624.0 (M+H), found 624.0.

[0259] [ka] Example 19: Preparation of Compound 54

[0260] Compound 54 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, was commercially available and 1-(propane-1-sulfonyl)piperazine was prepared as described in Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 31 H 40 N 5 O 6Calculated for S: 610.0 (M+H), found 610.0.

[0261] [ka] Example 20: Preparation of Compound 55

[0262] Compound 55 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(Cyclopropylsulfonyl)piperazine hydrochloride was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 31 H 38 N 5 O 6 Calculated for S: 608.0 (M+H), found 608.0.

[0263] [ka] Example 21: Preparation of Compound 56

[0264] Compound 56 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 3-hydroxy-2-methylbenzaldehyde. 1-(isopropylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 31 H 40 N 5 O 5 Calculated for S: 594.0 (M+H), found 594.0.

[0265] [ka] Example 22: Preparation of Compound 57

[0266] Compound 57 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-ethoxy-3-hydroxybenzaldehyde. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 30 H 38 N 5 O 6 Calculated for S: 596.0 (M+H), found 596.0.

[0267] [ka] Example 23: Preparation of Compound 58

[0268] Compound 58 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(Cyclopentylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 33 H 42 N 5 O 6 Calculated for S: 636.0 (M+H), found 636.0.

[0269] [ka] Example 24: Preparation of Compound 59

[0270] Compound 59 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(ethylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 30 H 38 N5 O 6 Calculated for S: 596.0 (M+H), found 596.0.

[0271] [ka] Example 25: Preparation of Compound 60

[0272] Compound 60 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2,6-difluoro-3-hydroxybenzaldehyde. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 28 H 32 F2N 5 O 5 Calculated for S: 588.0 (M+H), found 588.0.

[0273] [ka] Example 26: Preparation of Compound 61

[0274] Compound 61 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-fluoro-3-hydroxybenzaldehyde. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 28 H 33 FN 5 O 5 Calculated for S: 570.0 (M+H), found 570.0.

[0275] [ka] Example 27: Preparation of Compound 62

[0276] Compound 62 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-methyl-3-hydroxybenzaldehyde. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 29 H 36 N 5 O 5 Calculated for S: 566.0 (M+H), found 566.0.

[0277] [ka] Example 28: Preparation of Compound 63

[0278] Compound 63 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-chloro-3-hydroxybenzaldehyde. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 28 H 33 ClN 5 O 5 Calculated for S: 587.0 (M+H), found 587.0.

[0279] [ka] Example 29: Preparation of Compound 64

[0280] Compound 64 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are methyl 4-(2-bromoethyl)benzoate and 2-methyl-3-hydroxybenzaldehyde. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6.

[0281] Scheme 15 illustrates the preparation of compound 65.

[0282] [ka] Preparation of compound 249

[0283] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), tert-butyl 4-aminopiperazine-1-carboxylate 248 (23 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ), and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 249.

[0284] Example 30: Preparation of Compound 65

[0285] Amide 249 was dissolved in a minimum amount of DCM, then 4 mL of 4 M HCl in dioxane was added and the reaction mixture was stirred for 12 h. Removal of the solvent afforded amine 250 as the HCl salt, which was used directly in the next step. To a stirred solution of amine 250 (40 mg, 0.073 mmol, 1 equiv) and TEA (37 mg, 0.365 mmol, 5 equiv) in DCM (5 mL) at 0 °C, methanesulfonyl chloride (0.010 g, 0.093 mmol, 1.2 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, 10% aqueous HCl and brine. The organic layer was dried (NaSO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give 65. Mass Spectrum (LCMS, ESI Pos.) 29 H 37 N 6 O 6 Calculated for S: 597.0 (M+H), found 597.0.

[0286] [ka] Example 31: Preparation of Compound 66

[0287] Compound 66 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-methylmorpholine. Mass Spectrum (LCMS, ESI Pos.) C 29 H 35 N 4 O 5 Calculated value for: 519.0 (M+H), found value 519.0.

[0288] [ka] Example 32: Preparation of Compound 67

[0289] Compound 67 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2,6-dimethylmorpholine. Mass Spectrum (LCMS, ESI Pos.) C 30 H 37 N 4 O 5 Calculated value for: 533.0 (M+H), found value 533.0.

[0290] [ka] Example 33: Preparation of Compound 68

[0291] Compound 68 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is methyl 4-(bromomethyl)-3-fluorobenzoate. 1-(Methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 30 H 38 N 5 O 6 Calculated for S: 596.0 (M+H), found 596.0.

[0292] [ka] Example 34: Preparation of Compound 69

[0293] Compound 69 was prepared using the synthetic procedure used to synthesize compound 4. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is morpholine. Mass Spectrum (LCMS, ESI Pos.) C 28 H 33 N 4 O 5Calculated value for: 505.0 (M+H), found value 505.0.

[0294] [ka] Example 35: Preparation of Compound 70

[0295] Compound 70 was prepared using the synthetic procedure used to synthesize compound 4. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-methylmorpholine. Mass Spectrum (LCMS, ESI Pos.) C 29 H 35 N 4 O 5 Calculated value for: 519.0 (M+H), found value 519.0.

[0296] [ka] Example 36: Preparation of Compound 71

[0297] Compound 71 was prepared using the synthetic procedure used to synthesize compound 4. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 1-acetylpiperazine. Mass Spectrum (LCMS, ESI Pos.) C 30 H 36 N 5 O 5 Calculated value for: 546.0 (M+H), found value 546.0.

[0298] [ka] Example 37: Preparation of Compound 72

[0299] Compound 72 was prepared using the synthetic procedure used to synthesize compound 4. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(isopropylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 31 H 40 N 5 O 6 Calculated for S: 610.0 (M+H), found 610.0.

[0300] [ka] Example 38: Preparation of Compound 73

[0301] Compound 73 was prepared using the synthetic procedure used to synthesize compound 4. The required triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2,6-dimethylmorpholine. Mass Spectrum (LCMS, ESI Pos.) C 30 H 37 N 4 O 5 Calculated value for: 533.0 (M+H), found value 533.0.

[0302] [ka] Example 39: Preparation of Compound 74

[0303] Compound 74 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is methyl-5-bromomethylpyridine-2-carboxylate. Mass Spectrum (LCMS, ESI Pos.) C 28 H 35 N 6 O 6 Calculated for S: 583.0 (M+H), found 583.0.

[0304] [ka] Example 40: Preparation of Compound 75

[0305] Compound 75 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 3-hydroxy-2-methylbenzaldehyde and methyl-5-bromomethylpyridine-2-carboxylate. Mass Spectrum (LCMS, ESI Pos.) C 28 H 35 N 6 O 5 Calculated for S: 567.0 (M+H), found 563.0.

[0306] [ka] Example 41: Preparation of Compound 76

[0307] Compound 76 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 3-hydroxy-2-methylbenzaldehyde and methyl 6-(bromomethyl)nicotinate. Mass Spectrum (LCMS, ESI Pos.) C 28 H 35 N 6 O 5 Calculated for S: 567.0 (M+H), found 563.0.

[0308] [ka] Example 42: Preparation of Compound 77

[0309] Compound 77 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is methyl 6-(bromomethyl)nicotinate. Mass Spectrum (LCMS, ESI Pos.) C 28 H 35 N 6 O 6 Calculated for S: 583.0 (M+H), found 583.0.

[0310] [ka] Example 43: Preparation of Compound 78

[0311] Compound 78 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 1-lambda(6),2,5-thiadiazepane-1,1-dione. Mass Spectrum (LCMS, ESI Pos.) C 28 H 34 N 5 O 6 Calculated for S: 568.0 (M+H), found 568.0.

[0312] [ka] Example 44: Preparation of Compound 79

[0313] Compound 79 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is thiomorpholine 1,1 dioxide. Mass Spectrum (LCMS, ESI Pos.) C 28 H 33 N 4 O 6 Calculated for S: 568.0 (M+H), found 568.0.

[0314] [ka] Example 45: Preparation of Compound 80

[0315] Compound 80 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 29 H 33 F 3 N 5 O 6 Calculated for S: 636.0 (M+H), found 636.0.

[0316] [ka] Example 46: Preparation of Compound 81

[0317] Compound 81 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available. 1-(methylsulfonyl)piperazine was prepared according to Scheme 6. Mass Spectrum (LCMS, ESI Pos.) C 28 H 33 ClN 5 O 5 Calculated for S: 587.0 (M+H), found 587.0.

[0318] [ka] Example 47: Preparation of Compound 82

[0319] Compound 82 was prepared using the synthetic procedure used to synthesize compound 9. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is morpholine. Mass Spectrum (LCMS, ESI Pos.) C 27 H 30 ClN 4 O 4 Calculated value for: 510.0 (M+H), found value 510.0.

[0320] [ka] Example 48: Preparation of Compound 83

[0321] Compound 83 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 1-(piperazin-1-yl)propan-1-one. Mass Spectrum (LCMS, ESI Pos.) C 31 H 40 N 5 O 4 Calculated value for: 546.0 (M+H), found value 546.0.

[0322] [ka] Example 49: Preparation of Compound 84

[0323] Compound 84 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 2-methyl-1-(piperazin-1-yl)propan-1-one. Mass Spectrum (LCMS, ESI Pos.) C 32 H 42 N 5 O 4 Calculated value for: 560.0 (M+H), found value 560.0.

[0324] [ka] Example 50: Preparation of Compound 85

[0325] Compound 85 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as is 1-(3-methylbutanoyl)piperazine. Mass Spectrum (LCMS, ESI Pos.) C 33 H 44 N 5 O 4 Calculated value for: 574.0 (M+H), found value 574.0.

[0326] [ka] Example 51: Preparation of Compound 86

[0327] Compound 86 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 1,3-bis(bromomethyl)benzene and 2-methylmorpholine. Mass Spectrum (LCMS, ESI Pos.) C 29 H 37 N 4 O 4 Calculated value for: 505.0 (M+H), found value 505.0.

[0328] [ka] Example 52: Preparation of Compound 87

[0329] Compound 87 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 1,3-bis(bromomethyl)benzene and 2,6-dimethylmorpholine. Mass Spectrum (LCMS, ESI Pos.) C 30 H 39 N 4 O 4 Calculated value for: 519.0 (M+H), found value 519.0.

[0330] [ka] Example 53: Preparation of Compound 88

[0331] Compound 88 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 1,3-bis(bromomethyl)benzene and 1-acetylpiperazine. Mass Spectrum (LCMS, ESI Pos.) C 30 H 38 N 5 O 4 Calculated value for: 532.0 (M+H), found value 532.0.

[0332] [ka]

[0333] Example 54: Preparation of Compound 89

[0334] Compound 89 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 1,3-bis(bromomethyl)benzene and morpholine. Mass Spectrum (LCMS, ESI Pos.) C 28 H 35 N4 O 4 Calculated value for: 491.0 (M+H), found value 491.0.

[0335] [ka] Example 55: Preparation of Compound 90

[0336] Compound 90 was prepared using the synthetic procedure used to synthesize compound 39. The requisite triazole carboxylic acid, 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid, is commercially available, as are 1,3-bis(bromomethyl)benzene and morpholine. Mass Spectrum (LCMS, ESI Pos.) calculated for C27H32ClNO3: 496.0 (M+H), found 496.0.

[0337] Scheme 16 illustrates the preparation of compound 91. [ka]

[0338] Preparation of Compound 252

[0339] To a solution of sulfonyl chloride 251 (0.244 g, 0.914 mmol, 1.5 equiv) in DCM (5 ml) at 0° C. was added TEA (0.123 g, 1.22 mmol, 2.0 equiv) and 1-methanesulfonylpiperazine 242 (0.100 g, 0.609 mmol, 1.0 equiv). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 3 h. The reaction mixture was diluted with DCM and then washed with saturated sodium bicarbonate solution. The DCM layer was washed with water, brine, dried over NaSO4, and evaporated under vacuum to give the crude sulfonamide, which was used directly in the next step.

[0340] Example 56: Preparation of Compound 91

[0341] To a stirred solution of compound 205 (0.315 g, 0.698 mmol, 1.2 equiv.) in DMF (5 ml) was added Cs2CO3 (0.574 g, 1.45 mmol, 2.5 equiv.) and crude bromide 252 (0.230 g, 0.582 mmol, 1.2 equiv.) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine and diluted with NaSO. 4 The mixture was dried at 40° C. and evaporated under vacuum to give a residue which was purified by column chromatography to give the desired alkylated product 253. The alkylated product 253 was taken up in 1:1 DCM:TFA and stirred at room temperature for 12 hours. The TFA and DCM were then removed under vacuum to give a residue which was purified by column chromatography to give compound 91. Mass Spectrum (LCMS, ESI Pos.) C 28 H 36 N 5 O 7 S 2 Calculated value for: 618.0 (M+H), found value 618.0.

[0342] Scheme 17 illustrates the preparation of compound 92. [ka]

[0343] Preparation of compound 255

[0344] To a solution of sulfonyl chloride 251 (0.244 g, 0.914 mmol, 1.5 equiv) in DCM (5 ml) at 0° C. was added TEA (0.123 g, 1.22 mmol, 2.0 equiv) and N-methylpiperazine 254 (0.100 g, 0.609 mmol, 1.0 equiv). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 3 h. The reaction mixture was diluted with DCM and then washed with saturated sodium bicarbonate solution. The DCM layer was washed with water, brine, dried over NaSO4, and evaporated under vacuum to give the crude sulfonamide, which was used directly in the next step.

[0345] Example 57: Preparation of Compound 92

[0346] To a stirred solution of compound 205 (0.315 g, 0.698 mmol, 1.2 equiv) in DMF (5 ml) was added Cs 2 CO 3 (0.574 g, 1.45 mmol, 2.5 equiv.) and crude bromide 255 (0.230 g, 0.582 mmol, 1.2 equiv.) were added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine and diluted with NaSO. 4 The mixture was dried over 1000 ml of ethyl acetate and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired alkylated product 256. The alkylated product 256 was taken up in 1:1 DCM:TFA and stirred at room temperature for 12 hours. The TFA and DCM were then removed in vacuo to give a residue. The residue was taken up in DCM and diluted with saturated NaHCO 3 The DCM layer was collected, dried and evaporated to give the crude product, which was purified by column chromatography to give compound 92. Mass Spectrum (LCMS, ESI Pos.) C 28 H 36 N 5 O 5 Calculated for S: 554.0 (M+H), found 554.0.

[0347] Scheme 18 illustrates the preparation of compound 93. [ka]

[0348] Example 58: Preparation of Compound 93

[0349] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), amine 257 (26 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 93. Mass Spectrum (LCMS, ESI Pos.) 31 H 40 N 5 O 6 Calculated for S: 610.0 (M+H), found 610.0.

[0350] Scheme 19 illustrates the preparation of compound 94. [ka]

[0351] Example 59: Preparation of Compound 94

[0352] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), amine 242 (24 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 94. Mass Spectrum (LCMS, ESI Pos.) 30 H 38 N 5 O 6 Calculated for S: 596.0 (M+H), found 596.0.

[0353] Scheme 20 illustrates the preparation of compound 95. [ka]

[0354] Example 60: Preparation of Compound 95

[0355] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), amine 258 (24 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 95. Mass Spectrum (LCMS, ESI Pos.) 30 H 38 N 5 O 6 Calculated for S: 596.0 (M+H), found 596.0.

[0356] Scheme 21 illustrates the preparation of compound 96. [ka]

[0357] Example 61: Preparation of Compound 96

[0358] To a stirred solution of acid 212 (60 mg, 0.137 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol, 5 equiv), amine 259 (24 mg, 0.114 mmol, 1.0 equiv) and HATU (0.065 g, 0.172 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The organic layer was then washed with water (2 times), brine (1 time), dried (Na 2 SO 4) and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired amide 96. Mass Spectrum (LCMS, ESI Pos.) 31 H 40 N 5 O 6 Calculated for S: 610.0 (M+H), found 610.0.

[0359] Scheme 22 illustrates the preparation of compound 265. [ka]

[0360] Preparation of compound 262

[0361] To a solution of methyl 3-formyl-2-methoxybenzoate 260 (500 mg, 2.58 mmol, 1.0 equiv) in toluene was added 2,4-dimethoxybenzylamine 261 (430 mg, 2.58 mmol, 1.0 equiv) and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at 65° C. for 24 h. The solvent was removed and the residue was taken up in MeOH and cooled in an ice bath. Sodium borohydride (195 mg, 5.16 mmol, 2.0 equiv) was then added slowly and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed and the residue was taken up in ethyl acetate and then saturated NaHCO 3 was added and the mixture was stirred for 1 h. The organic layer was separated and dried (MgSO 4 ), and the solvent was removed to give amine 262, which was used in the next step without further purification.

[0362] Preparation of compound 263

[0363] To a solution of crude amine 262 (2.58 mmol, 1.0 equiv) in DMF (10 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid 204 (477 mg, 2.84 mmol, 1.1 equiv), HATU (1.18 g, 3.09 mmol, 1.2 equiv), and DIEA (1.67 g, 12.95 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired amide 263. Mass Spectrum (LCMS, ESI Pos.) 27 H 32 N 3 O 6 Calculated value for: 494.0 (M+H), found value 494.0.

[0364] Preparation of compound 264

[0365] Amide 263 (500 mg, 1.01 mmol) was taken in a 1:1 mixture of TFA:DCM and stirred at room temperature for 24 h. The solvent was removed to give a residue which was purified by column chromatography to give compound 264. Mass Spectrum (LCMS, ESI Pos.) C 18 H 22 N 3 O 4 Calculated value for: 344.0 (M+H), found value 344.0.

[0366] Preparation of Compound 265

[0367] Ester 264 (400 mg, 1.17 mmol, 1.0 equiv) was dissolved in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (107 mg, 4.66 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected and purified by HCl chromatography. 2O (1x), dried and concentrated to give the crude acid 265 which was used without further purification.

[0368] Scheme 23 illustrates the preparation of compound 97. [ka]

[0369] Example 62: Preparation of Compound 97

[0370] To a solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid 265 (82 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (160 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give compound 97. Mass Spectrum (LCMS, ESI Pos.) 22 H 30 N 5 O 5 Calculated for S: 476.0 (M+H), found 476.0.

[0371] [ka] Example 63: Preparation of Compound 98

[0372] Compound 98 was prepared using the synthetic procedure used to synthesize compound 97. 1-Methanesulfonyl-3-methylpiperazine is commercially available. Mass Spectrum (LCMS, ESI Pos.) C 23 H 32 N5O 4Calculated for S: 474.0 (M+H), found 474.0.

[0373] [ka] Example 64: Preparation of Compound 99

[0374] Compound 99 was prepared using the synthetic procedure used to synthesize compound 97. 1-Methanesulfonyl-2,5-dimethylpiperazine is commercially available. Mass Spectrum (LCMS, ESI Pos.) Calculated for C24H34N5O4: 488.0 (M+H), Found 488.0.

[0375] Scheme 24 illustrates the preparation of compound 100. [ka]

[0376] Preparation of compound 267

[0377] To a solution of methyl 4-(aminomethyl)benzoate 266 (108 mg, 0.653 mmol, 1.2 equiv) in DMF (10 mL) was added crude acid 265 (179 mg, 0.544 mmol, 1.0 equiv), HATU (248 mg, 0.653 mmol, 1.2 equiv), and DIEA (351 mg, 2.72 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 267. Mass Spectrum (LCMS, ESI Pos.) 22 H 29 N 4 O 5 Calculated value for: 477.0 (M+H), found value 477.0.

[0378] Preparation of compound 268

[0379] The ester (400 mg, 0.84 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65° C. for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected and purified by HCl chromatography. 2 It was washed with O (1x), dried and concentrated to give the crude acid, which was used directly in the next step without further purification.

[0380] Example 65: Preparation of Compound 100

[0381] To a solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid 268 (115 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv), and DIEA (160 mg, 1.245 mmol, 5.0 equiv), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected, dried (MgSO4), and evaporated to give a residue that was purified by column chromatography (EtOAc / hexanes) to give amide 100. Mass spectrum (LCMS, ESI Pos.) calculated for C30H37N6O6S: 609.0 (M+H), found 609.0.

[0382] Scheme 25 illustrates the preparation of compound 101. [ka]

[0383] Preparation of compound 270

[0384] To a solution of methyl 4-aminobenzoate 269 (99 mg, 0.653 mmol, 1.2 equiv.) in DMF (10 mL) was added crude acid 265 (179 mg, 0.544 mmol, 1.0 equiv.), HATU (248 mg, 0.653 mmol, 1.2 equiv.), and DIEA (351 mg, 2.72 mmol, 5.0 equiv.) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the amide 270. Mass Spectrum (LCMS, ESI Pos.) calculated for C25H27N4O5: 463.0 (M+H), found 463.0.

[0385] Preparation of compound 271

[0386] The ester (388 mg, 0.84 mmol, 1.0 equiv.) was dissolved in H 2 The mixture was taken up in a 1:5 mixture of 2H2O:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65° C. for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected and purified by H 2 It was washed with O (1x), dried and concentrated to give the crude acid, which was used directly in the next step without further purification.

[0387] Example 66: Preparation of Compound 101

[0388] To a solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid 271 (112 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (160 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 101. Mass Spectrum (LCMS, ESI Pos.) calculated for C29H35N6O6S: 595.0 (M+H), found 595.0.

[0389] Scheme 26 illustrates the preparation of compound 102. [ka]

[0390] Preparation of compound 273

[0391] To a stirred solution of compound 205 (300 mg, 0.665 mmol) in DMF, methyl 2-bromo-2,2-difluoroacetate 272 (300 mg) and DBU (300 mg) were added and the reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was diluted with EtOAc and washed with 10% aqueous HCl, H 2 The organic layer was dried and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired compound 273. Mass Spectrum (LCMS, ESI Pos.) C 28 H 32 F 2 N 3 O 7 Calculated value for: 560.0 (M+H), found value 560.0.

[0392] Preparation of compound 274

[0393] The ester 273 was dissolved in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 25 h. The solvent was removed and the residue was purified by column chromatography to give 274. Mass spectrum (LCMS, ESI Pos.) calculated for C19H22F2N3O5: 410.0 (M+H), found 410.0.

[0394] Preparation of compound 275

[0395] Ester 274 (344 mg, 0.84 mmol, 1.0 equiv) was dissolved in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected and purified by HCl chromatography. 2 It was washed with O (1x), dried and concentrated to give the crude acid, which was used directly in the next step without further purification.

[0396] Example 67: Preparation of Compound 102

[0397] To a solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid (98 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (160 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the amide 102. Mass Spectrum (LCMS, ESI Pos.) calculated for C23H30F2N5O6S: 542.0 (M+H), found 542.0.

[0398] Scheme 27 illustrates the preparation of compound 103. [ka]

[0399] Preparation of compound 278

[0400] To a stirred solution of bromide 276 (100 mg, 0.1944 mmol, 1.0 equiv) in dioxane (8 ml) and water (2 ml) was added K2CO3 (67 mg, 0.486 mmol, 2.5 equiv) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (61 mg, 0.233 mmol, 1.2 equiv). The reaction mixture was purged with argon for 5 min and then Pd(PPh3)4 (11 mg, 0.00972 mmol, 0.05 equiv) was added. The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was taken up in EtOAc and washed with water and brine. The combined organic layers were dried and evaporated under vacuum to give a residue which was purified by column chromatography to give the desired product 278. Mass spectrum (LCMS, ESI Pos.) calculated for C33H35N3O6: 570.0 (M+H), found 570.0.

[0401] Preparation of compound 279

[0402] The ester was dissolved in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 25 h. The solvent was removed and the residue was purified by column chromatography to give ester 279. Mass Spectrum (LCMS, ESI Pos.) C 24 H 26 N 3 O 4 Calculated value for: 420.0 (M+H), found value 420.0.

[0403] Preparation of Compound 280

[0404] The ester (344 mg, 0.84 mmol, 1.0 equiv) was dissolved in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65° C. for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (×1), dried and concentrated to give the crude acid which was used directly in the next step without further purification.

[0405] Example 68: Preparation of Compound 103

[0406] To a solution of 1-(methylsulfonyl)piperazine (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid (98 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv), and DIEA (160 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 103. Mass Spectrum (LCMS, ESI Pos.) 23 H 30 F 2 N 5 O 6 Calculated for S: 542.0 (M+H), found 542.0.

[0407] Scheme 28 illustrates the preparation of compound 104. [ka]

[0408] Preparation of compound 283

[0409] To a solution of 2-methyl-3-nitrobenzaldehyde 281 (426 mg, 2.58 mmol, 1.0 equiv) in toluene was added 2,4-dimethoxybenzylamine 282 (430 mg, 2.58 mmol, 1.0 equiv) and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at 65° C. for 24 h. The solvent was removed and the residue was taken up in MeOH and cooled in an ice bath. Sodium borohydride (195 mg, 5.16 mmol, 2.0 equiv) was then added slowly and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed and the residue was dissolved in ethyl acetate and then saturated NaHCO 3 was added and the mixture was stirred for 1 h. The organic layer was separated and dried (MgSO 4 ), and the solvent was removed to give the amine, which was used in the next step without further purification.

[0410] Preparation of compound 284

[0411] To a solution of crude amine 283 (2.58 mmol, 1.0 equiv) in DMF (10 mL) were added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (477 mg, 2.84 mmol, 1.1 equiv), HATU (1.18 g, 3.09 mmol, 1.2 equiv), and DIEA (1.67 g, 12.95 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected, dried (MgSO4), and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired amide compound 284. Mass spectrum (LCMS, ESI Pos.) calculated for C27H32N3O6: 494.0 (M+H), found 494.0.

[0412] Preparation of Compound 285

[0413] To a stirred solution of amide 284 (600 mg, 1.25 mmol, 1.0 equiv) in acetic acid (15 ml) was added zinc powder (0.163 g, 2.5 mmol, 2 equiv) and the reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried and evaporated in vacuo to give crude amine 285, which was used in the next step without further purification.

[0414] Preparation of compound 287

[0415] To a stirred solution of crude amine 285 (398 mg, 0.92 mmol, 1.0 equiv) in pyridine (15 ml) at 0° C. was added DIEA (178 mg, 1.38 mmol, 1.5 equiv), methyl 4-(chlorocarbonyl)benzoate 286 (219 mg, 1.104 mmol, 1.2 equiv) and DMAP (11 mg, 0.092 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was dissolved in ethyl acetate, washed with water, brine, dried and evaporated in vacuo to give the crude amide which was purified by column chromatography to give the desired amide 287.

[0416] Example 69: Preparation of Compound 104

[0417] The ester was dissolved in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was purified by column chromatography to give compound 104. Mass spectrum (LCMS, ESI Pos.) calculated for C25H27N4O4: 446.0 (M+H), found 447.0.

[0418] Scheme 29 illustrates the preparation of compound 105. [ka]

[0419] Preparation of compound 289

[0420] Ester 288 (374 mg, 0.84 mmol, 1.0 equiv) was dissolved in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid which was used directly in the next step without further purification.

[0421] Example 70: Preparation of Compound 105

[0422] To a stirred solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid (107 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (160 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 (1x) and water (3x). The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 105. Mass Spectrum (LCMS, ESI Pos.) 29 H 35 N 6 O 5 Calculated for S: 579.0 (M+H), found 579.0.

[0423] Scheme 30 illustrates the preparation of compound 106. [ka]

[0424] Preparation of compound 292

[0425] To a stirred solution of crude amine 290 (398 mg, 0.92 mmol, 1.0 equiv) in pyridine (15 ml) at 0° C. was added DIEA (178 mg, 1.38 mmol, 1.5 equiv), methyl 4-chlorosulfonylbenzoate 291 (259 mg, 1.104 mmol, 1.2 equiv) and DMAP (13 mg, 0.1064 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was taken up in ethyl acetate, washed with water, brine, dried and evaporated in vacuo to give the crude sulfonamide which was purified by column chromatography to give the desired compound 292.

[0426] Example 70: Preparation of Compound 106

[0427] Sulfonamide 292 was dissolved in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was purified by column chromatography to give compound 106. Mass spectrum (LCMS, ESI Pos.) calculated for C24H27N4O5S: 483.0 (M+H), found 483.0.

[0428] Scheme 31 illustrates the preparation of compound 107. [ka]

[0429] Preparation of compound 293

[0430] The ester 106 (405 mg, 0.84 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid 293 which was used directly in the next step without further purification.

[0431] Example 71: Preparation of Compound 107

[0432] To a stirred solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid 293 (116 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2) and DIEA (160 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 107. Mass Spectrum (LCMS, ESI Pos.) 28 H 35 N 6 O 6 S 2 Calculated value for: 615.0 (M+H), found value 615.0.

[0433] [ka] Example 72: Preparation of Compound 108

[0434] Compound 108 was prepared using the synthetic procedure used to synthesize compound 106. Methanesulfonyl chloride is commercially available. Mass Spectrum (LCMS, ESI Pos.) C 17 H 23 N 4 O 3 Calculated for S: 363.0 (M+H), found 363.0.

[0435] [ka] Example 73: Preparation of Compound 109

[0436] Compound 109 was prepared using the synthetic procedure used to synthesize compound 106. (E)-ethyl 4-chloro-4-oxobut-2-enoate is commercially available. Mass Spectrum (LCMS, ESI Pos.) C 22 H 27 N 4 O 4 Calculated value for: 411.0 (M+H), found value 411.0.

[0437] [ka] Example 74: Preparation of Compound 110

[0438] Compound 110 was prepared from compound 109 following the procedure used to make compound 106. Calculated for C25H33N6O5S: 529.0 (M+H), found 529.0.

[0439] Scheme 32 illustrates the preparation of compound 111. [ka]

[0440] Preparation of compound 294

[0441] To a stirred solution of amine 290 (452 ​​mg, 1.04 mmol, 1.0 equiv) in DMF (10 ml) was added Cs 2 CO 3 (507 mg, 1.56 mmol, 1.5 equiv.) and methyl 3-(bromomethyl)benzoate 293 (286 mg, 1.25 mmol, 1.2 equiv.) were added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated NaHCO 3 Washing with aqueous solution, 10% HCl solution, brine, drying and evaporation in vacuo gave crude amide 294.

[0442] Preparation of Compound 295

[0443] The amide was dissolved in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was purified by column chromatography to give ester 295. Mass spectrum (LCMS, ESI Pos.) calculated for C25H28N4O4: 449.0 (M+H), found 449.0.

[0444] Preparation of Compound 296

[0445] Ester 295 (376 mg, 0.84 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid which was used directly in the next step without further purification.

[0446] Example 75: Preparation of Compound 111

[0447] To a stirred solution of morpholine 297 (26 mg, 0.299 mmol, 1.2 equiv) in DMF (10 mL) was added crude acid 296 (108 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (160 mg, 1.245 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 111. Mass Spectrum (LCMS, ESI Pos.) 28 H 34 N 5 O 4 Calculated value for: 504.0 (M+H), found value 504.0.

[0448] [ka] Example 76: Preparation of Compound 112

[0449] Compound 112 was prepared following the procedure used to prepare compound 111, except that commercially available methyl 4-(chloromethyl)benzoate was used in the first step and 1-(methylsulfonyl)piperazine was used in the last step to acylate the carboxylic acid.

[0450] [ka] Example 77: Preparation of Compound 113

[0451] Compound 112 was prepared following the procedure used to prepare compound 111, except that commercially available methyl 4-[(methylamino)methyl]benzoate was used in the first step and 1-(methylsulfonyl)piperazine was used in the last step to acylate the carboxylic acid.

[0452] Scheme 33 illustrates the preparation of compound 114. [ka]

[0453] Preparation of Compound 300

[0454] To a stirred solution of bromide 298 (200 mg, 0.389 mmol, 1.0 equiv) in toluene (5 ml) was added sodium tert-butoxide (93 mg, 0.9725 mmol, 2.5 equiv), methyl 4-[(methylamino)methyl]benzoate 299 (84 mg, 0.466 mmol, 1.2 equiv) and BINAP (24 mg, 0.039 mmol, 0.1 equiv). The reaction mixture was purged with argon for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.039 mmol, 0.1 equiv) was added and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was evaporated under vacuum to give a residue which was taken up in ethyl acetate and washed with water and brine. The organic layer was dried and evaporated under vacuum to give the crude product which was purified by column chromatography to give amine 300. Mass Spectrum (LCMS, ESI Pos.) C 35 H 41 N 4 O 6 Calculated value for: 613.0 (M+H), found value 613.0.

[0455] Preparation of Compound 301

[0456] The amine was taken up in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was purified by column chromatography to give ester 310. Mass spectrum (LCMS, ESI Pos.) calculated for C26H31N4O4: 463.0 (M+H), found 463.0.

[0457] Preparation of Compound 302

[0458] The ester 301 (388 mg, 0.84 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (77 mg, 3.36 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid 302 which was used directly in the next step without further purification.

[0459] Example 78: Preparation of Compound 114

[0460] To a stirred solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (25 mL) was added crude acid (112 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (161 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 114. Mass Spectrum (LCMS, ESI Pos.) 30 H 39 N 6 O 5 Calculated for S: 595.0 (M+H), found 595.0.

[0461] [ka]

[0462] 115

[0463] Example 79: Preparation of Compound 115

[0464] Compound 115 was prepared according to the procedure used to prepare compound 111, except that commercially available methyl piperazine-1-carboxylate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 22 H 30 N 5 O 3 Calculated value for: 412.0 (M+H), found value 412.0.

[0465] [ka] Example 80: Preparation of Compound 116

[0466] Compound 116 was prepared according to the procedure used to prepare compound 111, except that commercially available piperazine-1-carboxylic acid dimethylamide was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 23 H 33 N 6 O 2 Calculated value for: 425.0 (M+H), found value 425.0.

[0467] [ka] Example 81: Preparation of Compound 117

[0468] Compound 117 was prepared according to the procedure used to prepare compound 111, except that commercially available 1-(methylsulfonyl)piperazine was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 21 H 30 N 5 O 3 Calculated for S: 432.0 (M+H), found 432.0.

[0469] [ka] Example 82: Preparation of Compound 118

[0470] Compound 118 was prepared according to the procedure used to prepare compound 111, except that commercially available 1-(methylsulfonyl)piperazine was used in the first step. Mass spectrum (LCMS, ESI Pos.) calculated for C21H30N5O4S: 448.0 (M+H), found 448.0.

[0471] Scheme 34 illustrates the preparation of compound 119. [ka]

[0472] Preparation of Compound 305

[0473] To a stirred solution of bromide 303 (500 mg, 0.96 mmol, 1.0 equiv) in toluene was added sodium tert-butoxide (230 mg, 2.41 mmol, 2.5 equiv), amine 303 (1.2 equiv) and BINAP (119 mg, 0.19 mmol, 0.2 equiv). The reaction mixture was purged with argon and then purified with Pd 2 (dba) 3 (88 mg, 0.096 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100° C. for 5 h. Toluene was removed under vacuum to give a residue, which was dissolved in EtOAc and washed with water. The organic layer was dried and evaporated to give a residue, which was purified by column chromatography to give compound 305. Mass Spectrum (LCMS, ESI Pos.) C 29 H 37 ClN 5 O 3 Calculated value for: 539.0 (M+H), found value 539.0.

[0474] Example 83: Preparation of Compound 119

[0475] Compound 305 was taken up in a 1:1 mixture of DCM:TFA and stirred at room temperature for 12 hours. The solvent was removed and the residue was purified by column chromatography to give the desired product 119. Mass Spectrum (LCMS, ESI Pos.) C 20 H 27 ClN 5 Calculated for O: 388.0 (M+H), found 388.0.

[0476] Scheme 35 illustrates the preparation of compound 121. [ka]

[0477] Preparation of compound 308

[0478] To a solution of 4-bromo-3-(trifluoromethyl)benzaldehyde 306 (653 mg, 2.58 mmol, 1.0 equiv) in toluene was added 2,4-dimethoxybenzylamine 307 (430 mg, 2.58 mmol, 1.0 equiv) and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at 65° C. for 24 h. The solvent was removed and the residue was taken up in MeOH and cooled in an ice bath. Sodium borohydride (195 mg, 5.16 mmol, 2.0 equiv) was then added slowly and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed and the residue was taken up in ethyl acetate and then saturated NaHCO 3 was added and the mixture was stirred for 1 h. The organic layer was separated and dried (MgSO 4 ), and the solvent was removed to give the amine, which was used in the next step without further purification.

[0479] Preparation of Compound 309

[0480] To a solution of crude amine 308 (2.58 mmol, 1.0 equiv) in DMF (10 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid 204 (477 mg, 2.84 mmol, 1.1 equiv), HATU (1.18 g, 3.09 mmol, 1.2 equiv), and DIEA (1.67 g, 12.95 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired amide compound 310. Mass Spectrum (LCMS, ESI Pos.) 25 H 26 BrF 3 N 3 O 3 Calculated value for: 553.0 (M+H), found value 553.0.

[0481] Preparation of Compound 310

[0482] To a stirred solution of bromide 309 (400 mg, 0.724 mmol, 1.0 equiv) in toluene (10 ml) was added sodium tert-butoxide (173 mg, 1.81 mmol, 2.5 equiv), 1-(methylsulfonyl)piperazine (142 mg, 0.868 mmol, 1.2 equiv) 242 and BINAP (45 mg, 0.0724 mmol, 0.1 equiv). The reaction mixture was purged with argon for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.0724 mmol, 0.1 equiv) was added and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was evaporated under vacuum to give a residue which was taken up in ethyl acetate and washed with water and brine. The organic layer was dried and evaporated under vacuum to give the crude product which was purified by column chromatography to give amide 310. Mass spectrum (LCMS, ESI Pos.) calculated for C30H37F3N5O5S: 636.0 (M+H), found 636.0.

[0483] Example 84: Preparation of Compound 121

[0484] The amide 310 was taken up in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was purified by column chromatography to give compound 121. Mass Spectrum (LCMS, ESI Pos.) C 21 H 27 F 3 N 5 O 3 Calculated for S: 486.0 (M+H), found 486.0.

[0485] [ka] Example 85: Preparation of Compound 122

[0486] Compound 122 was prepared according to the procedure used to prepare compound 120, except that commercially available 1-(acetyl)piperazine was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 22 H 27 F 3 N 5 O 2 Calculated value for: 450.0 (M+H), found value 450.0.

[0487] [ka] Example 86: Preparation of Compound 123

[0488] Compound 123 was prepared according to the procedure used to prepare compound 120, except that commercially available 1-(methyl)piperazine was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 21 H 27 F 3 N 5 Calculated for O: 422.0 (M+H), found 422.0.

[0489] [ka] Example 87: Preparation of Compound 124

[0490] Compound 124 was prepared according to the procedure used to prepare compound 120, except that commercially available methyl piperazine-1-carboxylate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 22 H 27 F 3 N 5 O 3 Calculated value for: 466.0 (M+H), found value 466.0.

[0491] [ka] Example 88: Preparation of Compound 125

[0492] Compound 125 was prepared according to the procedure used to prepare compound 120, except that commercially available piperazine-1-carboxylic acid dimethylamide was used in the first step. Mass spectrum (LCMS, ESI Pos.) calculated for C23H30F3N6O2: 479.0 (M+H), found 479.0.

[0493] Scheme 36 illustrates the preparation of compound 126. [ka]

[0494] Preparation of compound 312

[0495] To a stirred solution of compound 2-methyl-3-nitrophenol 311 (100 mg, 0.653 mmol, 1.0 equiv.) in DMF (10 ml) was added Cs 2 CO 3(318 mg, 0.98 mmol, 1.5 equiv.) and methyl 4-(chloromethyl)benzoate 209 (181 mg, 0.98 mmol, 1.5 equiv.) were added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine and NaSO. 4 The mixture was dried at 40° C. and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired alkylated product 312.

[0496] Preparation of compound 313

[0497] To a stirred solution of the nitro compound (150 mg, 0.498 mmol, 1.0 equiv) in acetic acid (10 ml) was added zinc powder (48 mg, 0.74 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried and evaporated under vacuum to give crude amine 313, which was used in the next step without further purification.

[0498] Preparation of compound 314

[0499] To a solution of crude amine 313 (105 mg, 0.43 mmol, 1.0 equiv) in DMF (10 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid 204 (77 mg, 0.464 mmol, 1.2 equiv), HATU (220 mg, 0.58 mmol, 1.5 equiv), and DIEA (250 mg, 1.93 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired ester compound 314. Mass Spectrum (LCMS, ESI Pos.) 24 H 26 N 3 O 4Calculated value for: 420.0 (M+H), found value 420.0.

[0500] Preparation of compound 315

[0501] The ester 314 (120 mg, 0.576 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (48 mg, 1.14 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid 315 which was used directly in the next step without further purification.

[0502] Example 89: Preparation of Compound 126

[0503] To a stirred solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (15 mL) was added crude acid 315 (101 mg, 0.249 mmol, 1.0 equiv), HATU (114 mg, 0.299 mmol, 1.2 equiv) and DIEA (161 mg, 1.245 mmol, 5.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 126. Mass Spectrum (LCMS, ESI Pos.) 28 H 34 N 5 O 5 Calculated for S: 552.0 (M+H), found 552.0.

[0504] Scheme 36 illustrates the preparation of compound 127. [ka]

[0505] Preparation of compound 317

[0506] To a solution of 2,4-dimethoxybenzylamine 319 (547 mg, 3.27 mmol, 1.1 equiv) in DMF (10 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid 204 (500 mg, 2.97 mmol, 1.0 equiv), DIEA (1.92 g, 14.85 mmol, 5.0 equiv) and HATU (1.35 g, 3.56 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO3 (1x), and water (3x). The organic layer was collected, dried (MgSO4) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired amide compound 317. Mass spectrum (LCMS, ESI Pos.) calculated for C17H22N3O3: 316.0 (M+H), found 316.0.

[0507] Preparation of Compound 320

[0508] To a solution of amide 317 (200 mg, 0.635 mmol, 1.0 equiv) in THF at 0° C. was slowly added 2M lithium aluminum hydride solution in THF (0.65 mL, 1.27 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was cooled to 0° C., then 0.048 mL of water, 0.048 mL of 15% NaOH and 0.15 mL of water were added. The reaction mixture was then extracted with ethyl acetate (3 times). The combined organic layers were dried and evaporated to give crude amine 318, which was used in the next step without further purification.

[0509] Preparation of Compound 321

[0510] To a solution of crude amine 318 (0.635 mmol, 1.0 equiv) in DMF (10 mL) was added 3-hydroxy-2-methylbenzoic acid (106 mg, 0.700 mmol, 1.1 equiv), DIEA (410 mg, 3.18 mmol, 5.0 equiv) and HATU (290 mg, 0.762 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with 10% aqueous HCl (1x), saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired amide compound 320. Mass Spectrum (LCMS, ESI Pos.) 25 H 30 N 3 O 4 Calculated value for: 436.0 (M+H), found value 436.0.

[0511] Preparation of Compound 321

[0512] To a stirred solution of amide 320 (284 mg, 0.653 mmol, 1.0 equiv) in DMF (15 ml) was added Cs2CO3 (318 mg, 0.98 mmol, 1.5 equiv) and methyl 4-(chloromethyl)benzoate 209 (181 mg, 0.98 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mass was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over NaSO4 and evaporated under vacuum to give a residue which was purified by column chromatography to give the desired alkylated product 321. Mass spectrum (LCMS, ESI Pos.) calculated for C25H30N3O4: 436.0 (M+H), found 436.0.

[0513] Preparation of compound 322

[0514] The ester was taken up in a 1:1 mixture of TFA:DCM and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was purified by column chromatography to give the desired compound 322. Mass spectrum (LCMS, ESI Pos.) calculated for C25H28N3O4: 434.0 (M+H), found 434.0.

[0515] Preparation of compound 323

[0516] Ester 322 (249 mg, 0.576 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (18 mL) and then LiOH (48 mg, 1.14 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid which was used directly in the next step without further purification.

[0517] Example 90: Preparation of Compound 127

[0518] To a stirred solution of 1-(methylsulfonyl)piperazine 242 (49 mg, 0.299 mmol, 1.2 equiv) in DMF (15 mL) was added crude acid (104 mg, 0.249 mmol, 1.0 equiv), DIEA (161 mg, 1.245 mmol, 5.0 equiv), and HATU (114 mg, 0.299 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and saturated NaHCO 3 The organic layer was collected and dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give amide 127. Mass Spectrum (LCMS, Pos.) 29 H 36 N 5 O 5 Calculated for S: 566.0 (M+H), found 566.0.

[0519] Scheme 37 illustrates the preparation of compound 128. [ka]

[0520] Preparation of Compound 325

[0521] To a stirred solution of 1-(methylsulfonyl)piperazine 242 (500 mg, 3.04 mmol, 1 equiv) in DCM (10 ml) at 0° C., DIEA (590 mg, 4.57 mmol, 1.5 equiv), DMAP (32.7 mg, 0.304 mmol, 0.1 equiv) and p-tolyl chloroformate (570 mg, 3.34 mmol, 1.1 equiv) 324 were added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with DCM and washed with saturated NaHCO 3 The reaction mixture was quenched with solution. The reaction mixture was extracted with DCM (x2) and the combined organic layers were washed with water, brine and dried (Na 2 SO 4 ) and evaporated in vacuo to give a residue which was purified by column chromatography to give carbamate 325. Mass Spectrum (LCMS, ESI Pos.) 13 H 19 N 2 O 4 Calculated for S: 299.0 (M+H), found 299.0.

[0522] Preparation of Compound 326

[0523] To a stirred solution of carbamate 325 (200 mg, 0.670 mmol, 1.0 equiv) in CCl4 (15 ml) was added NBS (143 mg, 0.805 mmol, 1.2 equiv) and benzoyl peroxide (19 mg, 0.081 mmol, 0.1 equiv) and the reaction mixture was heated to reflux for 12 h. The reaction mixture was filtered through a pad of Celite and evaporated to give a residue which was purified by column chromatography to give the desired bromide 326. Mass Spectrum (LCMS, ESI Pos.) C 13 H 18 BrN 2 O 4Calculated for S: 378.0 (M+H), found 378.0.

[0524] Preparation of compound 327

[0525] To a stirred solution of compound 205 (100 mg, 0.222 mmol, 1.0 equiv) in DMF (10 ml) was added Cs 2 CO 3 (108 mg, 0.333 mmol, 1.5 equiv) and bromide 326 (87 mg, 0.222 mmol, 1.0 equiv) were added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine and NaSO. 4 The mixture was dried at 40° C. and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired alkylated product 327.

[0526] Example 91: Preparation of Compound 128

[0527] The crude alkylation product 327 was taken up in a 1:1 mixture of DCM:TFA and the reaction mixture was stirred at room temperature for 12 h. The solvent was evaporated under vacuum to give a residue which was purified by column chromatography to give the desired product compound 128. Mass Spectrum (LCMS, ESI Pos.) C 29 H 36 N 5 O 7 Calculated for S: 598.0 (M+H), found 598.0.

[0528] [ka] Example 92: Preparation of Compound 129

[0529] Compound 129 was prepared according to the procedure used to prepare compound 127, except that commercially available p-tolyl isocyanate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 29 H 37 N 6 O 6Calculated for S: 597.0 (M+H), found 597.0.

[0530] Scheme 38 illustrates the preparation of compound 130. [ka]

[0531] Preparation of Compound 329

[0532] To a stirred solution of compound 205 (200 mg, 0.442 mmol, 1.0 equiv) in DMF (15 ml) was added Cs 2 CO 3 (216 mg, 0.640 mmol, 1.5 equiv) and methyl 4-fluorobenzoate 328 (89 mg, 0.531 mmol, 1.2 equiv) were added and the reaction mixture was heated at 100° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine and NaSO 4 The mixture was dried at 40° C. and evaporated in vacuo to give a residue which was purified by column chromatography to give the desired product 329. Mass Spectrum (LCMS, ESI Pos.) C 34 H 38 N 3 O 7 Calculated value for: 600.0 (M+H), measured value 600.0.

[0533] Preparation of Compound 330

[0534] Ester 329 (100 mg, 0.166 mmol, 1.0 equiv) was taken up in a 1:5 mixture of HO:MeOH (12 mL) and then LiOH (28 mg, 0.667 mmol, 4.0 equiv) was added. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was evaporated in vacuo to give a residue which was stirred in a mixture of 10% aqueous HCl and ethyl acetate for 30 min. The organic layer was collected, washed with HO (1 x), dried and concentrated to give the crude acid which was used directly in the next step without further purification.

[0535] Preparation of Compound 331

[0536] To a stirred solution of 1-(methylsulfonyl)piperazine (33 mg, 0.199 mmol, 1.2 equiv) in DMF (15 mL) was added crude acid (0.166 mmol, 1.0 equiv), DIEA (107 mg, 0.83 mmol, 5.0 equiv), and HATU (76 mg, 0.199 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with EtOAc and washed with saturated NaHCO3 (1x), 10% aqueous HCl (1x), and water (3x). The organic layer was collected, dried (MgSO4), and evaporated to give 331.

[0537] Example 93: Preparation of Compound 130

[0538] The amide 331 was taken up in a 1:1 mixture of DCM:TFA and stirred at room temperature for 12 h. The solvent was evaporated to give a residue which was purified by column chromatography (EtOAc / Hexanes) to give the desired product 130. Mass Spectrum (LCMS, ESI Pos.) C 28 H 34 N 5 O 6 Calculated for S: 568.0 (M+H), found 568.0.

[0539] [ka] Example 94: Preparation of Compound 131

[0540] Compound 131 was prepared according to the procedure used to prepare compound 130, except that commercially available methyl 5-chloropyrazine-2-carboxylate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 26 H 32 N 7 O 6 Calculated for S: 570.0 (M+H), found 570.0.

[0541] [ka] Example 95: Preparation of Compound 132

[0542] Compound 132 was prepared according to the procedure used to prepare compound 130, except that commercially available methyl 2-chloropyrimidine-5-carboxylate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 26 H 32 N 7 O 6 Calculated for S: 570.0 (M+H), found 570.0.

[0543] [ka] Example 96: Preparation of Compound 133

[0544] Compound 133 was prepared according to the procedure used to prepare compound 130, except that commercially available methyl 6-chloropyridazine-3-carboxylate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 26 H 32 N 7 O 6 Calculated for S: 570.0 (M+H), found 570.0.

[0545] [ka] Example 97: Preparation of Compound 134 Compound 134 was prepared according to the procedure used to prepare compound 130, except that commercially available methyl 6-chloronicotinate was used in the first step. Mass Spectrum (LCMS, ESI Pos.) C 27 H 33 N 6 O 6 Calculated for S: 569.0 (M+H), found 569.0.

[0546] General procedure for the preparation of heteroaromatic alkyl bromides To a stirred solution of methyl heteroaromatic compound (1.0 equiv.) in CCl4, NBS (1.2 equiv.) and benzoyl peroxide (0.1 equiv.) were added and the reaction mixture was heated to reflux for 12 h. The reaction mixture was filtered through a pad of Celite and evaporated to give a residue which was purified by column chromatography to give the desired bromide. Bromides prepared include, for example, [ka] Includes:

[0547] The above bromides were used to prepare heteroaromatic analogs of compound 9, such as compounds 135 to 144, using procedures similar to those used to prepare compound 9.

[0548] Scheme 39 illustrates the preparation of compound 145. [ka]

[0549] Preparation of compound 334

[0550] To a stirred solution of 3-chloro-4-hydroxybenzaldehyde 332 (1.0 g, 6.41 mmol, 1.0 equiv) in DMF (20 mL) was added Cs 2 CO 3 (5.22 g, 16.02 mmol, 2.5 equiv.) and 4-(3-chloropropyl)morpholine 333 (1.56 g, 9.61 mmol, 1.5 equiv.) were added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water (3 times), brine (1 time), dried and evaporated in vacuo to give the crude residue, which was purified by column chromatography to give aldehyde 334.

[0551] Preparation of Compound 336

[0552] To a stirred solution of aldehyde 334 (800 mg, 2.82 mmol, 1.0 equiv) in toluene (15 mL) was added 2,4-dimethoxybenzylamine 335 (0.51 g, 3.10 mmol, 1.1 equiv) and a catalytic amount of p-toluenesulfonic acid, and the reaction mixture was stirred at 65 °C for 24 h. The solvent was removed in vacuo to give the crude imine, which was used directly in the next step. To a stirred solution of the crude imine (1.00 g, 2.31 mmol, 1.0 equiv) in MeOH (20 mL) at 0 °C was added NaBH 4 (0.18 g, 3.46 mmol, 1.5 equiv) was added slowly. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated to give a solid, which was taken up in ethyl acetate and saturated sodium bicarbonate solution was added. The reaction mixture was stirred for 1 h. The organic layer was washed with brine, dried and evaporated in vacuo to give crude amine 336, which was used in the next step without further purification.

[0553] Preparation of compound 338

[0554] To a stirred solution of crude amine 336 (0.20 g, 0.45 mmol, 1.0 equiv) in DMF (10 ml) was added DIEA (290 mg, 2.25 mmol, 5.0 equiv), and 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid 337 337 (83 mg, 0.495 mmol, 1.1 equiv) and HATU (256 mg, 0.68 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated NaHCO 3 The solution was washed with water, dried and evaporated in vacuo to give crude 338.

[0555] Example 98: Preparation of Compound 145

[0556] The crude ether 338 was taken up in a 1:1 mixture of DCM and TFA and stirred at room temperature for 12 h. The solvent was evaporated to give a residue which was purified by column chromatography to give the desired product 145. Mass Spectrum (LCMS, ESI Pos.) C 22 H 32 ClN 4 O3 Calculated value for: 435.0 (M+H), found value 435.0.

[0557] [ka] Example 99: Preparation of Compound 146

[0558] Compound 146 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 3-tert-butyl-1-methylpyrazole-5-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 23 H 34 ClN 4 O 3 Calculated value for: 449.0 (M+H), found value 449.0.

[0559] [ka] Example 100: Preparation of Compound 147

[0560] Compound 147 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 1,3-dimethyl-1H-pyrazole-5-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 23 H 34 ClN 4 O 3 Calculated value for: 449.0 (M+H), found value 449.0.

[0561] [ka] Example 101: Preparation of Compound 148

[0562] Compound 148 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 3-trifluoromethyl-1-methylpyrazole-5-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 20 H 28 ClN 4 O 3 Calculated value for: 407.0 (M+H), found value 407.0.

[0563] [ka] Example 102: Preparation of Compound 149

[0564] Compound 149 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 3-cyclopropyl-1-methylpyrazole-5-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 21 H 28 ClN 4 O 3 Calculated value for: 419.0 (M+H), found value 419.0.

[0565] [ka] Example 103: Preparation of Compound 150

[0566] Compound 150 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 4-methylthiazole-2-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 19 H 25 ClN 3 O 3 Calculated for S: 410.0 (M+H), found 410.01.

[0567] [ka] Example 104: Preparation of Compound 151

[0568] Compound 151 was prepared according to the procedure used to prepare compound 145, except that commercially available 5-methyl-1H-imidazole-2-carboxylic acid was used to acylate the amine intermediate. Mass Spectrum (LCMS, ESI Pos.) C 19 H 26 ClN 4 O 3 Calculated value for: 393.0 (M+H), found value 393.0.

[0569] [ka] Example 105: Preparation of Compound 152

[0570] Compound 152 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 4-methylthiophene-2-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 20 H 26 ClN 2 O 3 Calculated for S: 409.0 (M+H), found 409.0.

[0571] [ka] Example 106: Preparation of Compound 153

[0572] Compound 153 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 4-chloro-3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 22 H 29 CI 2 N 4 O 3Calculated value for: 468.0 (M+H), found value 468.0.

[0573] [ka] Example 107: Preparation of Compound 154

[0574] Compound 154 was prepared according to the procedure used to prepare compound 145, except that commercially available 4-methylpyrrole-2-carboxylic acid was used to acylate the amine intermediate. Mass Spectrum (LCMS, ESI Pos.) C 20 H 27 ClN 3 O 3 Calculated value for: 392.0 (M+H), found value 392.0.

[0575] [ka] Example 108: Preparation of Compound 155

[0576] Compound 155 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available thiazole-4-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C 18 H 23 ClN 3 O 3 Calculated for S: 396.0 (M+H), found 396.0.

[0577] [ka] Example 109: Preparation of Compound 156

[0578] Compound 156 was prepared according to the procedure used to prepare compound 145, except that the amine intermediate was acylated using commercially available 6-methylpyridazine-3-carboxylic acid. Mass Spectrum (LCMS, ESI Pos.) C20 H 26 ClN 4 O 3 Calculated value for: 405.0 (M+H), found value 405.0.

[0579] [ka] Example 110: Preparation of Compound 157

[0580] Compound 157 was prepared according to the procedure used to prepare compound 145, except that commercially available 4-hydroxy-3-(trifluoromethyl)benzaldehyde was used in the first step and commercially available 3-cyclopropyl-1H-pyrazole-5-carboxylic acid was used to acylate the amine intermediate. Mass Spectrum (LCMS, ESI Pos.) C 23 H 33 N 4 O 4 Calculated value for: 429.0 (M+H), found value 429.0.

[0581] [ka] Example 111: Preparation of Compound 158

[0582] Compound 158 was prepared according to the procedure used to prepare compound 145, except that commercially available 4-hydroxy-3-(trifluoromethoxy)benzaldehyde was used in the first step and commercially available 3-cyclopropyl-1H-pyrazole-5-carboxylic acid was used to acylate the amine intermediate. Mass Spectrum (LCMS, ESI Pos.) C 23 H 30 F 3 N 4 O 4 Calculated value for: 483.0 (M+H), found value 483.0.

[0583] [ka] Example 112: Preparation of Compound 159

[0584] Compound 159 was prepared according to the procedure used to prepare compound 145, except that commercially available 4-hydroxy-3-(methoxy)benzaldehyde was used in the first step and commercially available 3-cyclopropyl-1H-pyrazole-5-carboxylic acid was used to acylate the amine intermediate. Mass Spectrum (LCMS, ESI Pos.) C 23 H 33 N 4 O 4 Calculated value for: 429.0 (M+H), found value 429.0.

[0585] Scheme 40 illustrates the preparation of compound 160. [ka]

[0586] Preparation of Compound 341

[0587] To a stirred solution of methyl 2-(3-chloro-4-hydroxyphenyl)acetate 339 (100 mg, 0.50 mmol, 1.0 equiv) in DMF (5 mL) was added Cs 2 CO 3 (407 mg, 1.25 mmol, 2.5 equiv.) and 4-(3-chloropropyl)morpholine 340 (122 mg, 0.75 mmol, 1.5 equiv.) were added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with water (3 times), brine, dried and evaporated in vacuo to give the crude residue, which was purified by column chromatography to give the desired product 341. Mass Spectrum (LCMS, ESI Pos.) C 16 H 23 ClNO 4 Calculated value for: 328.0 (M+H), found value 328.0.

[0588] Preparation of compound 342

[0589] To a stirred solution of ester 341 (100 mg, 0.305 mmol, 1.0 equiv) in a 5:1 mixture of methanol:water (6 ml) was added LiOH (15 mg, 0.61 mmol, 2.0 equiv) and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed to give crude acid 342, which was used directly in the next step.

[0590] Example 112: Preparation of Compound 160

[0591] To a stirred solution of crude acid 342 (0.305 mmol, 1.0 equiv) in DMF (5 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine 343 (50 mg, 0.366 mmol, 1.2 equiv), DIEA (197 mg, 1.525 mmol, 5.0 equiv) and HATU (139 mg, 0.366 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water (2 times), brine, dried and evaporated under vacuum to give the crude amide, which was purified by preparative column chromatography to give the desired product 160. Mass Spectrum (LCMS, ESI Pos.) C 22 H 30 ClN 4 O 3 Calculated value for: 433.0 (M+H), found value 433.0.

[0592] Scheme 41 illustrates the preparation of compound 161. [ka]

[0593] Example 113: Preparation of Compound 161

[0594] To a stirred solution of crude acid 342 (0.305 mmol, 1.0 equiv) in DMF (5 mL) was added (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methanamine 344 (55 mg, 0.366 mmol, 1.2 equiv), DIEA (197 mg, 1.525 mmol, 5.0 equiv) and HATU (139 mg, 0.366 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water (2 times), brine, dried and evaporated under vacuum to give the crude amide, which was purified by preparative column chromatography to give the desired product 161. Mass Spectrum (LCMS, ESI Pos.) C 22 H 30 ClN 4 O 3 Calculated value for: 433.0 (M+H), found value 433.0.

[0595] Scheme 42 illustrates the preparation of compound 162. [ka]

[0596] Preparation of compound 346

[0597] To a solution of compound 5 (5.0 g, 11.0 mmol, 1.0 equiv.) in DMF (30 mL) was added cesium carbonate (7.2 g, 22.0 mmol, 2.0 equiv.) and 1,3-dibromopropane 345 (4.40 g, 22.0 mmol, 2.0 equiv.) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water (3 times). The organic layer was dried (MgSO 4 ) and evaporated to give a residue which was purified by column chromatography (hexane / EtOAc) to give bromide 348. Mass Spectrum (LCMS, ESI Pos.) 27 H 32 BrClN 3 O 4 Calculated value for: 577.0 (M+H), found value 577.0.

[0598] Preparation of compound 347

[0599] Bromide 348 was taken up in a 1:1 mixture of DCM:TFA and stirred for 12 h. The solvent was removed under vacuum to give a crude residue which was purified by column chromatography to give the desired bromide 347. Mass Spectrum (LCMS, ESI Pos.) C 18 H 22 BrClN 3 O 2 Calculated value for: 427.0 (M+H), found value 427.0.

[0600] Example 114: Preparation of Compound 162

[0601] To a stirred solution of bromide 347 (185 mg, 0.434 mmol, 1.0 equiv) in DMF (10 mL) was added DIEA (224 mg, 1.74 mmol, 4.0 equiv) and piperazin-2-one 348 (65 mg, 0.651 mmol, 1.5 equiv) and the reaction mixture was stirred at 70° C. for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water (4 times). The organic layer was collected, dried and the solvent was removed to give the crude residue, which was purified by column chromatography (DCM / MeOH) to give the desired compound 162. Mass Spectrum (LCMS, ESI Pos.) C 22 H 29 ClN 5 O 3 Calculated value for: 446.0 (M+H), found value 446.0.

[0602] [ka] Example 115: Preparation of Compound 163

[0603] Compound 163 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available 1-acetylpiperazine. Mass Spectrum (LCMS, ESI Pos.) C 24 H 33 ClN 5 O 3 Calculated value for: 475.0 (M+H), found value 475.0.

[0604] [ka] Example 116: Preparation of Compound 164

[0605] Compound 164 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available methyl piperazine-1-carboxylate. Mass Spectrum (LCMS, ESI Pos.) C 24 H 33 ClN 5 O 4 Calculated value for: 490.0 (M+H), found value 490.0.

[0606] [ka] Example 117: Preparation of Compound 165

[0607] Compound 165 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available N,N-dimethylpiperazine-1-carboxamide. Mass Spectrum (LCMS, ESI Pos.) C 25 H 36 ClN 6 O 3 Calculated value for: 504.0 (M+H), found value 504.0.

[0608] [ka] Example 118: Preparation of Compound 166

[0609] Compound 166 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available 1-methanesulfonylpiperazine. Mass Spectrum (LCMS, ESI Pos.) C 23 H 33ClN 5 O 4 Calculated for S: 510.0 (M+H), found 510.0.

[0610] [ka] Example 119: Preparation of Compound 167

[0611] Compound 167 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available 1,2-oxazinane hydrochloride. Mass Spectrum (LCMS, ESI Pos.) C 22 H 30 ClN 4 O 3 Calculated value for: 433.0 (M+H), found value 433.0.

[0612] [ka] Example 120: Preparation of Compound 168

[0613] Compound 168 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available N,N-dimethylpyrrolidin-3-amine. Mass Spectrum (LCMS, ESI Pos.) C 24 H 35 ClN 5 O 2 Calculated value for: 461.0 (M+H), found value 461.0.

[0614] [ka] Example 121: Preparation of Compound 169

[0615] Compound 169 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available isoxazolidine. Mass Spectrum (LCMS, ESI Pos.) C 21 H 28 ClN 4 O 3 Calculated value for: 419.0 (M+H), found value 419.0.

[0616] [ka] Example 122: Preparation of Compound 170

[0617] Compound 170 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available azetidine. Mass Spectrum (LCMS, ESI Pos.) C 21 H 27 ClN 4 O 2 Calculated value for: 403.0 (M+H), found value 403.0.

[0618] [ka] Example 123: Preparation of Compound 171

[0619] Compound 171 was prepared according to the procedure used to prepare compound 162, except that bromide 347 was alkylated using commercially available pyrrolidine. Mass Spectrum (LCMS, ESI Pos.) C 21 H 27 ClN 4 O 2 Calculated value for: 403.0 (M+H), found value 403.0.

[0620] Scheme 43 illustrates the preparation of compound 172.

[0621] [ka] Preparation of Compound 350

[0622] To a stirred solution of compound 205 (200 mg, 0.44 mmol, 1.0 equiv) in DMF (10 mL) was added Cs 2 CO 3 (360 mg, 1.10 mmol, 2.5 equiv) and methyl 4-bromobutanoate 349 (0.120 g, 0.66 mmol, 1.50 equiv) were added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with water (2x), brine, dried and evaporated in vacuo to give the crude product, which was purified by column chromatography to give 350.

[0623] Preparation of Compound 351

[0624] MeOH:H 2 To a stirred solution of ester 350 (180 mg, 0.29 mmol, 1.0 equiv) in a 5:1 mixture of 2H2O (12 mL) was added LiOH (34 mg, 0.72 mmol, 2.5 equiv) and the reaction mixture was stirred at room temperature for 6 h. The solvent was evaporated to give a residue which was neutralized with 10% aqueous HCl and then extracted with ethyl acetate (2 times). The combined organic layers were dried and evaporated under vacuum to give crude acid 352 which was used in the next step without further purification.

[0625] Preparation of Compound 352

[0626] To a stirred solution of crude acid 351 (150 mg, 0.27 mmol, 1.0 equiv) in DMF (10 mL) was added 1-(methylsulfonyl)piperazine (38 mg, 0.23 mmol, 1.1 equiv), DIEA (90 mg, 0.69 mmol, 2.5 equiv) and HATU (159 mg, 0.41 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with saturated NaHCO 3 The organic layer was then dried and evaporated in vacuo to give crude amide 352.

[0627] Example 124: Preparation of Compound 172

[0628] The crude amide 352 was taken up in a 1:1 mixture of DCM:TFA and stirred for 12 h. The solvent was removed to give a residue which was purified by column chromatography to give compound 172. Mass Spectrum (LCMS, ESI Pos.) C 25 H 36 N 5 O 6 Calculated for S: 534.0 (M+H), found 534.0.

[0629] Scheme 44 illustrates a general procedure for the preparation of amines 353. [ka]

[0630] General procedure for the preparation of amines of 353

[0631] To a solution of compound 7 (200 mg, 0.34 mmol) in DMF (10.0 mL), Cs 2 CO 3 (332 mg, 1.02 mmol, 3.0 equiv.) and secondary amine 8 (0.68 mmol, 2.0 equiv.) were added and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water (3 times). The organic layer was collected, dried and evaporated to give a viscous liquid which was purified by column chromatography to give intermediate 353.

[0632] [ka] Example 125: Preparation of Compound 19

[0633] Prepared according to the general procedure for the preparation of amine 353. Mass Spectrum (LCMS, ESI Pos.) 29 H 35 F 2 N 4 O3 Calculated value for: 525.0 (M+H), found value 525.0.

[0634] [ka] Example 126: Preparation of Compound 173

[0635] Prepared according to the general procedure for the preparation of amine 353. Mass Spectrum (LCMS, ESI Pos.) 33 H 44 N 5 O 7 Calculated for S: 654.0 (M+H), found 654.0.

[0636] [ka] Example 127: Preparation of Compound 18

[0637] Prepared according to the general procedure for the preparation of amine 353. Mass Spectrum (LCMS, ESI Pos.) 28 H 35 N 4 O 3 Calculated value for: 475.0 (M+H), found value 475.0.

[0638] [ka] Example 128: Preparation of Compound 174

[0639] Prepared according to the general procedure for the preparation of amine 353. Mass Spectrum (LCMS, ESI Pos.) 31 H 38 N 5 O 6 Calculated value for: 576.0 (M+H), found value 576.0.

[0640] [ka] Prepared according to the general procedure for the preparation of amine 353. Mass Spectrum (LCMS, ESI Pos.) C 30 H 38 N 5 O 4 Calculated value for: 532.0 (M+H), found value 532.0.

[0641] Scheme 45 illustrates a general procedure for the preparation of 3,4 analogs 35. [ka]

[0642] To a solution of chloride 355 (181 mg, 0.34 mmol) in DMF (10.0 mL), 2 CO 3 (332 mg, 1.02 mmol, 3.0 equiv) and secondary amine 8 (0.68 mmol, 2.0 equiv) were added and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×). The organic layer was collected, dried and evaporated to give a viscous liquid which was purified by column chromatography to give amine 356. The crude amine 356 was taken up in a 1:1 mixture of DCM:TFA and stirred for 12 h. The solvent was removed to give a residue which was purified by column chromatography to give intermediate 357.

[0643] [ka] Example 129: Preparation of Compound 175

[0644] Prepared according to the general procedure for the preparation of amine 353. Mass Spectrum (LCMS, ESI Pos.) 28 H 35 ClN 5 O 2 Calculated value for: 509.0 (M+H), found value 509.0.

[0645] Infectivity assay protocol

[0646] MDCK cells were infected with FLUV at MOI=0.01 or MRC-5 cells were infected with huCoV229e at MOI=0.01 and vehicle or drug was added at final concentrations of 1uM, 100nM, 25nM or 6.25nM. 48 hours post-infection, media was collected and centrifuged at 100kxrpm / 24min in a TL100.2 tabletop ultracentrifuge rotor and the supernatant was aspirated. Pelleted material was resuspended in loading buffer and analyzed by SDS-PAGE before being transferred to 0.2u PVDF and western blotting for FLUV or CoV nucleoprotein, respectively, as previously described (Selvarajah et al., https: / / www.biorxiv.org / content / 10.1101 / 2021.01.17.426875v1). The spread of infection was measured using uninfected and infected vehicle-treated samples as negative and positive controls, as well as a known active compound: [ka] was used as an internal positive control previously validated by plaque assay and TCID50, as determined by the quantified intensity of full-length nuclear protein bands (FLUV, 55 kDa; CoV; 42 kDa).

[0647] The results of the infection assay protocol for selected compounds are shown in Table 2 below.

[0648] [Table 2]

[0649] Efficacy Testing:

[0650] MRC-5 cells were seeded at 10,000 cells per well in 96-well black, clear-bottom plates (Costar 3603) the day before infection. The following day, cells were incubated at a multiplicity of infection of 0.01 and 50% tissue culture infectious dose (TCID 50) approximately 100 and infected with recombinant Nipah virus expressing ZsGreen fluorescent protein (rNiV-ZsG). The level of rNiV-ZsG replication was determined by measuring the mean ZsGreen fluorescent signal intensity (418 ex / 518 em ) at 72 hours after infection. The fluorescence signal intensity assayed in DMSO-treated virus-infected cells was set as 100% ZsGreen fluorescence. The concentration of compound that inhibits 50% of the green fluorescence signal (EC 50 ) were calculated from dose-response data, fitted to the mean values ​​of experiments performed at each concentration in a 10-point, 3-fold dilution series using a 4-parameter nonlinear logistic regression curve with variable slope using GraphPad Prism 9 (GraphPad Software, La Jolla, CA, USA). References: Lo, MK, Nichol, ST, Spiropoulou, CF, 2014. Evaluation of luciferase and GFP-expressing Nipah viruses for rapid quantitative antiviral screening. Antiviral Res. 106, 53-60. https: / / doi.org / 10.1016 / j.antiviral.2014.03.011.

[0651] Toxicity testing:

[0652] Cell viability was assayed in MRC-5 cells in minimal essential medium supplemented with 5 mM glucose using Alamar Blue HS reagent (Thermofisher) according to the manufacturer's recommendations, and after 4 h of incubation with the reagent, fluorescence (560 ex / 590 em) was measured. Fluorescence levels assayed in DMSO-treated uninfected cells (indicating a reduction in resazurin as a surrogate marker for cell viability) were set as 100% cell viability. Dose-response curves were fitted to the mean values ​​of experiments performed at each concentration in a 10-point, 3-fold dilution series using a 4-parameter nonlinear logistic regression curve with variable slope. All Alamar Blue assays were performed in 96-well black plates with clear bottom. The concentration of compound that inhibits 50% of the fluorescent signal (CC 50 ) were calculated from dose-response data fitted to the mean values ​​of experiments performed at each concentration in a 10-point, 3-fold dilution series using a four-parameter nonlinear logistic regression curve with variable slope using GraphPad Prism 9 (GraphPad Software, La Jolla, CA, USA).

[0653] The results of efficacy and toxicity studies of selected compounds are shown in Table 3 below.

[0654] [Table 3-1]

[0655] [Table 3-2]

[0656] [Table 3-3]

[0657] [Table 3-4]

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R １ and R ２ is independently alkyl, alkenyl, cycloalkyl, or cycloalkenyl; R ３ is —H or alkyl; a is 1, 2 or 3; R ４ is -H, halo, alkyl, -OR ７ and R ５ is —H, halo, alkyl, substituted alkyl, 【Chemistry 2】 , —C(O)NR ７６ R ７７ , -NR ７８ R ７９ , -NHC(O)R ８０ , -OR １１ and b is 0, 1, 2 or 3; R ６ is -H, alkyl, 【Chemistry 3】 Or -OR １５ and c is 1, 2 or 3; X is 【Chemistry 4】 , substituted aryl, heteroaryl, substituted heteroaryl; R ８ is —H, —C(O)NR １６ R １７ , -CH ２ OC(O)NR １８ R １９ , -NR ２０ R ２１ , -CH ２ NR ２２ R ２３ or -SO ２ R ２４ R ２５ and R ９ is —H, —C(O)NR ２６ R ２７ , -CH ２ OC(O)NR ２８ R ２９ , -NR ３０ R ３１ , -CH ２ NR ３２ R ３３ or -SO ２ R ３４ R ３５ and R １０ is —H, —C(O)NR ３６ R ３７ , -CH ２ OC(O)NR ３８ R ３９ , -NR ４０ R ４１ , -CH ２ NR ４２ R ４３ or -SO ２ R ４４ R ４５ and R １２ is —H, —C(O)NR ４６ R ４７ , -CH ２ OC(O)NR ４８ R ４９ , -NR ５０ R ５１ , -CH ２ NR ５２ R ５３ or -SO ２ R ５４ R ５５ and R １３ is —H, substituted alkyl, —C(O)NR ５６ R ５７ , -CH ２ OC(O)NR ５８ R ５９ , -NR ６０ R ６１ or -CH ２ NR ６２ R ６３ or -SO ２ R ６４ R ６５ and R １４ is -H, -C(O)N ６６ R ６７ , -CH ２ OC(O)NR ６８ R ６９ , -NR ７０ R ７１ or -CH ２ NR ７２ R ７３ or -SO ２ R ７４ R ７５ and R ７ , R １１ and R １５ is independently alkyl, substituted alkylalkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl; R １６ and R １７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R １８ and R １９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ２０ and R ２１ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ２２ and R ２３ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ２４ and R ２５ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ２６ and R ２７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ２８ and R ２９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ３０ and R ３１ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ３２ and R ３３ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ３４ and R ３５ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ３６ and R ３７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ３８ and R ３９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ４０ and R ４１ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ４２ and R ４３ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ４４ and R ４５ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ４６ and R ４７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ４８ and R ４９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ５０ and R ５１ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ５２ and R ５３ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ５４ and R １５ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ５６ and R ５７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ５８ and R ５９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ６０ and R ６１ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ６２ and R ６３ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ６４ and R ６５ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ６６ and R ６７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ６８ and R ６９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ７０ and R ７１ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ７２ and R ７３ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ７４ and R ７５ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ７６ , R ７７ , R ７８ , or R ７９ is independently alkyl, substituted alkylalkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl; or R ７６ and R ７７ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring, or R ７８ , or R ７９ together with the atoms to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; R ８０ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, aryl, or substituted aryl; However, R ５ or R ６ at least one of is not —H; R ８ -R １０ at least one of is not —H; R １２ -R １４ at least one of which is not —H).

2. Formula (II): 【Chemistry 5】 The compound according to claim 1.

3. Formula (III): 【Chemistry 6】 The compound according to claim 1.

4. Formula (IV): 【Chemistry 7】 The compound according to claim 1.

5. Formula (V): 【Chemistry 8】 The compound according to claim 1.

6. R １ and R ２ The compound of claim 1 , wherein is independently alkyl or cycloalkyl.

7. The compound of claim 1 , wherein a, b, and c are 1.

8. R ７ The compound of claim 1 , wherein is alkyl or substituted alkyl.

9. R ９ The compound of claim 1 , wherein is an alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

10. R １１ The compound of claim 1 , wherein is an alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

11. R １ and R ２ are independently alkyl or cycloalkyl, a, b and c are 1, and R ７ is alkyl or substituted alkyl, and R １１ is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle, and R １５ The compound of claim 1 , wherein is an alkyl substituted with a heterocycle or a substituted heterocycle, or a haloalkyl.

12. R ５ is -H, halo or -OR ９ 3. The compound of claim 2, wherein:

13. R ９ 13. The compound of claim 12, wherein is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

14. R ６ but, 【Chemistry 9】 Or -OR １５ 3. The compound of claim 2, wherein:

15. R １１ 15. The compound of claim 14, wherein is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

16. R ５ The compound of claim 2, wherein is —H or halo.

17. R ５ but, 【Chemistry 10】 Or -OR １１ 17. The compound of claim 16, wherein:

18. R １ and R ２ 18. The compound of claim 17, wherein is independently alkyl or cycloalkyl and a is 1.

19. R ６ but, 【Chemistry 11】 Or -OR １５ 4. The compound of claim 3, wherein:

20. R ９ 20. The compound of claim 19, wherein is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

21. R １ and R ２ 21. The compound of claim 20, wherein is independently alkyl or cycloalkyl and a is 1.

22. R ６ but, 【Chemistry 12】 Or -OR １５ 5. The compound of claim 4, wherein:

23. R １１ 23. The compound of claim 22, wherein is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

24. R １ and R ２ 24. The compound of claim 23, wherein is independently alkyl or cycloalkyl and a is 1.

25. R ５ but, 【Chemistry 13】 Or -OR １１ 6. The compound of claim 5, wherein:

26. R ９ 26. The compound of claim 25, wherein is alkyl or haloalkyl substituted with a heterocycle or substituted heterocycle.

27. R １ and R ２ 27. The compound of claim 26, wherein is independently alkyl or cycloalkyl and a is 1.

28. R １２ and R １３ 23. The compound of any one of claims 13, 19 and 22, wherein is hydrogen.

29. R ８ and R ９ 26. The compound of any one of claims 14, 17 and 25, wherein is hydrogen.

30. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable vehicle.

31. A method for treating or preventing respiratory infections in a mammal other than a human, comprising administering a compound of claim 1 to said mammal other than a human in need thereof.

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